Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:13]C.Br.CCOC(C)=O>C(O)(=O)C>[OH:13][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:2]=1[OH:1])[CH:6]=[O:7]
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: Br
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Temperature: 90 °C
Yield: 39.5 %

Procedure:
To a solution of 4-hydroxy-3-methoxy-5-nitrobenzaldehyde (3 g, 15.2 mmol) in acetic acid (3.1 mL) was added 40% hydrobromic acid (9.24 mL). The mixture was heated at 90° C. for 17 h. Reaction mixture was cooled and poured into ice water (100 mL), followed by a standard aqueous/EtOAc workup and purified by column chromatography on silica gel (petroleum ether/ethyl acetate=5:1) to give 3,4-dihydroxy-5-nitrobenzaldehyde (1.1 g, yield 39.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([C@H:18]([NH:20][C:21](=[O:27])OC(C)(C)C)[CH3:19])=[N:16][N:17]=3)[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[N:28]([C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)=C=O.CCN(C(C)C)C(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([C@H:18]([NH:20][C:21]([NH:28][C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)=[O:27])[CH3:19])=[N:16][N:17]=3)[N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1nnc2ccc(Nc3cccc(Cl)c3)nn12
Reactant: O=C=Nc1cccnc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)Nc1cccnc1)c1nnc2ccc(Nc3cccc(Cl)c3)nn12
Reaction time: 0.33 h

Procedure:
(Step 2-i) tert-Butyl (R)-1-(6-(3-chlorophenylamino)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethylcarbamate (50 mg, 0.13 mmol) was dissolved in 5 mL TFA:CH2Cl2 (1:1) and left standing for 20 min. The solvent was removed under reduced pressure and CH2Cl2 was added and removed 4 times to remove residual TFA. The amine was dissolved in 1 mL NMP and 3-isocyanatopyridine (20 mg, 0.17 mmol) was added followed by the addition of DIEA (0.086 mL, 0.5 mmol). The reaction mixture was microirradiated at 100° C. for 10 min, loaded onto a preparative reversed-phase HPLC column, and the column eluted with a H2O/CH3CN 0.1% TFA gradient. Fractions containing pure product were combined and concentrated, 6M HCl was added, and the resulting solution concentrated to give the product, 1-((R)-1-(6-(3-chlorophenylamino)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl)-3-(pyridin-3-yl)urea, as the HCl salt (31 mg, 0.076 mmol, 58% yield): 1H NMR (500 MHz, DMSO-d6) 10.30 (s, 1H), 10.00 (s, 1H), 9.10 (d, J=2.2 Hz, 1H), 8.45 (d, J=5.4 Hz, 1H), 8.31 (dd, J=1.2, 8.7 Hz, 1H), 8.16 (d, J=9.8 Hz, 1H), 7.94-7.89 (m, 2H), 7.76 (dd, J=1.5, 8.2 Hz, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.36 (t, J=8.1 Hz, 1H), 7.23 (d, J=9.9 Hz, 1H), 7.06 (dd, J=1.4, 8.0 Hz, 1H), 5.52 (t, J=7.3 Hz, 1H), 1.68 (d, J=7.0 Hz, 3H); MH+409.20.
Reaction SMILES: [O:1]1[C:5]2=[N:6][CH:7]=[C:8]([C:10]([O:12]CC)=[O:11])[CH:9]=[C:4]2[CH:3]=[C:2]1[C:15]([O:17]CC)=[O:16].Cl>[OH-].[Na+]>[O:1]1[C:5]2=[N:6][CH:7]=[C:8]([C:10]([OH:12])=[O:11])[CH:9]=[C:4]2[CH:3]=[C:2]1[C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)c1cnc2oc(C(=O)OCC)cc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cnc2oc(C(=O)O)cc2c1
Temperature: 70 °C
Yield: 98.2 %

Procedure:
A suspension of diethyl furo[2,3-b]pyridine-2,5-dicarboxylate (10.5 g, 40 mmol) in 1N sodium hydroxide (100 mL) was warmed at 70° C. for two hours. The cooled solution was acidified with conc. hydrochloric acid and the precipitate was collected by filtration and successively washed with water, ethanol and diethyl ether to give pure product (8.14 g, 98.5% yield) mp: >315° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH2:9][NH2:10])=[N:5][CH:6]=[CH:7][N:8]=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.[CH2:32]([O:39][C:40]([NH:42][CH2:43][C@H:44]1[CH2:49][CH2:48][C@H:47]([C:50](O)=[O:51])[CH2:46][CH2:45]1)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl>[CH2:32]([O:39][C:40](=[O:41])[NH:42][CH2:43][C@H:44]1[CH2:49][CH2:48][C@H:47]([C:50](=[O:51])[NH:10][CH2:9][C:4]2[C:3]([Cl:2])=[N:8][CH:7]=[CH:6][N:5]=2)[CH2:46][CH2:45]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NCc1nccnc1Cl
Reactant: O=C(NC[C@H]1CC[C@H](C(=O)O)CC1)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NC[C@H]1CC[C@H](C(=O)NCc2nccnc2Cl)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of C-(3-chloropyrazin-2-yl)methylamine hydrochloride salt (0.100 g, 0.533 mmol) in DCM (1.35 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.16 g, 0.83 mmol), N,N-diisopropylethylamine (0.14 mL, 0.83 mmol), (0.075 g, 0.56 mmol) and trans-4-({[(benzyloxy)carbonyl]amino}methyl)cyclohexanecarboxylic acid (0.21 g, 0.70 mmol). The reaction was stirred at rt overnight then diluted with DCM, washed with sat. NaHCO3 (aq) and brine, then dried over Na2SO4 and the solvent removed in vacuo. The residue thus isolated was chromatographed over silica gel eluting with EtOAc/hexane (1:1) to afford 0.173 g of the title compound. 1H NMR (400 MHz, CDCl3): δ 1.00-1.03 (m, 2H), 1.45-1.51 (m, 2H), 1.83-1.89 (m, 2H), 1.99-2.03 (m, 2H), 2.20 (m, 1H), 3.05-3.12 (m, 3H), 4.68 (d, J=4.4 Hz, 2H), 4.79 (br, 1H), 5.10 (s, 2H), 6.79 (br, 1H), 7.31-7.37 (m, 5H), 8.33 (d, J=2.8 Hz, 1H), 8.46 (d, J=2.8 Hz, 1H). MS (ES+): m/z 417.14 [MH+].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])[CH:27]=4)[N:20]=3)=[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:38]1([C:44]2([C:47](O)=[O:48])[CH2:46][CH2:45]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH3:37][N:35]([CH3:36])[CH2:34][CH2:33][O:32][C:28]1[CH:27]=[C:26]([NH:25][C:21]2[N:20]=[C:19]([C:18]3[C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:47]([C:44]5([C:38]6[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=6)[CH2:46][CH2:45]5)=[O:48])[CH:7]=[CH:6][CH:5]=4)=[N:9][N:10]4[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=34)[CH:24]=[CH:23][N:22]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: COc1ccc2c(-c3ccnc(Nc4cccc(OCCN(C)C)c4)n3)c(-c3cccc(N)c3)nn2c1
Reactant: O=C(O)C1(c2ccccc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(-c3ccnc(Nc4cccc(OCCN(C)C)c4)n3)c(-c3cccc(NC(=O)C4(c5ccccc5)CC4)c3)nn2c1
Reaction time: 16 h
Yield: 40.9 %

Procedure:
4-[2-(3-Aminophenyl)-6-(methyloxy)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-{[2-(dimethylamino)ethyl]oxy}phenyl)-2-pyrimidinamine (100 mg, 0.21 mmol), 1-phenylcyclopropanecarboxylic acid (41 mg, 0.25 mmol), and diisopropylethylamine (0.10 mL, 1.0 mmol) were combined in DMF (1 mL) followed by the addition of HATU [O-(7-azabenzotriazole-1 yloxy)tripyrrolidinophosphonium hexafluorophosphate] (78 mg, 0.21 mmol). The mixture was stirred for 2 h at rt after which time additional HATU (80 mg, 0.21 mmol), 1-phenylcyclopropanecarboxylic acid (40 mg, 0.25 mmol), and diisopropylethylamine (0.10 mL, 1.0 mmol) were added. The mixture was stirred for 16 h after which time the mixture was poured into water, extracted with DCM, and the organic phase concentrated and purified by silica get chromatography to afford the title compound as a yellow solid (55 mg, 41%). 1H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 9.24 (s, 1H), 8.53 (d, J=2.1 Hz, 1H), 8.43 (d, J=10.4 Hz, 1H), 8.20 (d, J=5.2 Hz, 1H), 7.85 (br s, 1H), 7.66 (d, J=8.3 Hz, 1H), 7.52 (br s, 1H), 7.39-7.31 (m, 5H), 7.28-7.20 (m, 4H), 7.13 (t, J=8.1 Hz, 1H), 6.51 (dd, J=7.9, 2.3 Hz, 1H), 6.43 (d, J=5.2 Hz, 1H), 3.97 (t, J=6.5 Hz, 2H), 3.86 (s, 3H), 2.65-2.60 (m, 2H), 2.20 (s, 6H), 1.42 (m, 2H), 1.09 (m, 2H). ES-LC/MS m/z=640 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[N+:5]([C:8]1[CH:18]=[CH:17][C:11]2[NH:12][CH2:13][CH2:14][CH2:15][O:16][C:10]=2[CH:9]=1)([O-:7])=[O:6]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[N+:5]([C:8]1[CH:18]=[CH:17][C:11]2[N:12]([C:1](=[O:3])[CH3:2])[CH2:13][CH2:14][CH2:15][O:16][C:10]=2[CH:9]=1)([O-:7])=[O:6]
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])c1ccc2c(c1)OCCCN2
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)N1CCCOc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
Acetyl chloride (0.080 mL, 1.1 mmol) was added to 3-Nitro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene (203 mg, 1.04 mmol) and 4-Dimethylaminopyridine (13 mg, 0.10 mmol) in Pyridine (3.5 mL) and the reaction was stirred at room temperature overnight. The mixture was partitioned between 20 mL EtOAc and 20 mL satd. sodium bicarbonate, the org. was then washed with 1N HCl (20 mL) and brine (20 mL), dried and conc. in vacuo to give 1-(3-Nitro-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl)-ethanone as yellow solids (225 mg, 91%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[CH:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(N(CC)CC)C>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.[Pd](Cl)Cl.O1CCCC1>[C:11]([C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[CH:7][C:6]=2[CH:10]=1)#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: Brc1ccc2sccc2c1
Reactant: C#CCCCCCCCC
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCC#Cc1ccc2sccc2c1
Temperature: 25 °C
Yield: 88.7 %

Procedure:
To a solution of 5-bromobenzothiophene (50.0 g), 1-decyne (35.7 g), triethylamine (71.2 g) and dry tetrahydrofuran (150 ml), under nitrogen, was added bis(triphenylphosphine)palladium (11) chloride (1.65 g) followed by copper (1) iodide (0.233 g) with stirring, at room temperature. The reaction mixture was covered with foil and stirred at reflux, under nitrogen, over the weekend. Additional bis-triphenylphosphine)palladium (II) chloride (0.5%) and 0.25% copper (I) iodide were added, and the reaction mixture was stirred at reflux for three days, cooled, filtered through a bed of celite and the filter cake was washed with ether. The residue was flash chromatographed (silica, 1% ethyl acetate-heptane). The appropriate fractions were collected and evaporated to give 56.3 g (89%) of product.
Reaction SMILES: [OH-].[K+].C[O:4][C:5]([CH:7]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[CH2:12][C:11]2[C:22]([C:26]([F:29])([F:28])[F:27])=[CH:23][CH:24]=[CH:25][C:10]=2[NH:9][C:8]1=[O:30])=[O:6]>CO.O1CCOCC1>[C:5]([CH:7]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[CH2:12][C:11]2[C:22]([C:26]([F:28])([F:29])[F:27])=[CH:23][CH:24]=[CH:25][C:10]=2[NH:9][C:8]1=[O:30])([OH:6])=[O:4]
Reactant: COC(=O)C1C(=O)Nc2cccc(C(F)(F)F)c2CC1c1ccccc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccccc1C1Cc2c(cccc2C(F)(F)F)NC(=O)C1C(=O)O
Reaction time: 8 h

Procedure:
To a stirred warm solution of 58.0 g (0.88 mol) of potassium hydroxide (85%) in 500 ml of methanol was added portionwise 81.7 g (0.21 mol) of 1,3,4,5-tetrahydro-3-(methoxycarbonyl)-4-(methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepin-2-one - most of the solid dissolved. The mixture was diluted with 100 ml of dioxane and the resulting solution was refluxed for 6 hours. After standing overnight at room temperature, about 50% of the solvent was removed on a rotary evaporator and the residue was diluted with 4 liters of cold water. The insoluble material was filtered and dried (10 g) and the filtrate was cooled and treated portionwise with 270 ml of acetic acid to give a colorless granular solid. The latter was filtered, washed with cold water and dried in a desicator; yield 69.0 g, melting point 179°-181° C. (s. 128° C.).
Reaction SMILES: [C:1](=[N:14][C:15]1[C:20]([F:21])=[C:19]([CH2:22][O:23][Si](C(C)(C)C)(C)C)[CH:18]=[CH:17][N:16]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OCC)(=O)C>[C:1](=[N:14][C:15]1[C:20]([F:21])=[C:19]([CH2:22][OH:23])[CH:18]=[CH:17][N:16]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccnc(N=C(c2ccccc2)c2ccccc2)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Product: OCc1ccnc(N=C(c2ccccc2)c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of benzhydrylidene-[4-(tert-butyldimethylsilyloxymethyl)-3-fluoropyridin-2-yl]-amine (14 mg, 32 μmol) and tetrabutylammonium fluoride (1 mol/L in THF) (65 μL, 65 μmol) in THE (0.5 mL) was stirred at room temperature for 30 minutes. Ethyl acetate was then added to the reaction solution, and the solution was washed with sodium hydrogen carbonate solution and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. The resultant residue was purified by silica gel column chromatography to yield the title compound.
Reaction SMILES: [C:1](=[S:3])=S.[NH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:7][CH:6]1[CH3:15]>O1CCCC1>[N:4]([C@H:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:7][C@H:6]1[CH3:15])=[C:1]=[S:3]
Reactant: COC(=O)N1CCC(N)C(C)C1
Reactant: S=C=S
Solvent: C1CCOC1
Product: COC(=O)N1CC[C@H](N=C=S)[C@H](C)C1
Yield: 100 %

Procedure:
To a stirred and cooled (-10° C.) mixture of 138.6 parts of carbon disulfide, 113.8 parts of N,N'-methanetetraylbis[cyclohexanamine] and 450 parts of tetrahydrofuran were added dropwise 106 parts of methyl 4-amino-3-methyl-1-piperidinecarboxylate at this low temperature. The reaction mixture was allowed to attain room temperature. After stirring for 1 hour at room temperature, the mixture was evaporated and the residue was stirred in 2,2'-oxybispropane. The precipitate was filtered off and the filtrate was evaporated, yielding 141.1 parts (100%) of methyl cis-4-isothiocyanato-3-methyl-1-piperidinecarboxylate as a residue (interm. 28).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:23]=[CH:22][CH:21]=[C:20](F)[C:17]=2[C:18]#[N:19])[CH2:10][CH2:9]1.C(=O)(O)O.[NH2:29][C:30]([NH2:32])=[NH:31]>CC(N(C)C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][C:16]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:17]=2[C:18]([NH2:19])=[N:31][C:30]([NH2:32])=[N:29]3)[CH2:12][CH2:13]1
Reactant: N#Cc1c(F)cccc1OCC1CCN(c2ccccc2Cl)CC1
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: O
Solvent: CC(=O)N(C)C
Product: Nc1nc(N)c2c(OCC3CCN(c4ccccc4Cl)CC3)cccc2n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 28.9 %

Procedure:
2-[1-(2-Chlorophenyl)piperidin-4-ylmethoxy]-6-fluorobenzonitrile (0.28 g; 0.81 mmol) and guanidine carbonate (0.293 mg; 1.6 mmol) were heated at 140° C. in dimethylacetamide for 2 days, then cooled back to room temperature. The reaction mixture was diluted with water, stirred for 45 minutes, filtered, triturated with ethanol, and filtered. Solids were dried to afford 90 milligrams of 5-[1-(2-chlorophenyl)-piperidin-4-ylmethoxy)quinazoline-2,4-diamine (29% yield).
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5]CC)=[O:4].[NH2:14][C:15]1[C:16]([CH3:21])=[CH:17][CH:18]=[CH:19][CH:20]=1.CCN(C(C)C)C(C)C.O.[OH-].[Li+].[ClH:34]>C(#N)C.O1CCOCC1.O>[ClH:34].[C:8]1([CH:2]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[C:3]([OH:5])=[O:4])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cc1ccccc1N
Reactant: CCOC(=O)C(Br)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccccc1NC(C(=O)O)c1ccccc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
Ethyl 2-bromo-2-phenylacetate (0.28 mL, 1.64 mmol), ortho-toluidine (0.26 mL, 2.47 mmol) and DIPEA (0.43 mL, 2.47 mmol) are dissolved in acetonitrile (5 mL) and stirred under MW irradiation at 100° C. for 1 hour (Conversion complete by UPLC/MS-UV). Lithium hydroxide hydrate (207 mg, 4.94 mmol) and water (3 mL) are added and the mixture is stirred at RT for 16 hours. 4M HCl in dioxane is added until pH is about 1, then the solvents are evaporated, the residue is suspended in water, sonicated, cooled at 0° C. and the resulting solid is recovered by filtration and dried under vacuum to get intermediate I86 as a off-white solid (290 mg, 63% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4](O)[N:3]=1.C(N(CC)C(C)C)(C)C.P(Cl)(Cl)([Cl:36])=O.[OH-].[Na+]>C(#N)C.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([Cl:36])[N:3]=1
Reactant: Nc1nc(O)cc(C2CCCN(C(=O)OCc3ccccc3)C2)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(Cl)cc(C2CCCN(C(=O)OCc3ccccc3)C2)n1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
4.14 g (12.60 mmol) of benzyl 3-(2-amino-6-hydroxypyrimidin-4-yl)piperidine-1-carboxylate (from example LXXI) are suspended in 150 ml of acetonitrile. 3.29 ml (18.91 mmol) of N,N-diisopropylethylamine and 0.57 g (2.52 mmol) of benzyltriethylammonium chloride are added successively. The mixture is cooled to 0° C. At 0° C., 4.7 ml (50.43 mmol) of phosphoryl chloride are then slowly added dropwise. The mixture is stirred at room temperature for 18 hours. For work-up, the reaction solution is cooled to 0° C. and carefully added dropwise to ice water (150 ml). The aqueous suspension is neutralized using a 45% strength sodium hydroxide solution and extracted three times with ethyl acetate (in each case 70 ml). The organic phase is dried over anhydrous magnesium sulfate and concentrated. The residue is purified on a silica gel column using dichloromethane/methanol 30:1. This gives 2.80 g (64% of theory) of product.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:12][CH2:11][C@H:10](O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:1]1([CH2:7][N:8]2[CH2:12][CH2:11][C@@H:10]([N:18]3[C:14](=[O:24])[C:15]4[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:17]3=[O:19])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O[C@H]1CCN(Cc2ccccc2)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1[C@@H]1CCN(Cc2ccccc2)C1
Reaction time: 18 h
Yield: 79 %

Procedure:
To a suspension of 8.9 g (50 mmol) of (S)-1-phenylmethyl-3-hydroxypyrrolidine [Synth. Commun., 15, 587 (1985)], 9.8 g (50 mmol) of phthalimide, 13.1 g (50 mmol) of triphenylphosphine and 100 ml of tetrahydrofuran was added, dropwise, a solution of 8.8 g (50 mmol) of diethyl azodicarboxylate at room temperature. The reaction was stirred for 18 hours and the solvent was removed in vacuo. The residue was triturated with ether and the solid was removed by filtration and chromatographed on silica gel (E. Merck-240-400 mesh) eluting with chloroform/ethyl acetate (80:20). Fractions were combined based on thin layer chromatography and evaporated in vacuo to give 12.1 g of the title compound.
Reaction SMILES: [Cl-].[CH3:2][Zn+].Cl[C:5]1[N:10]=[C:9]2[N:11](S(C3C=CC=CC=3)(=O)=O)[CH:12]=[CH:13][C:8]2=[CH:7][CH:6]=1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:2][C:5]1[N:10]=[C:9]2[C:8]([CH:13]=[CH:12][NH:11]2)=[CH:7][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2ccc(Cl)nc21
Reactant: C[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1ccc2cc[nH]c2n1
Temperature: 0 °C
Yield: 88 %

Procedure:
A solution of methylzinc chloride in THF (2 M) (9 mL, 12 mmol) was added to 6-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.600 g, 2.05 mmol) and Pd(PPh3)4 (0.095 g, 0.08 mmol) in THF (30 mL). The mixture was refluxed for 40 h, cooled to 0° C., quenched with water and extracted with Et2O. The organic layer was concentrated and the residue was purified over a silica gel column eluting with EtOAc/hexane (1:5) to give N-protected 6-methyl-7-azaindole (0.495 g, 88%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[C:21](Cl)[N:20]=[C:19]([C:24]#[N:25])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:26]1[C:29]2([CH2:34][CH2:33][CH:32]([CH2:35][NH2:36])[CH2:31][CH2:30]2)[CH2:28][CH2:27]1.C([O-])([O-])=O.[K+].[K+]>CC#N.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[C:21]([NH:36][CH2:35][CH:32]3[CH2:31][CH2:30][C:29]4([CH2:28][CH2:27][CH2:26]4)[CH2:34][CH2:33]3)[N:20]=[C:19]([C:24]#[N:25])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2cc(Cl)nc(C#N)n2)CC1
Reactant: NCC1CCC2(CCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(CCOc2cc(NCC3CCC4(CCC4)CC3)nc(C#N)n2)CC1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a solution of 4-[2-(6-chloro-2-cyanopyrimidin-4-yloxy)ethyl]piperidine-1-carboxylic acid tert-butyl ester (0.82 mmol) and C-spiro[3.5]non-7-ylmethylamine (0.86 mmol) in CH3CN (10 mL) is added K2CO3 (2.2 mmol) at room temperature. After stirring at 80° C. for 12 h, the reaction mixture is cooled to room temperature and diluted with AcOEt. The organic layer is washed twice with H2O and dried over MgSO4 and evaporated in vacuo to give a crude 4-(2-{2-cyano-6-[(spiro[3.5]non-7-ylmethyl)amino]pyrimidin-4-yloxy}ethyl)piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[C:10]([C:12]2[CH:32]=[CH:31][C:15]3[N:16]([CH3:30])[C:17]([CH2:19][NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=4)=[N:18][C:14]=3[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[OH-].[Na+]>ClCCl.C(O)C>[F:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[C:10]([C:12]2[CH:32]=[CH:31][C:15]3[N:16]([CH3:30])[C:17]([CH2:19][NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH2:29])=[CH:23][CH:22]=4)=[N:18][C:14]=3[CH:13]=2)=[O:11])=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCC(=O)O)c3ccc(F)cc3)ccc21
Yield: 89 %

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(4-fluorophenyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution. Yield: 89% of theory, C26H25FN6O3 (488.5) Rf value: 0.15 (silica gel; dichloromethane/ethanol=4:1) ##EQU128##
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]2[C:6]([C:9]3[CH:16]=[CH:15]C(C#N)=[CH:11][CH:10]=3)=[CH:7][N:8]=[C:2]12.S(=O)(=O)(O)O.[C:22]([OH:25])(=[O:24])[CH3:23]>>[S:1]1[CH2:5][CH2:4][N:3]2[C:6]([C:9]3[CH:16]=[CH:15][C:23]([C:22]([OH:25])=[O:24])=[CH:11][CH:10]=3)=[CH:7][N:8]=[C:2]12
Reactant: N#Cc1ccc(-c2cnc3n2CCS3)cc1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccc(-c2cnc3n2CCS3)cc1
Temperature: 100 °C

Procedure:
2.00 g (8.80 mmol) of contaminated 4-(2,3-dihydroimidazo[2,1-b]thiazol-5-yl)benzonitrile is placed in 60 mL of 50% acetic acid solution at 0° C. and slowly combined with 30 mL of concentrated sulfuric acid with stirring and cooling in the ice bath. The reaction mixture is heated to 100° C. for 17 hours and then poured into 500 mL of ice water. The precipitated product formed is filtered off. The mother liquor is combined with sodium chloride and extracted with 300 mL of ethyl acetate, washed with saturated sodium chloride solution, dried with magnesium sulfate, and the solvent is distilled off. The residue remaining is combined with the above precipitate. Yield: 1.25 g (40% over 2 steps); Rf value: 0.55 (silica gel; ethyl acetate/ethanol=9:1); C12H10N2O2S (246.29); mass spectrum: (M+H)+=247