Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]2[NH:9][N:10]=[CH:11][C:3]=12.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.CC1C=CC(S(O)(=O)=O)=CC=1>CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]2[N:9]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][O:12]3)[N:10]=[CH:11][C:3]=12
Reactant: C1=COCCC1
Reactant: Cc1nc(Cl)c2cn[nH]c2n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Product: Cc1nc(Cl)c2cnn(C3CCCCO3)c2n1
Temperature: 90 °C
Yield: 98.9 %

Procedure:
A suspension of the above 4-chloro-6-methyl-1H-pyrazolo[3,4-d]pyrimidine (325 mg, 1928 μmol) in EtOAc (3 mL) was treated with 3,4-dihydro-2H-pyran (528 μL, 5783 μmol) and MP-TsOH resin (Biotage) (72 mg, 4.3 mmol/g, 0.15 eq) and the resulting suspension was heated at 90° C. for 3 h, after which time LCMS indicated essentially complete conversion. The solution was filtered, washed with EtOAc, and concentrated to give a pale yellow oil. Purification by flash chromatography (EtOAc/hexane; 5% to 20%) gave 4-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (482 mg, 98.9% yield) as a colorless oil. 1H NMR (400 MHz, d6-DMSO) δ 8.44 (s, 1H); 5.91-6.02 (m, 1H); 3.91-3.99 (m, 1H); 3.67-3.77 (m, 1H); 2.72 (s, 3H); 2.36-2.48 (m, 1H); 1.96-2.08 (m, 1H); 1.87-1.95 (m, 1H); 1.32-1.84 (m, 3H).
Reaction SMILES: [Cl:1][CH2:2][C:3](O)=O.C(N(CC)CC)C.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=1>C(#N)C>[Cl:1][C:2]1[N:13]=[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]2[CH:3]=1
Reactant: O=C(O)CCl
Reactant: Nc1ccc(Cl)cn1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Clc1ccc2nc(Cl)cn2c1
Yield: 11.2 %

Procedure:
Chloroacetic acid (9.5 g) is dissolved in 70 ml of acetonitrile, to which 10.1 g of triethylamine is portionwise added and further 12.9 g of 2-amino-5-chloropyrdine is added. The mixture is refluxed for 3 hours. After cooling, the precipitated 2-imino-5-chloro-1,2-dihydropyridin-1-ylacetic acid as crystals is collected by filtration and dried. The crystals are added to 40 ml of phosphorus oxychoride and refluxed for 5 hours. After cooling, the reaction mixture is poured into ice water and neutralized with aqueous ammonia. The precipitate collected by filtration is purified by silica gel chromatography(eluent: ethyl acetate) to give 2.1 g of the title compound as crystals. mp. 155°-156° C.
Reaction SMILES: C(C1C=CC(CN([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:14]=2)C)=CC=1)(C)(C)C.O(C1C=C(C)C=CC=1)C1C=CC=CC=1.[Br:42]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[O:19]([C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][Br:42])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CN(Cc1ccc(C(C)(C)C)cc1)Cc1cccc(Oc2ccccc2)c1
Agent: Cc1cccc(Oc2ccccc2)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cccc(Oc2ccccc2)c1

Procedure:
Following the process to be described below, Compound 1 was prepared. Namely, 10.16 g of m-phenoxytoluene, 9.82 g of N-bromosuccinimide and 0.15 g of benzoyl peroxide were weighed and added to 90 ml of carbon tetrachloride as a solvent. The resulting mixture was heated under reflux for 3 hours to conduct a reaction. The reaction mixture was allowed to cool down, the insoluble matter was filtered off, and the filtrate was then concentrated. The concentrate was purified by chromatography on a silica gel column (eluent: chloroform), whereby 10.9 g of 3-phenoxybenzyl bromide were obtained. In 20 ml of N,N-dimethylformamide, 2.79 g of N-(4-tert-butylbenzyl)methylamine and 1.67 g of sodium carbonate were mixed, to which a solution of 3.77 g of 3-phenoxybenzyl bromide in 25 ml of N,N-dimethylformamide was added dropwise under ice cooling. The temperature of the reaction mixture was allowed to rise to room temperature, at which a reaction was allowed to proceed for 12 hours. Chloroform and water were added to the reaction mixture to conduct liquid-liquid extraction. An organic layer was collected and then washed with water and a saturated aqueous solution of sodium chloride. The resulting solution was dried over anhydrous sodium sulfate and was then concentrated. The concentrate was purified by chromatography on a silica gel column (eluent:hexane:chloroform:ethyl acetate=9:1:0→0:10:0→0:0:100). Relevant fractions were concentrated, whereby 4.49 g of N-(4-tertiary-butylbenzyl)-N-methyl-3-phenoxybenzylamine (Compound 1) were obtained (yield: 87.8%). The following is its NMR data (CDCl3 δ ppm): 1.28(9H,s), 2.18(3H,s), 3.476(2H,s), 3.483(2H,s), 6.86-7.35(13H,m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1.[F:15][C:16]([F:32])([F:31])[C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=2)[C:25](O)=[O:26])[N:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:25]([C:24]3[CH:28]=[CH:29][CH:30]=[C:22]([C:19]4[N:18]=[C:17]([C:16]([F:31])([F:15])[F:32])[O:21][N:20]=4)[CH:23]=3)=[O:26])[CH2:11][CH2:10]2)=[N:7][CH:8]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: COc1ccc(N2CCNCC2)nc1
Product: COc1ccc(N2CCN(C(=O)c3cccc(-c4noc(C(F)(F)F)n4)c3)CC2)nc1
Yield: 36 %

Procedure:
This compound was synthesized from 1-(5-methoxypyridin-2-yl)piperazine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (60 mg, yield 36%). 1H NMR (400 MHz, MeOD) δ 8.28-8.25 (m, 1H), 8.21-8.20 (m, 1H), 7.87-7.86 (m, 1H), 7.74-7.72 (m, 2H), 7.32-7.29 (dd, J=9.2 Hz, 3.1 Hz, 1H), 6.89-6.86 (d, J=9.3 Hz, 1H), 3.93 (m, 2H), 3.80 (s, 3H), 3.62 (m, 2H), 3.55 (m, 2H), 3.43 (m, 2H). MS (ESI) m/z: Calculated for C20H18F3N6O3: 433.14. found: 434.0 (M+H)+
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]#[N:13])=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]#[N:13])=[CH:8][CH:9]=1
Reactant: N#CCCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: N#CCCc1ccc(N)cc1

Procedure:
3-(4-Nitrophenyl)propionitrile (38) (740 mg, 4.2 mmol) was reduced by using procedure described in Example 5 in methanol (100 mL) with 10% Pd/C as a catalyst to afford 3-(4-aminophenyl)propionitrile (39). 1H NMR (DMSO-d6): δ 6.91-6.88 (d, J=9.0 Hz, 2H), 6.49-6.46 (d, J=9.0 Hz, 2H), 4.92 (s, 2H), and 2.66 (s, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][CH2:20][CH3:21])=[C:6]([C:8]2[N:16]=[C:15]3[C:11](=[N:12][N:13]=[N:14]3)[C:10](=[O:17])[N:9]=2)[CH:7]=1.[NH2:22][C:23](N)=[O:24].Cl>O>[CH2:19]([O:18][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:23]([NH2:22])=[O:24])=[CH:7][C:6]=1[C:8]1[N:16]=[C:15]2[C:11](=[N:12][N:13]=[N:14]2)[C:10](=[O:17])[N:9]=1)[CH2:20][CH3:21]
Reactant: NC(N)=O
Reactant: CCCOc1ccc(N)cc1C1=NC(=O)C2=NN=NC2=N1
Agent: Cl
Solvent: O
Product: CCCOc1ccc(NC(N)=O)cc1C1=NC(=O)C2=NN=NC2=N1
Temperature: 175 °C
Yield: 30.4 %

Procedure:
An intimate mixture of 2-(5-amino-2-propoxyphenyl)-8-azapurin-6-one (2 g) and urea (6 g) was heated at 175° C. for one hour. The mixture was then dissolved in water (50 ml) and the solution was acidified by treatment with concentrated hydrochloric acid. The resulting suspension was heated to boiling point and filtered. The solid was dissolved in dilute aqueous ammonia solution (2 N) and this hot solution was acidified by treatment with concentrated hydrochloric acid. The cooled suspension was filtered to give 2-(2-propoxy-5-ureidophenyl)-8-azapurin-6-one (0.7 g), in the form of a microcrystalline solid, m.p. 264°-268° C. (with decomposition).
Reaction SMILES: N([Si](C)(C)C)=[N+]=[N-].[CH3:8][C:9]1([CH3:16])[CH2:14][CH2:13][C:12](=[O:15])[CH:11]=[CH:10]1.[I:17]I>N1C=CC=CC=1.ClCCl.C(OCC)(=O)C>[I:17][C:11]1[C:12](=[O:15])[CH2:13][CH2:14][C:9]([CH3:16])([CH3:8])[CH:10]=1
Reactant: II
Reactant: CC1(C)C=CC(=O)CC1
Agent: C[Si](C)(C)N=[N+]=[N-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)C=C(I)C(=O)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Freshly distilled azidotrimethylsilane (4.61 mL, 34.7 mmol) was added to a stirred solution of 4,4-dimethyl-2-cyclohexen-1-one (available from Aldrich Chemical Co., 3.04 mL, 23.2 mmol) and dichloromethane (35 mL) at 0° C. under argon. The solution was stirred for 2 hours at 0° C. before adding a solution of iodine (11.8 g, 46.3 mmol) in 35 mL of pyridine and 35 mL of dichloromethane. The resulting solution was stirred for 20 hours at room temperature, diluted with ethyl acetate, and was washed with 20% aqueous Na2S2O3, and 10% aqueous HCl, and water, and brine. The solvents were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (7:1, hexanes:ethyl acetate) to give the title compound as a yellow oil.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15]([NH:23][CH2:24][C@H:25]4[CH2:29][CH2:28][CH2:27][O:26]4)[C:16]4[CH2:22][NH:21][CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.[C:30](O)(=O)C.C=O.C([BH3-])#N.[Na+]>CO>[CH3:30][N:21]1[CH2:20][CH2:19][C:17]2[N:18]=[C:13]([NH:12][C:9]3[CH:8]=[CH:7][C:6]([C:5]4[O:1][CH:2]=[N:3][CH:4]=4)=[CH:11][CH:10]=3)[N:14]=[C:15]([NH:23][CH2:24][C@H:25]3[CH2:29][CH2:28][CH2:27][O:26]3)[C:16]=2[CH2:22]1
Reactant: CC(=O)O
Reactant: c1ncc(-c2ccc(Nc3nc4c(c(NC[C@H]5CCCO5)n3)CNCC4)cc2)o1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(NC[C@H]3CCCO3)c2C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33.3 %

Procedure:
(R)-N2-(4-(Oxazol-5-yl)phenyl)-N4-((tetrahydrofuran-2-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (135 mg, 0.34 mmol, example 80a) was dissolved in methanol (3 mL). Acetic acid (0.020 mL, 0.34 mmol) was added followed by formaldehyde (0.026 mL, 0.34 mmol). The reaction mixture was stirred at room temperature for 15 minutes and sodium cyanoborohydride (21.62 mg, 0.34 mmol) MP—CNBH3 was added. The reaction was stirred overnight, the MP—CNBH3 was filtered off and the solvent was evaporated under reduced pressure. The crude was dissolved in methanol, filtered and purified by HPLC yielding (R)-6-methyl-N2-(4-(oxazol-5-yl)phenyl)-N4-((tetrahydrofuran-2-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (46.0 mg, 30.3%). MS (ES+) m/z 407.2 (M+H)+
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[CH:9][CH:10]=2)[N:5]([CH2:18][CH:19]=[CH2:20])[CH:4]=[C:3]1[C:21](O)=[O:22].O=C1C2C(=CC(C3C=CN=CC=3)=CC=2)[NH:28]C=C1C(OCC)=O.C(Br)C=C>>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[CH:9][CH:10]=2)[N:5]([CH2:18][CH:19]=[CH2:20])[CH:4]=[C:3]1[C:21]([NH2:28])=[O:22]
Reactant: CCOC(=O)c1c[nH]c2cc(-c3ccncc3)ccc2c1=O
Reactant: C=CCn1cc(C(=O)O)c(=O)c2ccc(-c3ccncc3)cc21
Solvent: C=CCBr
Product: C=CCn1cc(C(N)=O)c(=O)c2ccc(-c3ccncc3)cc21

Procedure:
The starting acid, 1,4-dihydro-4-oxo-1-(2-propenyl)-7-(4-pyridinyl)-3-quinolinecarboxylic acid (golden crystals, m.p. 259.5°-261° C. from methanol), was prepared by hydrolysis of the corresponding ethyl ester (yellow powder, m.p. 155°-157° C.), in turn prepared by alkylation of ethyl 1,4-dihydro-4-oxo-7-(4-pyridinyl)-3-quinolinecarboxylate with allyl bromide.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[C:4]([Cl:10])[N:3]=1.[NH2:11][NH2:12]>C1COCC1>[Cl:10][C:4]1[N:3]=[C:2]2[NH:11][N:12]=[CH:8][C:7]2=[CH:6][CH:5]=1
Reactant: NN
Reactant: O=Cc1ccc(Cl)nc1Cl
Solvent: C1CCOC1
Product: Clc1ccc2cn[nH]c2n1
Yield: 21.6 %

Procedure:
To a solution of 2,6-dichloro-3-formylpyridine (0.89 mmol, 1 eq.) in 3 ml THF was added hydrazine (1.06 mmol, 1.2 eq.) at rt. The resultant solution was heated at 120° C. in sealed tube for overnight. The solvent was removed in vacuo, and the residue was dry loaded on silica gel column. Purification by silica gel chromatography provide 29.5 mg final product: HPLC retention time=2.17 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 0% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expect=154.0. found=154.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.CN(C=O)C.[O:21]1[C:27]2[CH:28]=[CH:29][C:30]([S:32](Cl)(=[O:34])=[O:33])=[CH:31][C:26]=2[O:25][CH2:24][CH2:23][CH2:22]1>>[O:21]1[C:27]2[CH:28]=[CH:29][C:30]([S:32]([N:8]3[C:9]4[C:5](=[C:4]([CH2:12][N:13]([CH3:14])[CH3:15])[C:3]([O:2][CH3:1])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)(=[O:34])=[O:33])=[CH:31][C:26]=2[O:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCCCO2
Reactant: COc1ccc2[nH]ccc2c1CN(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(ccn2S(=O)(=O)c2ccc3c(c2)OCCCO3)c1CN(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 17.2 %

Procedure:
To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylmethanamine (15 mg, 0.07 mmol; Intermediate 97) in DMF (1 mL) NaH (4 mg, 0.15 mmol) was added at rt. The reaction mixture was stirred at rt for 15 min and 3,4-dihydro-2H-1,5-benzodioxepine-7-sulfonyl chloride (27 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at rt over night. The reaction was quenched by addition of water. Purification by preparative HPLC/UV (System B) afforded the title product (5 mg, 17%) as a yellow solid. MS (ESI+) for C21H24N2O5S m/z 417 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].IC.[C:16](=O)(O)[O-].[Na+]>CC(N(C)C)=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([O:7][CH3:16])=[O:6]
Reactant: O=C([O-])O
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CI
Product: COC(=O)c1ccc([N+](=O)[O-])c(C)c1

Procedure:
3-Methyl-4-nitrobenzoic acid (67 g, 0.37 mole) is added to a mixture of dimethylacetamide (300 ml), iodomethane (85 g, 1.0 mole) and anhydrous sodium bicarbonate (84 g, 1.0 mole). The mixture is stirred and heated at reflux for two hours. The mixture is cooled, and filtered and the solids are washed with methanol before being discarded. The filtrate and washings are evaporated to a residue which crystallizes. Recrystallization from diethyl ether gives pure methyl 3-methyl-4-nitrobenzoate, 65.1 g, m.p. 73°-75.5° C.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2[N:11]=[C:12]([NH2:15])[S:13][CH:14]=2)[CH:6]=[CH:7][C:8]=1[Cl:9].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.Cl>N1C=CC=CC=1>[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2[N:11]=[C:12]([NH:15][S:22]([C:19]3[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=3)(=[O:24])=[O:23])[S:13][CH:14]=2)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc(-c2ccc(Cl)c(Cl)c2)cs1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3ccc(Cl)c(Cl)c3)cs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.9 %

Procedure:
A mixture of 0.5 g of 4-(3,4-dichloro-phenyl)-thiazol-2-ylamine hydrobromide with 0.50 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 30 ml of 1N hydrochloric acid and the solid which thereby separated was filtered off and dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.4 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. 0.33 g of N-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4-methyl-benzenesulfonamide was obtained as colorless crystals upon neutralization with concentrated hydrochloric acid.
Reaction SMILES: N(OCC(C)C)=O.N[C:9]1[CH:31]=[C:30]([C:32](=[O:34])[NH2:33])[CH:29]=[CH:28][C:10]=1[O:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][CH2:18][O:19]2)=[CH:14][C:13]=1[Cl:27].O>CN(C=O)C>[C:32]([C:30]1[CH:31]=[CH:9][C:10]([O:11][C:12]2[CH:21]=[C:20]3[C:15]([CH:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][CH2:18][O:19]3)=[CH:14][C:13]=2[Cl:27])=[CH:28][CH:29]=1)(=[O:34])[NH2:33]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(N)=O)cc3N)c(Cl)cc21
Agent: CC(C)CON=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(N)=O)cc3)c(Cl)cc21
Temperature: 68.5 °C
Reaction time: 0.62 h
Yield: 94.4 %

Procedure:
To a solution of isobutyl nitrite (3.92 g, 15.2 mmol) in DMF (100 mL) at 66° C. was added a solution of ethyl 7-(2-amino-4-carbamoylphenoxy)-6-chlorochroman-4-carboxylate (5.94 g, 15.2 mmol) in DMF (30 mL) dropwise over 14 minutes. The temperature rose to 70° C. during the addition and gas began to evolve. After 37 minutes of stirring at 68-69° C. the resulting solution was cooled to ambient temperature and poured into a reparatory funnel containing water (1500 mL). The resulting mixture was extracted with ethyl acetate (250 mL) and the organic layer was washed with 1M HCl, and brine, dried over sodium sulfate and concentrated to give 5.39 g of brown solid. The solid was triturated with ether and filtered to provide the desired product (4.86 g, 85%).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:28])[CH2:10][CH:11]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.[NH2:29][C@@H:30]([CH3:33])[CH2:31][OH:32].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[OH:32][CH2:31][C@@H:30]([NH:29][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:10][C:9]([C:4]2[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=2)=[O:28])=[CH:20][CH:21]=1)[CH3:33]
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1
Reactant: C[C@H](N)CO
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)N[C@@H](C)CO)cc1

Procedure:
In analogy to example 207, step 2, 4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzoic acid (example 207, step 1) was coupled with (S)-2-aminopropan-1-ol using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in tetrahydrofuran to give the title compound as an off-white solid, MS (ESI+): m/z=433.3 [M+H]+.
Reaction SMILES: C(OC(=O)N)(C)(C)C.[C:9]([O:13][C:14](=[O:48])[NH:15][C:16]1([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[C:35](=[O:36])[C:34]4[C:29](=[C:30]([NH:40][CH3:41])[C:31]([N+:37]([O-])=O)=[CH:32][CH:33]=4)[O:28][C:27]=3[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:22][CH:21]=2)[CH2:19][CH2:18][CH2:17]1)([CH3:12])([CH3:11])[CH3:10]>>[C:9]([O:13][C:14](=[O:48])[NH:15][C:16]1([C:20]2[CH:21]=[CH:22][C:23]([C:26]3[C:35](=[O:36])[C:34]4[C:29](=[C:30]([NH:40][CH3:41])[C:31]([NH2:37])=[CH:32][CH:33]=4)[O:28][C:27]=3[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:24][CH:25]=2)[CH2:17][CH2:18][CH2:19]1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CNc1c([N+](=O)[O-])ccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc12
Agent: CC(C)(C)OC(N)=O
Product: CNc1c(N)ccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc12
Yield: 89 %

Procedure:
Following the procedure used to prepare 1-[4-(7,8-diamino-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, {1-[4-(8-methylamino-7-nitro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted to give the title compound as a yellow oil (95 mg, 89%). LCMS (Method H): RT=3.69 min, [M+H]+=512.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[C:8]([NH:10][C:11]([CH:13]3[CH2:15][CH2:14]3)=[O:12])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[Cl:16][C:17]1[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[C:18]=1[C:19](Cl)=[O:20]>>[Cl:16][C:17]1[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[C:18]=1[C:19]([C:3]1[C:4]2[C:9](=[C:8]([NH:10][C:11]([CH:13]3[CH2:15][CH2:14]3)=[O:12])[N:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)=[O:20]
Reactant: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Reactant: O=C(Nc1cc2cc[nH]c2cn1)C1CC1
Product: O=C(c1c(Cl)cc(Cl)cc1Cl)c1c[nH]c2c(NC(=O)C3CC3)nccc12

Procedure:
N-[3-(2,4,6-Trichlorobenzoyl)-1H-pyrrolo[2,3-c]pyridin-7-yl]cyclopropanecarboxamide (Compound No. 45) was prepared using N-(1H-pyrrolo[2,3-c]pyridin-5-yl)cyclopropane carboxamide and 2,4,6-trichlorobenzoyl chloride.
Reaction SMILES: [CH3:1][N:2]([CH2:14][CH2:15][NH:16]C(=O)C(F)(F)F)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[NH2:16][CH2:15][CH2:14][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CCCCCCN(C)CCNC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)CCCCCCN(C)CCN
Reaction time: 20 h
Yield: 86.9 %

Procedure:
To a solution of ethyl 7-[methyl-[2-[(2,2,2-trifluoroacetyl)amino]ethyl]amino]heptanoate (4.89 g) in ethanol (80 ml) in an ice bath was added 10% aqueous potassium carbonate (30 ml) and stirring was continued for 20 hr. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate. The insoluble material was removed by filtration and the filtrate was concentrated to obtain the titled compound (3 g)
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:32]([C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1)#[N:33].O[CH:42]1[CH2:46][CH2:45][N:44]([C:47]2[CH:52]=[CH:51][N:50]=[CH:49][CH:48]=2)[CH2:43]1>O1CCCC1>[C:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:46]2[CH2:42][CH2:43][N:44]([C:47]3[CH:52]=[CH:51][N:50]=[CH:49][CH:48]=3)[CH2:45]2)=[CH:36][CH:35]=1)#[N:33]
Reactant: OC1CCN(c2ccncc2)C1
Reactant: N#Cc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(OC2CCN(c3ccncc3)C2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.1 %

Procedure:
A solution of diethyl azodicarboxylate (1.73 ml) in dried tetrahydrofuran (10 ml) was added dropwise to a stirred mixture of triphenylphosphine (3.15 g), 4-cyanophenol (1.31 g) and 4-(3-hydroxy-1-pyrrolidinyl)pyridine (1.64 g) in dried tetrahydrofuran (45 ml), under an atmosphere of argon, at 5-7° C. The resulting solution was stirred at ambient temperature for 16 hours. The solid, which had separated, was filtered off and washed with diethyl ether to give 4-[3-(4-cyanophenoxy)-1-pyrrolidinyl]pyridine (823 mg) as an off-white solid, mp 182-185° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[O:22][CH2:23][CH:24]1[CH2:26][CH2:25]1)[C:5]([NH:7][CH:8]1[CH2:17][CH2:16][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:10][CH:9]1[OH:18])=O.C(N(CC)CC)C.O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:18][C:9]3[CH2:10][C:11]4([O:12][CH2:13][CH2:14][O:15]4)[CH2:16][CH2:17][C:8]=3[N:7]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH2:23][CH:24]1[CH2:25][CH2:26]1
Reactant: O=C(NC1CCC2(CC1O)OCCO2)c1ccc(OCC2CC2)c(Cl)c1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Clc1cc(-c2nc3c(o2)CC2(CC3)OCCO2)ccc1OCC1CC1
Reaction time: 1 h
Yield: 50.7 %

Procedure:
To a solution of 3-chloro-4-(cyclopropylmethoxy)-N-(7-hydroxy-1,4-dioxaspiro[4.5]dec-8-yl)benzamide (20.8 g) in dimethyl sulfoxide (80 mL) were added triethylamine (22.8 mL) and sulfur trioxide-pyridine complex (26.0 g), and the mixture was stirred for 1 hr under a nitrogen stream. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a solution of the obtained residue in THF (80 mL) was added (methoxycarbonylsulfamoyl)triethylammonium hydroxide inner salt (21.4 g), and the mixture was stirred at 60° C. for 30 min. To the reaction mixture was added saturated brine, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (10.0 g).