Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO.CCOC(C)=O>[C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)Nc1ccc(CO)cc1

Procedure:
To a solution of 4-acetamidobenzaldehyde (10 g, 61.3 mmol) in methanol (100 mL) was added sodium borohydride (800 mg) at room temperature in portions. The reaction mixture was stirred over night, and the progress of reaction checked by TLC using 4:1 hexanes:EtOAc as eluent. Absence of starting material indicated the completion of reduction and the reaction mixture was concentrated in a rotavap. The residue was partitioned between water (25 mL) and ethyl acetate (4×50 mL) and the organic layer was washed with brine (25 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate and the removal of the solvent gave the alcohol as a pale yellow solid, which was dried under high vacuum. 8.6 g (85%); 1H NMR (DMSO-d6): δ 2.0 (s, 3H), 4.5 (d, 2H), 5.2 (t, 1H), 7.25 (d, 2H), 7.55 (d, 2H), 9.95 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[CH:3]=1.[C:17](#[N:19])[CH3:18].Cl.C(O)(=O)C>C(Cl)(Cl)Cl.[NH4+].[OH-].CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:17]([NH2:19])[CH3:18])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[CH:3]=1
Reactant: CC#N
Reactant: Nc1ccc(Cl)cc1Cc1ccccc1F
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(N)=Nc1ccc(Cl)cc1Cc1ccccc1F
Reaction time: 1 h

Procedure:
In 500 ml three-necked flask fitted with a stirrer, gas inlet tube, and a double condenser is placed 13.65 g (50 mmoles) of 4-chloro-2[(2-fluorophenyl)methyl]benzenamine and 200 ml of acetonitrile. Hydrogen chloride gas is bubbled into this stirred suspension. The temperature rises to ca. 38° C. and a solution is formed in about 10 min. The reaction mixture is then heated to gentle reflux while maintaining a stream of hydrogen chloride throught the reaction mixture. After 1 hr. TLC of an aliquent using 2% acetic acid, 10% MeOH in CHCl3 or 1% NH4OH/20% MeOH in CHCl3 on fluorescent silica plates shows only a trace of starting material. The reaction mixture is then concentrated in vacuo to a pale semi-solid. This is partitioned between 100 ml of methylene chloride and ca 30 ml of 3 N sodium hydroxide. The aqueous phase is back extracted with 100 ml of methylene chloride. The organic phases are combined, washed with 50 ml of brine, dried over potassium carbonate and concentrated in vacuo to pale yellow oil. This oil is crystallized from hexane with a little methylene chloride to give end product of m.p. 115°-119° C.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([C:14]#[N:15])[S:12][CH:13]=2)[C:4]1=[O:16].[Cl:17][C:18]1[N:23]=[C:22]2[CH:24]=[C:25]([S:27](Cl)(=[O:29])=[O:28])[S:26][C:21]2=[CH:20][CH:19]=1>>[C:14]([C:11]1[S:12][CH:13]=[C:9]([CH2:8][N:5]2[CH2:6][CH2:7][C@H:3]([NH:2][S:27]([C:25]3[S:26][C:21]4[C:22](=[N:23][C:18]([Cl:17])=[CH:19][CH:20]=4)[CH:24]=3)(=[O:28])=[O:29])[C:4]2=[O:16])[CH:10]=1)#[N:15]
Reactant: O=S(=O)(Cl)c1cc2nc(Cl)ccc2s1
Reactant: N#Cc1cc(CN2CC[C@H](N)C2=O)cs1
Agent: Cl
Product: N#Cc1cc(CN2CC[C@H](NS(=O)(=O)c3cc4nc(Cl)ccc4s3)C2=O)cs1

Procedure:
The title compound is prepared from 4-(3-(S)-amino-2-oxo-pyrrolidin-1-ylmethyl)-thiophene-2-carbonitrile hydrochloride as described in EXAMPLE 1, Part E using 5-chlorothieno[3,2-b]pyridine-2-sulfonyl chloride in place of benzo[b]thiophene-2-sulfonyl chloride. The product is triturated with Et2O/CH2Cl2 /hexanes to give a white solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:12]([OH:15])(=O)[CH3:13].[CH2:16](Cl)[Cl:17]>>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:15])[CH2:13][CH2:16][Cl:17])=[CH:8][CH:7]=1
Reactant: Brc1ccccc1
Reactant: CC(=O)O
Reactant: ClCCl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCCl)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
45.3 g of aluminium chloride are stirred at room temperature in 80 ml of CH2Cl2. Maintaining vigorous stirring, a solution of β-propionic acid chloride (38.09 g, 28.7 ml, 0.3 mol) is poured slowly into 20 ml of CH2Cl2. The CH2Cl2-AlCl3-acid chloride complex forms quickly and the solution turns dark red. A solution of bromobenzene (47.1 g, 31.6 ml, 0.3 mol) is then introduced dropwise into 20 ml of CH2Cl2. The solution is then stirred for 15 hours at room temperature. The mixture is hydrolysed over 190 g of ice, to which 7.6 ml of concentrated acetic acid have been added. The organic phase is washed neutral and the solvent is removed by evaporation under reduced pressure. A dark red oil is obtained, from which the title compound is obtained in the form of a yellowish solid by extraction while hot with petroleum ether.
Reaction SMILES: C(O[C:4]([C:6]1[C:11]([Br:12])=[N:10][CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])C.[CH3:14][C:15]1[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][N:16]=1>>[CH3:14][C:15]1[CH:20]=[C:19]([NH:21][C:4]([C:6]2[C:11]([Br:12])=[N:10][CH:9]=[C:8]([CH3:13])[N:7]=2)=[O:5])[CH:18]=[CH:17][N:16]=1
Reactant: Cc1cc(N)ccn1
Reactant: CCOC(=O)c1nc(C)cnc1Br
Product: Cc1cc(NC(=O)c2nc(C)cnc2Br)ccn1

Procedure:
The title compound, MS: m/e=307.2 (M+H+), was prepared in accordance with the general method of example 1, step 2 from 3-bromo-6-methyl-pyrazine-2-carboxylic acid ethyl ester and 2-methyl-pyridin-4-ylamine (Example B).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19](O)=[O:20])[CH:17]=2)[N:12](C2CCCCO2)[N:11]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:52][N:53]([CH3:58])[CH2:54][CH2:55][CH2:56][NH2:57]>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([NH:57][CH2:56][CH2:55][CH2:54][N:53]([CH3:58])[CH3:52])=[O:20])[CH:17]=2)[NH:12][N:11]=1
Reactant: O=C(O)c1ccc2c(c1)c(-c1cc3ccccc3o1)nn2C1CCCCO1
Reactant: CN(C)CCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CN(C)CCCNC(=O)c1ccc2[nH]nc(-c3cc4ccccc4o3)c2c1
Yield: 34 %

Procedure:
The title compound was prepared as described in Example 277 using of 3-benzo[d]furan-2-yl-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxylic acid (250 mg, 0.7 mmol), O-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (292 mg, 0.77 mmol) and 3-dimethylaminopropyl amine (176 μL, 1.4 mmol); (87 mg, 34% yield). 1H NMR (DMSO-d6) δ 13.8 (s, 1H), (8.7-8.8 (m, 2H), 8.0 (d, 1H), 7.6-7.8 (m, 4H), 7.3-7.5 (m, 2H), 2.3 (s, 2H), 1.75 (m, 2H), ES-MS (m/z) 363 [M+1]+.
Reaction SMILES: CS[C:3](=[C:6]([C:12]([O:14]CC)=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:4][CH3:5].[CH3:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[NH:27])=[CH:21][CH:20]=1.[K+].[Br-]>>[F:34][C:31]1[CH:30]=[CH:29][C:28]([C:26]2[N:25]([C:22]3[CH:23]=[CH:24][C:19]([S:18][CH3:17])=[CH:20][CH:21]=3)[C:12](=[O:14])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:3]([S:4][CH3:5])[N:27]=2)=[CH:33][CH:32]=1
Reactant: CCOC(=O)C(C(=O)OCC)=C(SC)SC
Reactant: CSc1ccc(NC(=N)c2ccc(F)cc2)cc1
Agent: [Br-]
Agent: [K+]
Product: CCOC(=O)c1c(SC)nc(-c2ccc(F)cc2)n(-c2ccc(SC)cc2)c1=O
Yield: 2.9 %

Procedure:
The title compound was prepared from diethyl [bis(methylthio)methylene]malonate (5.3 g, 20 mmol) and N-(4-methythiophenyl)-4-(fluoro)benzenecarboximidamide (5.2 g, 20 mmol) (prepared according to the procedure described in preparation 2) by following the procedure described in example 41 (0.25 g, yield 2.9%, mp 166-169° C., purity 96.84% by HPLC). 1H-NMR (CDCl3):δ 1.36-1.4 (t, 3H), 2.45 (s, 3H), 2.55 (s, 3H), 4.38-4.43 (q, 2H), 6.91-6.96 (m, 2H), 7.01-7.03 (d, 2H), 7.16-7.18 (d, 2H), 7.33-7.37 (m, 2H). IR (KBr) cm−1: 3447, 3069, 2989, 2900, 1733, 1666. MS m/z:431.2.0(M+).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=2)[CH2:19][NH2:20])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([C:15]1[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=1)[C:21]1[CH:22]=[N:23][C:24]([C:27]([F:29])([F:30])[F:28])=[N:25][CH:26]=1)=[O:6]
Reactant: NCC(c1ccncc1)c1cnc(C(F)(F)F)nc1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: O=C(NCC(c1ccncc1)c1cnc(C(F)(F)F)nc1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 2-(pyridin-4-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine. LCMS (MH+): m/z=441.1, tR (minutes, Method F)=2.43
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[N:6][CH:7]=1.[CH3:9][O-:10].[Na+].ClCCl>CO.O>[Br:1][C:2]1[C:3]([O:10][CH3:9])=[N:4][CH:5]=[N:6][CH:7]=1
Reactant: Clc1ncncc1Br
Reactant: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COc1ncncc1Br
Temperature: 5 °C

Procedure:
Twenty grams (0.13 mol) of 5-bromo-4-chloropyrimidine were dissolved in 100 mL of methanol and the solution was cooled to 5° C. by means of an ice bath. A solution consisting of 29.5 mL of a 25 percent solution of sodium methoxide in methanol and 20 mL of methanol was added with stirring and cooling. The temperature rose to 37° C. and then began to fall. The mixture was stirred for 4 hours at ambient temperature and was then diluted with 200 mL of water (which caused the formation of a white precipitate) and 200 mL of dichloromethane (which dissolved the precipitate). The phases were separated and the organic phase was washed with 150 mL of water, dried over sodium sulfate, and concentrated by evaporation under reduced pressure to obtain 18.2 g (93.8 percent of theory) of the title compound as a white crystalline solid melting at 73°-75° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[C:6]([NH2:15])=[CH:5][CH:4]=1.[C:16]([N:23]1[CH2:31][CH2:30][CH2:29][C@@H:25]([C:26](O)=[O:27])[CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:15][C:26]([C@@H:25]2[CH2:29][CH2:30][CH2:31][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:24]2)=[O:27])=[C:7]([NH:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:8]=1
Reactant: COCCCNc1cc(OC)ccc1N
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COCCCNc1cc(OC)ccc1NC(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 155.8 %

Procedure:
5-Methoxy-N1-(3-methoxypropyl)benzene-1,2-diamine (42B) (1.81 mmol, 380 mg) in DMF (20 mL) was added (R)-(−)-N-Boc-nipecotic acid (2.35 mmol, 541 mg) and N-methylmorpholine (5.43 mmol, 0.60 mL). The reaction mixture was stirred at rt for 5 min and then added HATU (2.72 mmol, 1.03 g) and kept stirring at rt overnight. The reaction mixture was poured into H2O, extracted with EtOAc. The extract was washed with H2O, NaHCO3, brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and purified by flash chromatography (silica gel, EtOAc-hexane: 1:2) to afford (R)-tert-butyl 3-(4-methoxy-2-(3-methoxypropylamino)phenylcarbarnoyl)piperidine-1-carboxylate (42C) (2.82 mmol, 1.19 g, three-step yield: 80.6%). ESI-MS: m/z 422.5 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:8]=1)([O-])=O>CO.[Pd]>[O:12]1[CH2:11][CH2:10][CH:9]([N:7]2[CH:8]=[C:4]([NH2:1])[CH:5]=[N:6]2)[CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1cnn(C2CCOCC2)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cnn(C2CCOCC2)c1
Yield: 95 %

Procedure:
A solution of 4-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole (568 mg, 2.88 mmol, 1 equiv) in methanol was circulated through a H-Cube® Continuous-flow hydrogenation reactor (ThalesNano) fitted with a palladium on carbon catalyst cartridge at 50° C. The collected solution was concentrated in vacuo to afford product, which was used without further purification (458 mg, 95% yield). LCMS (ESI) m/z: 168.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9][CH3:10])=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:19])C=1.CO>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([CH3:10])=[O:19])=[CH:4][N:3]=1
Reactant: CSCc1ccc(Cl)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CS(=O)Cc1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a solution of 2-chloro-5-[(methylthio)methyl]pyridine (A) (7.60 g, 40 mmol) in chloroform (100 mL) cooled in ice-water bath was added a solution of 70-75% m-chloroperbenzoic acid (mCPBA, 10.51 g, ca 44 mmol) in chloroform (110 mL) over a period of 1.5 h under stirring. The stirring was continued for another 1 h at 0° C. Methanol (12 mL) was added to the mixture, which was then bubbled with ammonia gas to precipitate the benzoic acid and the extra mCPBA if any. TLC showed there was small amount of unreacted starting material in the reaction mixture. Most of the ammonium salt was removed by filtration. The filtrate was concentrated before it was loaded onto a Et3N-treated silica gel plug, which was eluted with 10% MeOH in CH2Cl2 to give 7.6 g of 2-chloro-5-[(methylsulfinyl)methyl]pyridine (B) in 92% yield as a colorless oil that turned into a white solid upon drying in vacuo (m.p. 72-74° C.). LC-MS (ELSD): mass calcd for C7H8CINOS [M+H]+ 190.67. Found: 190.21.
Reaction SMILES: [C:1]1([C:7](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C1C=CC=CN=1)C.[F:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[C:38]1[CH:42]=[CH:41][NH:40][N:39]=1>N1C=CC=CC=1>[F:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[C:38]1[CH:42]=[CH:41][N:40]([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:39]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Fc1ccc(-c2cc[nH]n2)c(F)c1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: Fc1ccc(-c2ccn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c(F)c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 43 %

Procedure:
Add triphenylmethylchloride (4.78 g, 17.2 mmol)) and dimethylaminopyridine (0.350 g, 2.86 mmol) to a stirred solution of 3-(2,4-difluorophenyl)-1H-pyrazole (2.58 g, 14.33 mmol) in dry pyridine (30 mL). Stir at 80° C. for about 18 hours. Cool to RT, concentrate and purify (silica gel chromatography, eluting with a gradient of hexane dichloromethane 25:75 to 0:100) to give the desired compound (43%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=O)[C:4]([C:9]2[O:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)=[N:3]1.[CH3:17][N:18]([CH3:20])[NH2:19].C(O)C>C(O)(=O)C.O>[CH3:17][N:18]([CH3:20])[N:19]=[CH:7][C:5]1[C:4]([C:9]2[O:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)=[N:3][N:2]([CH3:1])[CH:6]=1
Reactant: CN(C)N
Reactant: Cn1cc(C=O)c(-c2ccc([N+](=O)[O-])o2)n1
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CN(C)N=Cc1cn(C)nc1-c1ccc([N+](=O)[O-])o1
Yield: 96 %

Procedure:
Stir together 2 g of 1-methyl-3-(5-nitro-2-furyl)pyrazole-4-carboxaldehyde, 0.65 g of N,N-dimethylhydrazine, 2 drops of glacial acetic acid and 30 ml of ethanol for 4 hours at room temperature. Add 30 ml of water dropwise thereto to obtain a 96% yield of 1-methyl-3-(5-nitro-2-furyl)pyrazole-4-carboxaldehyde-dimethylhydrazone [m.p. 164° to 165° C].
Reaction SMILES: P([O:8][CH2:9][CH3:10])(OCC)OCC.N1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:18].C[N:20]([CH:22]=O)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(Cl)(Cl)Cl>[NH2:20][C:22]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:18][CH:12]=[CH:13][CH:14]=2)[C:9]=1[OH:8]
Reactant: Cc1cccc(C)n1
Reactant: CCOP(OCC)OCC
Reactant: CN(C)C=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Product: Nc1ccc2ccccc2c1O
Reaction time: 0.08 h
Yield: 82 %

Procedure:
To dry DMF (60 mL) were added Pd2 dba3-CHCl3 (0.04 g, 0.038 mmol), and triethyl phosphite (0.04 mL, 0.229 mmol), and the solution was aged for 5 minutes at room temperature. The mixture was degassed with 3 nitrogen/vacuum cycles and stirred for 30 minutes until solution became yellow. Then the naphtholamine 145 (0.20 g, 0.80 mmol), CPI 5 (0.52 g, 0.88 mmol), and 2,6-lutidine (0.046 mL, 0.4 mmole) were added to the reaction solution and the resulting mixture was aged for 3 hours. Solvent was removed under reduced pressure and crude residue was purified by flash column chromatography with 97:3 CH2Cl2/MeOH to afford the desired couple product 146 as a yellow oil (0.47 g, 82% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[C:13]2[C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][N:16]=[C:15]3[N:24]([CH3:28])[N:25]=[C:26]([CH3:27])[C:14]=23)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[OH-].[K+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]([CH2:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[C:13]2[C:18]([C:19]([OH:21])=[O:20])=[CH:17][N:16]=[C:15]3[N:24]([CH3:28])[N:25]=[C:26]([CH3:27])[C:14]=23)(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cnc2c(c(C)nn2C)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(S(=O)(=O)N(Cc2cccnc2)c2c(C(=O)O)cnc3c2c(C)nn3C)cc1
Yield: 77.6 %

Procedure:
A mixture of 1.34 g (2.7 mmol) of ethyl 4-[(4-methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-carboxylate, 2.97 ml of 1N potassium hydroxide in 7.8 ml of ethanol and 4.83 ml of water was refluxed for 20 hr. Another 0.54 ml of 1N potassium hydroxide was added and the mixture refluxed 4 hrs. The solvent was removed under vacuum and toluene added and removed under vacuum. The residue was dissolved in water (20ml) and extracted with ethyl acetate. The aqueous layer was acidified with 2 N citric acid and the precipitated solid filtered off and washed with water. The solid was dried under vacuum to give 0.98 g of solid, mp 256-258° C.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([O:21][C:22]([C:24]1([C:37](C)(C)[O:38][SiH2]C(C)(C)C)[CH2:28][CH2:27][N:26]([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1)=[O:23])[CH3:20]>>[CH2:19]([O:21][C:22]([C:24]1([CH2:37][OH:38])[CH2:28][CH2:27][N:26]([CH2:29][C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[CH2:25]1)=[O:23])[CH3:20]
Reactant: CCOC(=O)C1(C(C)(C)O[SiH2]C(C)(C)C)CCN(CC(=O)OC(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CCOC(=O)C1(CO)CCN(CC(=O)OC(C)(C)C)C1
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
Tetrabutylammonium fluoride (1.8 ml, 1M in THF) was added to 1-tert-butoxycarbonylmethyl-3-(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidine-3-carboxylic acid ethyl ester (726 mg, 1.8 mmol). The reaction solution was stirred for half hour and purified by column chromatography using solution of ethyl acetate in hexanes (1:1), then ethyl acetate to provide the title product (350 mg, 68%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C@H:17]3[CH2:21][CH2:20][C@@:19]4([CH2:25][CH2:24][N:23]([CH3:26])[C:22]4=[O:27])[NH:18]3)[CH:12]=1)[NH:7][N:6]=[CH:5]2.N(C(OC(C)(C)C)=O)=NC(O[C:33](C)(C)[CH3:34])=O.C(O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:33]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([C@H:17]4[CH2:21][CH2:20][C@@:19]5([CH2:25][CH2:24][N:23]([CH3:26])[C:22]5=[O:27])[NH:18]4)[CH:12]=3)[CH:9]=2)[CH:5]=[N:6]1)[CH3:34]
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Reactant: CN1CC[C@@]2(CC[C@H](c3cc(-c4cc5[nH]ncc5cc4F)ccn3)N2)C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCO
Product: CCn1ncc2cc(F)c(-c3ccnc([C@H]4CC[C@@]5(CCN(C)C5=O)N4)c3)cc21
Temperature: 800 °C

Procedure:
To a Smith microwave vial was added (2R,5S)-2-[4-(5-fluoro-1H-indazol-6-yl)-2-pyridyl]-7-methyl-1,7-diazaspiro[4.4]nonan-6-one (which may be prepared as described in Example 186) (40 mg, 0.1100 mmol), di-tert-butyl azodicarboxylate (126.03 mg, 0.5500 mmol), ethanol (0.03 mL, 0.5500 mmol) and triphenyl phosphine (143.56 mg, 0.5500 mmol) in THF (1 mL). The reaction mixture was heated by microwave at 800° C. for 45 minutes. The reaction mixture was cooled and eluted on an SCX-2 cartrige (0.5 g) and washed with DCM followed by MeOH. The desired product was eluted off the cartridge with ammonia in MeOH (0.2M). Evaporation of solvents gave a colourless oil. The crude residue was purified by silica gel chromatography (silica 10 g) eluting with methanol (containing 10% 0.88 ammonia) in ethyl acetate (0-80%), to give the products as a mixture of isomers. These were separated by HPLC using a ChiralPak IA column and eluting with ethanol/n-heptane (20%:80%) to give (2R,5S)-2-[4-(1-ethyl-5-fluoro-indazol-6-yl)-2-pyridyl]-7-methyl-1,7-diazaspiro[4.4]nonan-6-one as the major isomer;
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH2:8]([Cl:11])[CH:9]=[CH2:10]>>[Cl-:11].[CH2:8]([N+:2]1([CH3:1])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1)[CH:9]=[CH2:10]
Reactant: CN1CCOCC1
Reactant: C=CCCl
Product: C=CC[N+]1(C)CCOCC1
Product: [Cl-]

Procedure:
20.2 grams of N-methyl morpholine was added to 50 grams of allyl chloride. A crystalline solid separated within 2 hours. After 18 days at 25° C. the solid was separated, washed with ethyl acetate, and dried. The product melted at 175°-185° C. with decomposition and contained 100.5% of the theoretical chloride content.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:31])=[C:6]([C:8]2[CH:13]=[C:12]([NH:14][C:15]3[C:16]4[C:17](=[CH:21][N:22]([CH2:24][CH:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)[N:23]=4)[N:18]=[CH:19][CH:20]=3)[CH:11]=[CH:10][N:9]=2)[CH:7]=1.C(N(CC)C(C)C)(C)C.[CH2:41]([N:43]=[C:44]=[O:45])[CH3:42]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:31])=[C:6]([C:8]2[CH:13]=[C:12]([NH:14][C:15]3[C:16]4[C:17](=[CH:21][N:22]([CH2:24][CH:25]5[CH2:30][CH2:29][N:28]([C:44]([NH:43][CH2:41][CH3:42])=[O:45])[CH2:27][CH2:26]5)[N:23]=4)[N:18]=[CH:19][CH:20]=3)[CH:11]=[CH:10][N:9]=2)[CH:7]=1
Reactant: Fc1ccc(Cl)cc1-c1cc(Nc2ccnc3cn(CC4CCNCC4)nc23)ccn1
Reactant: CCN=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCNC(=O)N1CCC(Cn2cc3nccc(Nc4ccnc(-c5cc(Cl)ccc5F)c4)c3n2)CC1
Temperature: 25 °C

Procedure:
N-(2-(5-Chloro-2-fluorophenyl)pyridin-4-yl)-2-(piperidin-4-ylmethyl)-2H-pyrazolo[4,3-b]pyridin-7-amine (20 mg, 0.046 mmol) and N,N-diisopropylethylamine (7.97 μl, 0.046 mmol) were combined in dichloromethane (1.5 mL) followed by ethyl isocyanate (3.62 μl, 0.046 mmol). The reaction was then stirred at room temperature over night. The solvent was then evaporated to give a residue which was partitioned between EtOAc and 1N NaOH. The organic layer was washed with water and then brine, dried over Na2SO4, filtered, concentrated, and evaporated in-vacuo to give the title compound as a light yellow solid. MS [M+H] found 507.0.