Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[CH:22][N:21]=[C:20]([NH:24][C:25]2[CH:34]=[C:33]([CH3:35])[C:28]3[NH:29][C:30](=[O:32])[O:31][C:27]=3[CH:26]=2)[CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1.CN(C=O)C>[CH3:35][C:33]1[C:28]2[NH:29][C:30](=[O:32])[O:31][C:27]=2[CH:26]=[C:25]([NH:24][C:20]2[N:21]=[CH:22][N:23]=[C:18]([N:1]3[CH2:2][CH2:3][CH:4]([N:7]4[C:15]5[C:10](=[N:11][CH:12]=[CH:13][CH:14]=5)[NH:9][C:8]4=[O:16])[CH2:5][CH2:6]3)[CH:19]=2)[CH:34]=1
Reactant: Cc1cc(Nc2cc(Cl)ncn2)cc2oc(=O)[nH]c12
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Product: Cc1cc(Nc2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)cc2oc(=O)[nH]c12
Temperature: 25 °C

Procedure:
276 mg (1.26 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, 350 mg (0.987 mmol) 6-(6-chloro-pyrimidin-4-ylamino)-4-methyl-3H-benzoxazol-2-one and 350 mg (2.53 mmol) potassium carbonate in 2 mL NMP were stirred for 2 h at 130° C. After cooling to RT the reaction mixture was diluted with DMF and purified by preparative HPLC. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]([CH2:17][CH2:18][C:19]([CH3:34])([S:30]([CH3:33])(=[O:32])=[O:31])[C:20]([NH:22][O:23]C3CCCCO3)=[O:21])[C:13](=[O:35])[CH:12]=2)=[CH:7][CH:6]=1.Cl>O1CCOCC1.CO>[OH:23][NH:22][C:20](=[O:21])[C:19]([CH3:34])([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:18][CH2:17][N:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][CH2:2][OH:1])=[CH:6][CH:7]=2)=[CH:12][C:13]1=[O:35]
Reactant: CC(CCn1ccc(-c2ccc(CCCO)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(CCn1ccc(-c2ccc(CCCO)cc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
To 4-{4-[4-(3-hydroxypropyl)phenyl]-2-oxopyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (213 mg, 0.420 mmol) was added 4 N hydrogen chloride in dioxane (5.0 mL) and methanol (0.50 mL). The reaction was stirred for 30 minutes and then evaporated to dryness. The residue was dissolved in minimal dichloromethane (2.0 mL) and diluted with ether to produce a precipitate. The suspension was stirred overnight at room temperature. The resulting solid was allowed to settle and the liquid was decanted off. The solid was rinsed twice with ether and dried on a vacuum pump to give the title compound as a white solid (164 mg, 92.4%). 1H NMR (400 MHz, CD3OD, δ ppm 1.72 (s, 3H), 1.83-1.91 (m, 2H), 2.41 (ddd, J=13.4, 10.9, 5.4 Hz, 1H), 2.66 (ddd, J=13.6, 10.8, 5.4 Hz, 1H), 2.76 (m, 2H), 3.10 (s, 3H), 3.59 (t, J=6.4 Hz, 2H), 4.05 (ddd, J=12.5, 10.5, 5.2 Hz, 1H), 4.38 (ddd, J=12.9, 10.7, 5.0 Hz, 1H), 6.95 (d, J=1.8 Hz, 1H), 7.00 (m, 1H), 7.38 (br d, J=8.3 Hz, 2H), 7.66 (br d, J=8.3 Hz, 2H), 7.87 (d, J=7.1 Hz, 1H). LCMS: 423.3 (M+1).
Reaction SMILES: C(O)C.[Na].[CH2:5]([OH:17])[C@H:6]([OH:16])[C@@H:7](O)[C@H:8]([OH:14])[C:9]([C:11]([OH:13])=[O:12])=[O:10].Cl>CC(C)=O>[O:12]=[C:11]1[O:13][C@H:7]([C@H:6]([CH2:5][OH:17])[OH:16])[C:8]([OH:14])=[C:9]1[OH:10]
Reactant: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: CC(C)=O
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O

Procedure:
JP-A 58-177986 describes a process which comprises the addition of ethanol and acetone to the sodium salt of 2-keto-L-gulonic acid, neutralization with hydrochloric acid, the removal of the precipitated sodium chloride by filtration and then the maintenance of the reaction mixture at temperatures in the range from 25° C. to 75° C., by means of which L-ascorbic acid is obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5](=[O:23])[N:6]([CH2:8][CH2:9][O:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=2)[N:7]=1.Cl.[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+].ClCCl>COCCOC>[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]2[CH:3]=[CH:4][C:5](=[O:23])[N:6]([CH2:8][CH2:9][O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=4)[N:14]=[CH:13][CH:12]=3)[N:7]=2)=[CH:29][CH:28]=1
Reactant: COc1ccc2c(OCCn3nc(Cl)ccc3=O)ccnc2c1
Reactant: NCc1ccc(B(O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: COc1ccc2c(OCCn3nc(-c4ccc(CN)cc4)ccc3=O)ccnc2c1
Temperature: 85 °C

Procedure:
A suspension of 6-chloro-2-(2-(7-methoxyquinolin-4-yloxy)ethyl)pyridazin-3(2H)-one (1250 mg, 3768 μmol), (4-aminomethylphenyl)boronic acid, hydrochloride (1412 mg, 7536 μmol), Na2CO3 (7536 μL, 15071 μmol) [2M], and [1,1′-bis(diphenylphosphino)ferrocene]dichloride palladium(II) complex with dichloromethane (276 mg, 377 μmol) in DME (2 mL) was sparged with argon for 5 minutes then heated to 85° C. for 4 hours. The reaction was then partitioned between DCM (50 mL) and 1 M NaOH (20 mL). The organic was dried over MgSO4, concentrated onto dry silica (10 g) then purified on silica (40 g) eluting with 0>5% MeOH/DCM. The product was isolated as an off white solid from ACN. MS (ESI pos. ion) m/z: 403 (MH+); calc'd for C23H22N4O3: 402. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.76 (s, 2 H) 3.87 (s, 3 H) 4.67 (s, 4 H) 6.95 (d, J=5.28 Hz, 1 H) 7.01 (dd, J=9.00, 2.54 Hz, 1 H) 7.08 (d, J=9.78 Hz, 1 H) 7.27 (d, J=2.35 Hz, 1 H) 7.41 (d, J=8.22 Hz, 2 H) 7.78 (d, J=8.41 Hz, 2 H) 7.90 (d, J=9.19 Hz, 1 H) 8.03 (d, J=9.78 Hz, 1 H) 8.62 (d, J=5.28 Hz, 1 H).
Reaction SMILES: [N:1]1([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([OH:32])([C:22]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]([CH3:31])[CH:23]=4)[C:18]([F:21])([F:20])[F:19])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[O:7])C=CN=[CH:2]1.[CH:33]1(N)C[CH2:34]1>N1C=CC=CC=1.CCOCC>[CH:2]1([NH:1][C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([OH:32])([C:22]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]([CH3:31])[CH:23]=4)[C:18]([F:20])([F:21])[F:19])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[O:7])[CH2:34][CH2:33]1
Reactant: Cn1cc(C(O)(c2ccc3c(cnn3C(=O)n3ccnc3)c2)C(F)(F)F)c2ccccc21
Reactant: NC1CC1
Solvent: CCOCC
Solvent: c1ccncc1
Product: Cn1cc(C(O)(c2ccc3c(cnn3C(=O)NC3CC3)c2)C(F)(F)F)c2ccccc21
Reaction time: 8 h

Procedure:
To a solution of imidazol-1-yl-{5-[2,2,2-trifluoro-1-hydroxy-1-(1-methyl-1H-indol-3-yl)ethyl]indazol-1-yl}-methanone (0.145 mmol) in 1 mL of pyridine was added cyclopropylamine (1.45 mmol). The mixture was stirred overnight, diluted with ether, washed with water and brine and dried over magnesium sulfate. The volatiles were removed in vacuo and the residue purified by flash silica gel chromatography using 33% ethyl acetate in hexanes. The product-rich fractions were concentrated in vacuo to provide the title compound, m.p. 116° C.-118° C.
Reaction SMILES: [CH2:1]([CH:10]1[CH2:14][CH2:13][CH2:12][NH:11]1)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:15]1([C:19](Cl)=[O:20])[CH2:18][CH2:17]C1>>[CH2:1]([CH:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:19]([CH:15]1[CH2:18][CH2:17]1)=[O:20])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C(=Cc1ccccc1)CC1CCCN1
Reactant: O=C(Cl)C1CCC1
Product: O=C(C1CC1)N1CCCC1C/C=C/c1ccccc1

Procedure:
Stage a) According to the method of Example 1.1, Stage a), from 2-(cinnamyl)pyrrolidine and cyclobutanecarboxylic acid chloride there is obtained, with a yield of 95%, 2-cinnamyl-1-cyclobutanecarbonylpyrrolidine (formula II; Ar=C6H5, m=1, n=1, R=cyclobutyl), which is introduced in the next stage without further treatment.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([S:14]([CH2:17][CH2:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])(=[O:16])=[O:15])[CH:5]=1.O.O.[OH-].[Li+].Cl>O1CCOCC1>[C:23]([O:22][C:20]([CH2:19][CH2:18][CH2:17][S:14]([C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([C:10]([F:13])([F:11])[F:12])[CH:7]=1)[C:3]([OH:27])=[O:2])(=[O:15])=[O:16])=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: COC(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)CCCC(=O)OC(C)(C)C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)CCCS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3-(3-tert-butoxycarbonyl-propane-1-sulfonyl)-5-trifluoromethyl-benzoic acid methyl ester (100 mg, 0.244 mmol) in dioxane (1 mL) was added water (1 mL) and lithiumhydroxide monohydrate (11.2 mg, 0.268 mmol) and the resulting suspension stirred at room temperature for 4 hours. The reaction mixture was acidified with 1M aqueous hydrochloric acid and extracted with EtOAc (30 mL) and the layers were separated. The aqueous layer was extracted a second time with EtOAc (30 mL). The organic layers were washed with brine (30 mL), dried over magnesium sulfate, filtered and concentrated under vacuum. Colorless solid (76 mg, 78.7%). MS (ESI−): m/z=395.08 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([OH:13])=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:35][CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH:37]1[NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:8][C:6]1[CH:5]=[C:4]([NH:9][CH2:10][C:11]([N:39]2[CH2:40][CH2:41][CH:36]([CH3:35])[CH:37]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:38]2)=[O:13])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: O=C(O)CNc1cc(Cl)cc(Cl)c1
Reactant: CC1CCNCC1NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1CCN(C(=O)CNc2cc(Cl)cc(Cl)c2)CC1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.7 %

Procedure:
To a solution of 2-(3,5-dichlorophenylamino)acetic acid (153 mg, 0.69 mmol) in DMF (5 mL) was added HOBt (141 mg, 1.0 mmol), EDCI (201 mg, 1.0 mmol), tert-butyl 4-methylpiperidin-3-ylcarbamate (150 mg, 0.69 mmol), and DIEA (0.18 mL, 1.3 mmol) at 0° C. Then the reaction mixture was stirred at rt for 5 h, partitioned between EtOAc and water. The organic phase was separated and washed with brine, and concentrated in vacuo to yield the crude product, which was purified by column chromatography using 0-2% MeOH: DCM solvent mixture to yield the titled intermediate (160 mg, 54%) as a thick liquid. 1H NMR (400 MHz, CDCl3): δ 6.92 (s, 1H), 6.49 (s, 1H), 6.38 (s, 1H), 6.29 (s, 1H), 5.22-5.15 (m, 1H), 4.65-4.56 (m, 1H), 4.35-4.16 (m, 2H), 3.25-2.89 (m, 2H), 2.85-2.69 (m, 2H), 1.82-1.75 (m, 2H), 1.69-1.45 (m, 1H), 1.22 and 1.14 (2s, 9H), 1.05 and 0.95 (2d, J=6.8 Hz, 3H). LC-MS: m/z [M+1]=416.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[CH3:24][C:25]1[N:26]2[CH:35]=[CH:34][N:33]=[C:27]2[S:28][C:29]=1[C:30](O)=[O:31]>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:30]([C:29]3[S:28][C:27]4=[N:33][CH:34]=[CH:35][N:26]4[C:25]=3[CH3:24])=[O:31])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: Cc1c(C(=O)O)sc2nccn12
Product: Cc1c(C(=O)NC[C@@H]2C[C@@H]3C[C@@H]3N2C(=O)c2nc(N)sc2-c2cccc(F)c2)sc2nccn12

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with 3-methyl-imidazo[2,1-b]thiazole-2-carboxylic acid. LC-MS (basic): tR=0.74 min; [M+H]+=497.2.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[CH3:22][O:23][C:24]([NH:26][C@H:27]1[C@H:31]([CH2:32][CH3:33])[CH2:30][NH:29][CH2:28]1)=[O:25].C(N(C(C)C)CC)(C)C>C(#N)C>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:29]2[CH2:30][C@@H:31]([CH2:32][CH3:33])[C@H:27]([NH:26][C:24]([O:23][CH3:22])=[O:25])[CH2:28]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CC[C@@H]1CNC[C@H]1NC(=O)OC
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC[C@@H]1CN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C[C@H]1NC(=O)OC
Yield: 56 %

Procedure:
A mixture of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.36 g), trans-3-methoxycarbonylamino-4-ethyl pyrrolidine (0.94 g), diisopropylethylamine (0.88 g), and acetonitrile (20 ml) was refluxed for 15 hours. The precipitated crystals wee collected by filtration, and dried to give 5-amino-1-cyclopropyl-7-(trans-3-methoxycarbonylamino-4-ethyl-1-pyrrolidinyl)-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.15 g), recrystallized from chloroform-ethanol, m.p. 231°-232° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2].[OH:15][CH:16]([CH2:24][OH:25])[CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([N:21]2[CH2:20][CH2:19][N:18]([CH2:17][CH:16]([OH:15])[CH2:24][OH:25])[CH2:23][CH2:22]2)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: OCC(O)CN1CCNCC1
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(SC)nc1N1CCN(CC(O)CO)CC1

Procedure:
Grams 4.6 of 2-methylthio-4-chloropyrimidine-5-carboxylic acid ethyl ester and 6.4 g of 1-(2,3-dihydroxypropyl)piperazine in 50 ml dioxane were refluxed for 30 minutes. The mixture was cooled and settled, then the solvent was evaporated and the dried residue purified on column eluting with chloroform:methanol (9:1). Grams 4.8 of 2-methylthio-4-[4-(2,3-dihydroxypropyl)piperazin-1-yl]pyrimidine-5-carboxylic acid ethyl ester as an oil, were obtained.
Reaction SMILES: [NH:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[CH2:4][CH2:3][C:2]1=[O:12].[C:13]([O:17][C:18]([NH:20][NH2:21])=[O:19])([CH3:16])([CH3:15])[CH3:14].C([BH3-])#N.[Na+]>CC(O)=O.O.[OH-].[Na+]>[C:13]([O:17][C:18]([NH:20][NH:21][CH:8]1[CH2:9][CH2:10][C:5]2([NH:1][C:2](=[O:12])[CH2:3][CH2:4]2)[CH2:6][CH2:7]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C1CCC2(CC1)CCC(=O)N2
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)NNC1CCC2(CCC(=O)N2)CC1
Temperature: 25 °C
Yield: 150.8 %

Procedure:
A solution of 1-Aza-spiro[4.5]decane-2,8-dione (Chembridge corporation, 800 mg; 4.78 mmol; 1.0 eq.) and hydrazinecarboxylic acid tert-butyl ester (309 mg; 2.34 mmol; 1.1 eq.) in AcOH (5 mL) was stirred at RT for 5 min. Sodium cyanoborohydride (133 mg; 2.13 mmol; 1.0 eq.) was then added and the reaction mixture was stirred O/N at RT. It was then diluted with water and basified to pH 9 by addition of a 5N solution of NaOH. During the addition, the reaction mixture was maintained at 20° C. by addition of crushed ice. It was extracted with DCM and the combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated to give the title compound as a yellow oil (1.0 g, 98%) which was used without further purification.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[N+:18]([O-])=O)[N:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+]>CO.[Pd]>[NH2:18][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[CH:16]=[CH:17][C:8]([CH2:7][N:1]1[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1)=[N:9]2
Reactant: O=[N+]([O-])c1cccc2nc(CN3CCOCC3)ccc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Nc1cccc2nc(CN3CCOCC3)ccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
190 mg (0.7 mmol) of 2-(morpholin-4-ylmethyl)-5-nitroquinoline is dissolved in 10 ml of methanol. After the addition of 19 mg of palladium on carbon and 19 mg of potassium carbonate, the reaction mixture is allowed to stir for 4 hours at room temperature under hydrogen atmosphere. It is then filtered on Celite and washed with ethyl acetate. After removal of the solvent in a vacuum and chromatography on silica gel with hexane-ethyl acetate (0–100%) as well as with ethyl acetate-methanol (0–100%), 134 mg (79% of theory) of the product is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:35]([S:42](Cl)(=[O:44])=[O:43])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[S:42]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)(=[O:44])=[O:43])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N(Cc3ccc4ccc(C#N)cc4c3)S(=O)(=O)Cc3ccccc3)cc2)CC1

Procedure:
Starting compound: 7-[[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile, benzylsulfonyl chloride.
Reaction SMILES: [N:1]1([C:6]([NH:8][C@H:9]([C:17]([O:19]C)=[O:18])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[N:1]1([C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)N1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)[C@H](Cc1ccccc1)NC(=O)N1CCCC1
Reaction time: 4 h

Procedure:
A mixture of the methyl ester product from part (a) (1.187 g., 4.3 mmole), aqueous 1N sodium hydroxide solution (5.15 ml., 5.15 mmole), and methanol (17 ml.) is stirred at 25° for 4 hours, after which it is concentrated in vacuo. 1N Hydrochloric acid and ethyl acetate are added to the residue, and the mixture is extracted with ethyl acetate. The extract is dried (MgSO4) and concentrated to give N-(1-pyrrolidinylcarbonyl)-L-phenylalanine; [α]D =12.8° (c=1, methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[C:16](Cl)[N:15]=[C:14]([NH:19][CH3:20])[N:13]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl.CN.[CH2:24]([N:26](CC)CC)C>CCO>[CH3:20][NH:19][C:14]1[N:13]=[C:12]([NH:11][S:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)(=[O:10])=[O:9])[CH:17]=[C:16]([NH:26][CH3:24])[N:15]=1
Reactant: CNc1nc(Cl)cc(NS(=O)(=O)c2cccc(Cl)c2)n1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: CCO
Product: CNc1cc(NS(=O)(=O)c2cccc(Cl)c2)nc(NC)n1
Temperature: 145 °C
Reaction time: 17 h
Yield: 40.7 %

Procedure:
0.10 g (0.00030 mol) of 3-chloro-N-(6-chloro-2-methylamino-pyrimidin-4-yl)-benzenesulfonamide was dissolved in 5 ml of EtOH, treated with 0.27 g (0.004 mol) of methylamine hydrochloride and 1 ml (0.007 mol) of triethylamine and stirred in an autoclave at 145° C. for 17 hours. The entire reaction mixture was partitioned in ethyl acetate/water and extracted. The residue was recrystallized from MeOH. There was obtained 0.04 g (41%) of N-(2,6-bis-methylamino-pyrimidin-4-yl)-3-chloro-benzenesulfonamide as white crystals; m.p. 167-168° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[N-:10]([C:13]#[N:14])[C:11]#[N:12].[Na+]>>[C:11]([N:10]=[C:13]([NH2:14])[NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([O:2][CH3:1])[CH:4]=1)#[N:12]
Reactant: N#C[N-]C#N
Reactant: COc1cccc(N)c1
Agent: [Na+]
Product: COc1cccc(NC(N)=NC#N)c1

Procedure:
3-Methoxyaniline and sodium dicyanamide were procesed as described in Example 71A to provide the desired compound.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][C:7]1[C:8]([C@@H:14]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:15]([CH3:17])[CH3:16])=[N:9][CH:10]=[C:11]([Cl:13])[CH:12]=1)(=[O:4])=[O:3].[C:26](OC(=O)N[C@H](C1C(C(O)C)=CC(Cl)=CN=1)C(C)C)(C)(C)C>>[CH3:1][S:2]([O:5][CH:6]([C:7]1[C:8]([C@@H:14]([NH:18][C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH:15]([CH3:17])[CH3:16])=[N:9][CH:10]=[C:11]([Cl:13])[CH:12]=1)[CH3:26])(=[O:3])=[O:4]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)c1ncc(Cl)cc1COS(C)(=O)=O
Reactant: CC(O)c1cc(Cl)cnc1[C@@H](NC(=O)OC(C)(C)C)C(C)C
Product: CC(OS(C)(=O)=O)c1cc(Cl)cnc1[C@@H](NC(=O)OC(C)(C)C)C(C)C
Reaction time: 0.02 h

Procedure:
Procedure same as that for (S)-(2-(1-((tert-butoxycarbonyl)amino)-2-methylpropyl)-5-chloropyridin-3-yl)methyl methanesulfonate, using tert-butyl((1S)-1-(5-chloro-3-(1-hydroxyethyl)pyridin-2-yl)-2-methylpropyl)carbamate as a starting material. LC-MS tR=1.03 min in 1 min chromatography, MS (ESI) m/z 407.4 [M+H]+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[Si:12]([C:16]#[CH:17])([CH3:15])([CH3:14])[CH3:13]>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:13][Si:12]([C:16]#[C:17][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2)([CH3:15])[CH3:14]
Reactant: C#C[Si](C)(C)C
Reactant: O=C1Cc2cc(I)ccc2N1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1ccc2c(c1)CC(=O)N2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 5-iodoindolin-2-one (518 mg, 2 mmol), TEA (3 ml) and CuI (38 mg) in DMF (3 ml) was added to PdCl2(PPh3)2 (70 mg). The mixture was cooled to 0° C. and a solution of TMS-acetylene (1 ml). The mixture was maintained same temperature for 3 h, then warmed to rt. After stirring for overnight, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography to give 5-((trimethylsilyl)ethynyl)indolin-2-one (451 mg).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:8]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:7]([O:20][CH:21]([CH3:23])[CH3:22])[CH:6]=2.C1C(=O)N([Br:41])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:41][CH2:1][C:2]1[C:3]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:8]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:7]([O:20][CH:21]([CH3:23])[CH3:22])[CH:6]=2
Reactant: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2cc(OC(C)C)c(S(C)(=O)=O)cc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(CBr)c(-c2cccc(C(F)(F)F)c2)nc2cc(OC(C)C)c(S(C)(=O)=O)cc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 3-methyl-7-[(1-methylethyl)oxy]-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (2.97 g, 6.17 mmol), NBS (1.427 g, 8.02 mmol) and diphenylperoxyanhydride (0.149 g, 0.617 mmol) in carbon tetrachloride (30 mL) was heated to 100° C. and stirred overnight. The mixture was cooled to room temperature, and the solvent was removed under reduced pressure to give methyl 3-(bromomethyl)-7-[(1-methylethyl)oxy]-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate. This material was used without further purification. MS (m/z) 562.0 (M+H+).