Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:14]1[CH2:19][CH2:18][CH2:17][N:16]([C:20](=[O:27])[CH2:21][O:22][CH2:23][C:24]([OH:26])=[O:25])[CH2:15]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.[CH3:28]S(O)(=O)=O>CO>[CH:1]([CH:14]1[CH2:19][CH2:18][CH2:17][N:16]([C:20](=[O:27])[CH2:21][O:22][CH2:23][C:24]([O:26][CH3:28])=[O:25])[CH2:15]1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)COCC(=O)N1CCCC(C(c2ccccc2)c2ccccc2)C1
Reactant: CS(=O)(=O)O
Solvent: CO
Product: COC(=O)COCC(=O)N1CCCC(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In a manner similar to that described in Example XXVI, 3.63 grams (10 millimoles) of [2-(3-benzhydrylpiperidino)-2-oxoethoxy]acetic acid (Example VIII), 150 milliliters of methanol and 300 milligrams of methanesulfonic acid are stirred together for about six hours at ambient temperature. Thereafter, the methanol is evaporated, the residue dissolved in ether, the ether solution washed, dried and the solvent evaporated to obtain a methyl [2-(3-benzhydrylpiperidino)-2-oxoethoxy]acetate product as residue.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14]([NH2:19])[CH:13]=2.[F:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][C@H:31]2[C:36](O)=[O:37])(=[O:29])=[O:28])=[CH:23][CH:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14]([NH:19][C:36]([C@@H:31]1[CH2:32][CH2:33][CH2:34][CH2:35][N:30]1[S:27]([C:24]1[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=1)(=[O:29])=[O:28])=[O:37])[CH:13]=2
Reactant: O=C(O)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1
Reactant: COc1nccc(Cl)c1-c1cc2ccc(N)cc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COc1nccc(Cl)c1-c1cc2ccc(NC(=O)[C@@H]3CCCCN3S(=O)(=O)c3ccc(F)cc3)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of 2-(4-chloro-2-methoxy-pyridin-3-yl)-1H-indol-6-ylamine (35 mg, 0.13 mmol) in CH2Cl2 (5 mL) was added (S)-1-(4-fluoro-benzenesulfonyl)-piperidine-2-carboxylic acid (37 mg, 0.13 mmol) and HATU (49 mg, 0.13 mol). The solution was stirred at 25° C. for 1 h and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown solid. Flash chromatography (70/30 hexanes/ethyl acetate) afforded (S)-1-(4-fluoro-benzenesulfonyl)-piperidine-2-carboxylic acid[2-(4-chloro-2-methoxy-pyridin-3-yl)-1H-indol-6-yl]-amide (60 mg, 86%) as a white solid. MH+ 543.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[NH2:12][C:13]1[CH:14]=[C:15]([CH:19]2[CH2:28][C:27]([CH3:30])([CH3:29])[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:31]#[N:32])[CH:25]=3)[NH:20]2)[CH:16]=[CH:17][CH:18]=1.N1C=CC=CC=1>ClCCl>[C:31]([C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]([C:15]1[CH:14]=[C:13]([NH:12][S:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])(=[O:10])=[O:9])[CH:18]=[CH:17][CH:16]=1)[CH2:28][C:27]2([CH3:30])[CH3:29])#[N:32]
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C#N)cc21
Reactant: O=S(=O)(Cl)c1ccccc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)CC(c2cccc(NS(=O)(=O)c3ccccc3F)c2)Nc2ccc(C#N)cc21
Reaction time: 8 h
Yield: 42.5 %

Procedure:
To a round bottom flask, 2-fluoro-benzenesulfonyl chloride (116 mg, 0.59 mmol) was added dropwise a mixture of 2-(3-amino-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (150 mg, 0.54 mmol) and pyridine (65 mg, 0.81 mmol) in dichloromethane (5 mL). The resultant mixture was allowed to stir overnight. The reaction mixture was washed by water, dried over magnesium sulfate. It was filtered and concentrated to provide the crude product. It was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=5:1) to afford N-[3-(6-cyano-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-2-fluoro-benzenesulfonamide as off-white solid (100 mg, yield: 42.4%). MS (ESI+APCI) M+1=436.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=N)[O:10][CH2:11][CH3:12])[CH:5]=[CH:6][C:7]=1[SH:8].O.S(=O)(=O)(O)[OH:16]>C(O)C.[Zn]>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[SH:8])[C:9]([O:10][CH2:11][CH3:12])=[O:16]
Reactant: O=S(=O)(O)O
Reactant: CCOC(=N)c1ccc(S)c(Br)c1
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ccc(S)c(Br)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Ethyl 3-bromo-4-mercaptobenzenecarboximidate (3.00 g) was dissolved in ethanol (100 ml), and water (10 ml) and then concentrated sulfuric acid (10 ml) were added dropwise thereto at 0° C. and stirred overnight at room temperature. Zinc (1 g) was added to the reaction system and the resulting mixture was stirred at room temperature for 2 hours to induce the production of a monomer. After the zinc powder was removed by filtration through Celite, the ethanol was distilled off under reduced pressure, followed by extraction with ethyl acetate, and the organic layer was washed with water (×4). The organic layer was dried over anhydrous sodium sulfate and then concentrated to obtain ethyl 3-bromo-4-mercaptobenzoate (2.58 g) as a light-yellow solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@@H:5]([CH3:7])[NH2:6].C(N(CC)CC)C.Cl[C:17]1[C:18]2[N:26]([CH3:27])[N:25]=[C:24]([CH3:28])[C:19]=2[N:20]=[C:21]([CH3:23])[N:22]=1>CN(C)C=O>[CH3:27][N:26]1[C:18]2[C:17]([NH:6][C@H:5]([CH3:7])[C:4]([O:3][CH3:2])=[O:8])=[N:22][C:21]([CH3:23])=[N:20][C:19]=2[C:24]([CH3:28])=[N:25]1
Reactant: COC(=O)[C@@H](C)N
Reactant: Cc1nc(Cl)c2c(n1)c(C)nn2C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](C)Nc1nc(C)nc2c(C)nn(C)c12
Reaction time: 0.25 h

Procedure:
D-alanine methyl ester hydrochloride (6 g, 0.043 mol) is dissolved in 30 ml of cold (5° C.) dimethylformamide and 7 ml (0.05 mol) of triethylamine is added dropwise. After stirring 15 minutes, 6 g of triethylamine hydrochloride is removed by filtering. To the filtrate is added 7 g (0.035 mol) of 7-chloro-1,3,5-trimethyl-1H-pyrazolo-[4,3-d]pyrimidine and another 6 ml of triethylamine. The mixture is stirred at 50°-55° C. for 60 hours and evaporated in vacuo. The residue is dissolved in 100 ml of methylene dichloride, washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated in vacuo to give 7.6 g of slightly impure (R)-2-[1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl]aminopropionic acid, methyl ester, mp 68°-70° C. from ether as a dihydrate.
Reaction SMILES: [CH3:1][O:2][CH:3]=[CH:4][C:5]1[N:10]=[C:9]2[CH2:11][O:12][C:13](=[O:14])[C:8]2=[CH:7][CH:6]=1.[CH3:15][OH:16]>S(=O)(=O)(O)O>[CH3:1][O:2][CH:3]([O:16][CH3:15])[CH2:4][C:5]1[N:10]=[C:9]2[CH2:11][O:12][C:13](=[O:14])[C:8]2=[CH:7][CH:6]=1
Reactant: CO
Reactant: COC=Cc1ccc2c(n1)COC2=O
Agent: O=S(=O)(O)O
Product: COC(Cc1ccc2c(n1)COC2=O)OC
Temperature: 70 °C
Yield: 83 %

Procedure:
To a solution of 2-(2-methoxy-vinyl)-7H-furo[3,4-b]pyridin-5-one (108 mg, 0.57 mmol) in anhydrous MeOH (10 mL) is added three drops of concentrated sulfuric acid. The reaction solution is stirred and heated at 70° C. for 18 h at which time the starting material is consumed. The reaction mixture is then diluted with EtOAc (100 mL), and then washed with saturated aqueous NaHCO3 (2×75 mL). The organic solution is dried (Na2SO4) and concentrated to give the title compound as a brown oil (104 mg, 83%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:30]([F:33])([F:32])[F:31])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:34][NH2:35]>>[Cl:29][C:24]1[CH:23]=[C:22]([C:21]2[C:15]3[O:14][CH:13]([CH2:12][NH:35][CH3:34])[CH2:17][C:16]=3[CH:18]=[C:19]([C:30]([F:33])([F:32])[F:31])[CH:20]=2)[CH:27]=[CH:26][C:25]=1[F:28]
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C(F)(F)F)cc(-c4ccc(F)c(Cl)c4)c3O2)cc1
Product: CNCC1Cc2cc(C(F)(F)F)cc(-c3ccc(F)c(Cl)c3)c2O1

Procedure:
The title compound was prepared (0.014 g, 19%) following the general procedure of Example 390 as a white solid, hydrochloride salt from [7-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.095 g, 0.19 mmol) and methylamine (0.12 g, 3.9 mmol). mp 229-230° C.
Reaction SMILES: Cl.[F:2][C@@H:3]1[CH2:7][NH:6][C@H:5]([C:8]([NH2:10])=O)[CH2:4]1.C(N(CC)C(C)C)(C)C.[Cl:20][CH2:21][C:22](Cl)=[O:23]>C(Cl)(Cl)Cl>[Cl:20][CH2:21][C:22]([N:6]1[CH2:7][C@@H:3]([F:2])[CH2:4][C@H:5]1[C:8]#[N:10])=[O:23]
Reactant: O=C(Cl)CCl
Reactant: NC(=O)[C@@H]1C[C@H](F)CN1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CCl
Reaction time: 0.5 h

Procedure:
A suspension of 1.4 g of (2S,4S)-4-fluoropyrrolidine-2-carboxamide monohydrochloride prepared according to the similar method as that described in a patent reference (International Publication WO02/38451 pamphlet), and 3.0 ml of N,N-diisopropylethylamine in 10 ml of chloroform was added dropwise to a solution of 0.73 ml of chloroacetyl chloride in 14 ml of chloroform under cooling with an ice-water bath, and the reaction mixture was stirred for 30 minutes under cooling with an ice-water bath. Then, the reaction mixture was concentrated under reduced pressure. To a solution of the resulting residue in 14 ml of chloroform, 2.4 ml of trifluoroacetic anhydride was added dropwise under cooling with an ice-water bath. Then, the reaction mixture was allowed to room temperature, and stirred for 1 hour. This was concentrated under reduced pressure, and 0.1 M hydrochloric acid was added to the resulting residue, and this was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed, and the solvent was removed under reduced pressure. The resulting residue was purified with silica gel column chromatography (eluent: chloroform to chloroform/methanol=30/1) to obtain 0.84 g of (2S,4S)-1-(chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=1.C(N(C(C)C)C(C)C)C.[C:23](Cl)(=[O:27])[CH:24]([CH3:26])[CH3:25]>C(Cl)Cl>[C:23]([NH:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=1)(=[O:27])[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)C(=O)Cl
Reactant: COC(=O)c1ccc(CN)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(CNC(=O)C(C)C)nc1
Temperature: 25 °C
Yield: 100 %

Procedure:
To an ice-cold suspension of methyl 6-(aminomethyl)nicotinate hydrochloride (1.00 g, 4.18 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.89 g, 2.55 mL, 14.6 mmol) in DCM (10 mL) was added dropwise a solution of isobutyryl chloride (535 mg, 526 μL, 5.02 mmol) in DCM (3 mL). The reaction mixture was allowed to warm to room temperature, washed with water (5 mL), 10% aqueous citric acid solution (5 mL), saturated aqueous sodium bicarbonate solution (5 mL), brine (5 mL), dried over magnesium sulfate, filtered and evaporated to yield the title compound as a pale orange solid (0.988 g, 100%):
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=2)[CH:13]=1)[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[NH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([Cl:36])[CH:30]=1>>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:26][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([Cl:36])[CH:30]=3)[N:19]=2)[CH:13]=1)[CH:8]([CH3:9])[CH3:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)N(Cc1cccc(-c2ccnc(Cl)n2)c1)C(=O)OC(C)(C)C
Reactant: NCCc1ccc(O)c(Cl)c1
Product: CC(C)N(Cc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1)C(=O)OC(C)(C)C

Procedure:
Intermediate 70 was coupled with Intermediate 71 following procedure F. LC-MS showed the product had the expected M+H+ of 497. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.3 (d, 1H) 7.9 (m, 2H) 7.4 (m, 2H) 7.2 (m, 2H) 7.0 (m, 3H) 4.4 (s, 2H) 3.7 (m, 2H) 2.8 (m, 2H) 1.4 (s, br, 10H) 1.0 (d, 6H).
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[OH-].[Na+].[CH2:10]1[O:12][CH2:11]1>O>[OH:12][CH2:11][CH2:10][NH:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4]
Reactant: N[C@@H](CS)C(=O)O
Reactant: C1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)[C@H](CS)NCCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
109.5 g (0.9 mol) L-cysteine was placed in a 2000 ml flask, and dissolved with 1000 ml water, to which was added 24 ml of 1 mol/l NaOH solution. In an ice bath, 96 ml (1.8 mol) ethylene oxide was slowly added dropwise into the cysteine solution. After stirring 1 h, the ice bath was removed and the mixture was warmed to room temperature and further reacted for 1 h. The reaction product was extracted with 1000 ml anhydrous ethyl ether for four times, while collecting the aqueous layers. The aqueous layers were evaporated to dryness obtaining a yellow crystal product. The yellow crystal product was recrystallized with water:ethanol=85 ml:350 ml, filtered, washed with 2000 ml of 95% ethanol, and dried obtaining 121.8 g of a white crystal product, yield 74.3%.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:17]2[CH:22]=[CH:21][NH:20][C:19](=[O:23])[CH:18]=2)[C:4]([CH3:16])=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[N:6]=1.I[CH2:25][CH2:26][OH:27]>>[CH3:1][C:2]1[N:3]([C:17]2[CH:22]=[CH:21][N:20]([CH2:25][CH2:26][OH:27])[C:19](=[O:23])[CH:18]=2)[C:4]([CH3:16])=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[N:6]=1
Reactant: OCCI
Reactant: Cc1cccc(C#Cc2nc(C)n(-c3cc[nH]c(=O)c3)c2C)c1
Product: Cc1cccc(C#Cc2nc(C)n(-c3ccn(CCO)c(=O)c3)c2C)c1

Procedure:
The title compound, light brown solid, MS: m/e=348.2 (M+H+), was prepared in accordance with the general method of example 3 from 4-[2,5-dimethyl-4-m-tolylethynyl-imidazol-1-yl]-1H-pyridin-2-one and 2-iodoethanol.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[C:9](Br)[CH:10]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[C:24]1(B2OC(C)(C)C(C)(C)O2)[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[C:9]([C:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=2)[CH:10]=1)=[O:4]
Reactant: CC1(C)OB(C2=CCCCC2)OC1(C)C
Reactant: COC(=O)c1cnc(OCC(F)(F)F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(OCC(F)(F)F)c(C2=CCCCC2)c1
Temperature: 80 °C
Reaction time: 48 h
Yield: 85.8 %

Procedure:
5-Bromo-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid methyl ester (500 mg, 1.59 mmol, CAN 1211589-51-3), potassium carbonate (660 mg, 4.78 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (65.0 mg, 79.6 μmol) were combined to give a light red solid. To this solid was added a solution of 2-(1-cyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (331 mg, 1.59 mmol, CAN 141091-37-4) in DMF (12.0 ml), that had been thoroughly degassed and flushed with argon. The reaction mixture was heated to 80° C. and stirred for 48 h. Subsequently the reaction mixture was cooled to ambient temperature and poured into 75 mL brine and extracted with isopropyl acetate (2×150 mL). The organic layers were washed with brine (2×50 mL), combined and dried with Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 50 g, 0% to 10%, n-heptane/isopropyl acetate) to give the title compound (0.43 g, 60%) as white solid; MS (EI) 316.3 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]([NH:11][CH:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][NH:21]3)=[CH:16][CH:15]=2)[CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].[CH3:26][O:27][CH2:28][C:29](O)=O>>[CH3:26][O:27][CH2:28][CH2:29][N:21]1[C:22]2[C:17](=[CH:16][CH:15]=[C:14]([CH:12]([NH:11][C:9](=[O:10])[CH:8]=[CH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH3:13])[CH:23]=2)[CH2:18][CH2:19][CH2:20]1
Reactant: CC(NC(=O)C=Cc1ccccc1)c1ccc2c(c1)NCCC2
Reactant: COCC(=O)O
Agent: [BH4-]
Agent: [Na+]
Product: COCCN1CCCc2ccc(C(C)NC(=O)C=Cc3ccccc3)cc21
Temperature: 23 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
To a stirred solution of 3-phenyl-N-[1-(1,2,3,4-tetrahydro-quinolin-7-yl)ethyl]acrylamide (Example 233) (75 mg, 0.245 mmol) in methoxyacetic acid (5 ml) was added, in small portions, NaBH4 (232 mg) over 30 minutes. The mixture was stirred at 23° C. for an additional 2 hours and then the excess hydride destroyed by adding MeOH. That solution was diluted with EtOAc and washed several times with water. The organic phase was dried (MgSO4) and evaporated. The crude material was purified by chromatography (SiO2, 25% EtOAc in hexane) yielding 59 mg (66%) of the desired compound as a thick oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[N:9]=[C:10]([C:17]3[CH:18]=[C:19]([C:23]4[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=4)[CH:20]=[N:21][CH:22]=3)[C:11]3[CH:16]=[CH:15][NH:14][C:12]=3[N:13]=2)[CH:5]=[CH:4][CH:3]=1.Cl.[CH3:32][NH2:33].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:32][NH:33][CH2:27][C:26]1[CH:29]=[CH:30][C:23]([C:19]2[CH:20]=[N:21][CH:22]=[C:17]([C:10]3[C:11]4[CH:16]=[CH:15][NH:14][C:12]=4[N:13]=[C:8]([C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=4)[N:9]=3)[CH:18]=2)=[CH:24][CH:25]=1
Reactant: Cc1cccc(-c2nc(-c3cncc(-c4ccc(C=O)cc4)c3)c3cc[nH]c3n2)n1
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CNCc1ccc(-c2cncc(-c3nc(-c4cccc(C)n4)nc4[nH]ccc34)c2)cc1
Reaction time: 0.08 h

Procedure:
To a suspension of 4-{5-[2-(6-methyl-pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyridin-3-yl}-benzaldehyde (Intermediate 58) (1 eq, 0.243 mmol, 100 mg) and methylamine hydrochloride (Sigma-Aldrich, St. Louis, USA) (1 eq, 0.243 mmol, 16.7 mg) in DCM (1 ml) is added AcOH (1.1 eq, 0.267 mmol, 15.3 ul). The solution is stirred for 5 min, then NaBH(OAc)3 (1.05 eq, 0.255 mmol, 57 mg) is added. After stirring the resulting mixture at r.t. for 1.5 h the solvents are removed in vacuo. The residue is taken up in aqueous NaHCO3 solution and extracted with DCM. The organic layer is washed with brine, dried over MgSO4, and filtered. The solvents are removed in vacuo and purification of the residue by reversed phase HPLC is yielding the title compound; [M+H]+=407; 1H-NMR (400 MHz, CDCl3): δ 12.52 (s, 1H), 9.43 (s, 1H), 8.95 (s, 1H), 8.73 (s, 1H), 8.66 (d, 1H), 7.83 (t, 1H), 7.64 (d, 2H), 7.49-7.46 (m, 3H), 7.32 (d, 1H), 6.88 (d, 1H), 3.86 (s, 2H), 2.75 (s, 3H), 2.56 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[CH3:17][N:18]([CH2:20][CH2:21][OH:22])[CH3:19].C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Br:1][C:2]1[C:7]([O:22][CH2:21][CH2:20][N:18]([CH3:19])[CH3:17])=[N:6][C:5]([NH2:11])=[N:4][C:3]=1[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Reactant: CN(C)CCO
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: CN(C)CCOc1nc(N)nc(-c2ccco2)c1Br

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, dimethylaminoethanol and DBU in dioxane. 329 (M{9Br}+H+, 95), 327 (M{10Br}+H+, 100).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:25])=[CH:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:32][CH3:33].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:10]2[C:9]3[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[C:7]([O:32][CH3:33])[CH:8]=3)[N:13]=[CH:12][CH:11]=2)=[C:18]([C:24]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:25])[CH:19]=1
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCCl
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCN1CCOCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
(2-{[7-(3-Chloropropoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (62 mg), morpholine (40 mg), and potassium carbonate (100 mg) were suspended in N,N-dimethylformamide (4 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (45 mg, yield 66%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH2:10][CH:9]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[O:8][N:7]=1)=O)C.[BH4-].[Na+].O>C1COCC1>[F:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH:9]2[O:8][N:7]=[C:6]([CH2:4][OH:3])[CH2:10]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)C1=NOC(Cc2ccc(F)cc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCC1=NOC(Cc2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
To a solution of 5-(4-Fluoro-benzyl)-4,5-dihydro-isoxazole-3-carboxylic acid ethyl ester (0.17 g, 0.677 mmol) in THF (10 ml), NaBH4 (0.051 g, 0.81 mmol) was added slowly at 0° C. The reaction mixture was stirred for 2 h at room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over Na2SO4 and concentrated under vacuum. The residue obtained was purified by column chromatography to obtain [5-(4-Fluoro-benzyl)-4,5-dihydro-isoxazol-3-yl]-methanol (140 mg, 100%) as an yellow oil.
Reaction SMILES: [C:1]([C:4]1[N:9]=[N:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17]C(=O)OC(C)(C)C)=[CH:6][C:5]=1[NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][CH3:34])[N:27]=1)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCl>[NH2:17][C@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[NH:10][C:7]1[N:8]=[N:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][CH3:34])[N:27]=2)[CH:6]=1
Reactant: CCOc1cccc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cccc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)nnc2C(N)=O)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.6 %

Procedure:
tert-Butyl (1S,2R)-2-(6-carbamoyl-5-(6-ethoxypyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (32.2 mg, 51.2 μmol) was dissolved in dichloromethane (1 mL) and treated with trifluoroacetic acid (744 mg, 0.5 mL, 6.53 mmol). The reaction was stirred at 25° C. for 3 h then concentrated in vacuo to a brown oil. This oil was dissolved in dichloromethane, washed with 1N NaOH (3×5 mL) and brine (5 mL), then the organic phase was dried (Na2SO4), filtered and concentrated to give an off-white solid. The solid was triturated with Et2O (3×5 mL) and dried overnight in vacuo to give an off-white solid, 6-((1R,2S)-2-aminocyclohexylamino)-4-(6-ethoxypyridin-2-ylamino)pyridazine-3-carboxamide (12.6 mg, 33.6 μmol, 66% yield), 1H NMR (DMSO-d6) δ: 11.65 (br. s., 1H), 8.40 (br. s., 1H), 7.71 (s, 1H), 7.64 (t, J=7.9 Hz, 2H), 6.77 (d, J=7.8 Hz, 1H), 6.54 (d, J=7.8 Hz, 1H), 6.36-6.42 (m, 1H), 4.35 (q, J=7.0 Hz, 2H), 3.85 (br. s., 1H), 3.09 (br. s., 1H), 1.48-1.74 (m, 6H), 1.20-1.40 (m, 5H); MS (EI/CI) m/z: 372.3 [M+H].