Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])[CH:5]=[CH:4][N:3]=1.[BH4-].[Na+]>CO.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]([CH:10]2[CH2:11][CH2:12]2)[OH:9])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(c1ccnc(Cl)n1)C1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: OC(c1ccnc(Cl)n1)C1CC1
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
To a solution of (2-chloropyrimidin-4-yl)(cyclopropyl)methanone (150 mg, 0.821 mmol) in MeOH (3 mL) at 0° C. was added sodium borohydride (31 mg, 0.821 mmol) and stirred for 30 min. The solution was diluted with EtOAc, washed with brine, dried with MgSO4, filtered, and concentrated to dryness to afford (2-chloropyrimidin-4-yl)(cyclopropyl)methanol (150 mg, 0.812 mmol, 99% yield). MS ESI: [M+H]+ m/z 185.1. 1H NMR (500 MHz, CDCl3) δ 8.60 (d, J=4.0, 1H), 7.41 (d, J=4.0, 1H), 4.12 (d, J=7.9, 1H), 1.12 (m, 1H), 0.64 (m, 2H), 0.56 (m, 2H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH:15]([F:17])[F:16])C=O)[CH2:3][CH2:2]1.[BH4-].[Na+].[OH-:20].[Na+]>C(O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([OH:20])[CH:11]=[CH:12][C:13]=2[O:14][CH:15]([F:17])[F:16])[CH2:3][CH2:2]1
Reactant: [OH-]
Reactant: O=Cc1ccc(OC(F)F)c(OCC2CC2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Oc1ccc(OC(F)F)c(OCC2CC2)c1

Procedure:
Crude 3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde (26.4 g) in absolute ethanol (200 mL) was treated with sodium borohydride (8.23 g, 217 mmol) under an argon atmosphere at room temperature for 0.33 h. Ten percent aqueous sodium hydroxide (150 mL) was added, the ethanol was removed in vacuo and the aqueous residue was extracted three times with ether. The organic extract was washed twice with brine, was dried (sodium sulfate), was filtered and was evaporated to a pale yellow oil (24.4 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[Li]CCCC.[CH:15](=[O:17])[CH3:16]>CCOCC>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([CH:15]([OH:17])[CH3:16])=[CH:3][CH:4]=1
Reactant: CC=O
Reactant: COc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1ccc(C(C)O)cn1
Temperature: 25 °C
Yield: 91 %

Procedure:
To a solution of 5-bromo-2methoxy-pyridine (19.3 g, 193 mmol) in anhydrous Et2O (200 mL) at −78° C. was added n-BuLi (2.5 M in hexanes, 50 mL) over 30 min. The resulting mixture was stirred at that temperature for addition 30 min before acetaldehyde (5 mL) was added. The reaction was slowly warmed up to room temperature and the solvent was removed in vacuo. The residue was purified by flash column chromatography to afford the desired product (14.3 g, 91% yield). 1H NMR (400 MHz, CDCl3): δ 1.50 (d, J=8.0 Hz, 3H), 3.93 (s, 3H), 4.87-4.92 (m, 1H), 6.75 (d, J=8.0 Hz, 3H), 7.63-7.66 (m, 1H), 8.12-8.14 (m, 1H).
Reaction SMILES: [C@@H:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH2:3][CH3:4])[CH3:2].C(O)(C(F)(F)F)=O.C(N)CN>ClCCl>[C@@H:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH2:3][CH3:4])[CH3:2]
Reactant: CC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Solvent: ClCCl
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 64.8 %

Procedure:
In a 10 mL round-bottom flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-sec-butyl)-amide (40 mg, 0.080 mmol) and TFA (0.9 ml, 11.7 mmol) were combined with dichloromethane (3 ml) to give an orange solution. The reaction mixture was stirred at room temperature for 2.5 h then concentrated under reduced pressure. The resultant crude solid was dissolved in dichloromethane (3 mL) and ethylenediamine (0.38 ml, 5.6 mmol) was added. The reaction mixture was stirred at room temperature for 18 h then concentrated and the residue was precipitated with water. The suspension was stirred for 1 h and the crude solid collected by filtration. The crude solid was purified by trituration (hot dichloromethane/heptane) to afford 19 mg (67%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-sec-butyl)-amide as an off-white solid. [M+H]+=367; 1H NMR (300 MHz, DMSO-d6) δ: 12.77 (br. s., 1H), 9.09 (s, 1H), 8.43 (s, 1H), 8.43 (dd, J=9.1, 5.5 Hz, 1H), 8.00 (d, J=8.7 Hz, 1H), 7.70 (dd, J=9.8, 1.9 Hz, 1H), 7.19 (td, J=9.1, 2.3 Hz, 1H), 4.15 (s, 3H), 4.03-4.14 (m, 1H), 1.57-1.73 (m, 2H), 1.28 (d, J=6.4 Hz, 3H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:25])=[CH:20][CH:19]=3)[N:9]=2)[CH2:3]1.[N:32]([CH:35]([CH3:37])[CH3:36])=[C:33]=[O:34]>C1COCC1.C(Cl)Cl>[CH:35]([NH:32][C:33](=[O:34])[NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[C:10]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:25])=[CH:22][CH:23]=3)[N:9]=2)[CH2:3]1)([CH3:37])[CH3:36]
Reactant: NC(=O)c1ccc(N2CCC[C@@H](N)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: CC(C)N=C=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)NC(=O)N[C@@H]1CCCN(c2ccc(C(N)=O)c(Nc3ccc(C(=O)N4CCOCC4)cc3)n2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.3 %

Procedure:
To a solution of (R)-6-(3-aminopiperidin-1-yl)-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide (35 mg, 0.082 mmol) in THF (2 mL) was added 2-isocyanatopropane (14.03 mg, 0.165 mmol) and stirred at rt for 10 min. The reaction mixture was diluted with CH2Cl2, washed with satd NaHCO3, separated, and concentrated. The residue was purified (ISCO, 5% NH4OH/MeOH/CH2Cl2, 40 g silica gel column) to obtained 30.2 mg of (R)-6-(3-(3-isopropylureido) piperidin-1-yl)-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide as a light yellow solid.
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:7][CH:6]=1)=[O:4].[C-]#N.[Na+].[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([NH:29][C:3]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[N:7][CH:6]=1)=[O:4])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)c1cnc(NC(=O)c2ccccc2)s1
Agent: [C-]#N
Agent: [Na+]
Product: O=C(Nc1ncc(C(=O)NCc2ccccc2)s1)c1ccccc1
Temperature: 80 °C
Reaction time: 70 h
Yield: 5 %

Procedure:
A mixture of 2-benzoylaminothiazole-5-carboxylic acid methyl ester (0.40 g, 1.52 mmol), sodium cyanide (0.19 g, 3.79 mmol) and benzylamine (4 mL) was stirred at 80° C. for 70 h. The mixture was filtered, washed with ethyl ether, and the filtrate was concentrated in vacuo. The residue was dissolved in a mixture of methanol and tetrahydrofuran and aqueous lithium hydroxide solution (0.24 g in 6 mL water) was added. The mixture was stirred at 50° C. for 4 d. The organic solvents were removed in vacuo. The solid obtained was collected by filtration, washed with water, methanol and dried. The title compound was obtained as a white solid in 5% yield (0.005 g); 1H NMR (DMSO-d6, 300 MHz) δ 8.93 (s, 1H), 8.20-8.03 (m, 3H), 7.62-7.41 (m, 3H), 7.39-7.14 (m, 6H), 4.43 (d, J=3.9 Hz, 2H); MS (ES+) m/z 338.5 (M+1).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][CH:4]([NH:6][C:7](=[O:9])[OH:8])[CH2:3]1.[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1>[C:11]([O:9][C:7]([NH:6][CH:4]1[CH2:5][CH:2]([O:1][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3]1)=[O:8])([CH3:16])([CH3:12])[CH3:10]
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(O)NC1CC(O)C1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NC1CC(OC(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a solution of (3-hydroxycyclobutyl)carbamic acid tent-butyl ester (180 mg, 0.96 mmol) in pyridine (4 mL) was added benzoyl chloride (116 μL, 1.0 mmol). The reaction mixture was stirred at room temperature for 2 hrs and then concentrated under reduced pressure. The residue was dissolved in EtOAc (20 mL), washed with 1 N HCl, water and brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Et2O/pentane: gradient 0% to 50%) to give benzoic acid 3-tert-butoxycarbonylaminocyclobutyl ester as a white solid (262 mg, yield: 94%). LCMS (ESI) m/z: 192 [M+H-BOC]+
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:9].[Br-].[C:11]([N:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1)(=[O:13])[CH3:12].[NH4+].[Cl-]>C(OCC)C>[C:11]([N:14]1[CH2:19][CH2:18][C:17]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:9])([OH:20])[CH2:16][CH2:15]1)(=[O:13])[CH3:12]
Reactant: CC(=O)N1CCC(=O)CC1
Reactant: Cc1ccccc1Br
Agent: [Br-]
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Product: CC(=O)N1CCC(O)(c2ccccc2C)CC1
Yield: 8.3 %

Procedure:
To magnesium turnings (1.82 g, 0.075 mol), covered by dry diethylether (100 mL) under a N2 atmosphere was dropwise added 2-bromotoluene (14.22 g, 0.083 mol). After addition of approximately 1/5 of the bromide the reaction was initiated by gently heating the mixture. The remaining 2-bromotoluene was added over a period of 5 min. When addition was completed the resulting mixture was refluxed for 1.5 h. 1-Acetyl-4-piperidone (9.53 g, 0.068 mol) was added dropwise at ambient temperature and diethylether (100 mL) was added. The reaction mixture was stirred at reflux temperature for 30 min and 1 h at room temperature. 4M NH4Cl (aq) (100 mL) was added and the phases were separated. The organic phase was washed with brine (10 mL), dried (MgSO4) and the solvent evaporated in vacuo. The residual oil was purified on a silica gel column (Eluent: CH2Cl2 /methanol (19:1)) to give the title compound 1.31 g (8%). M.p. 145-146° C.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[S:16]1[CH:20]=[CH:19][C:18]([C:21]2[NH:22][CH:23]=[CH:24][N:25]=2)=[CH:17]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>[Cl-].[Na+].O>[CH3:9][N:8]([CH3:10])[C:6](=[O:7])[C:5]1[CH:11]=[CH:12][C:2]([N:25]2[CH:24]=[CH:23][N:22]=[C:21]2[C:18]2[CH:19]=[CH:20][S:16][CH:17]=2)=[C:3]([N+:13]([O-:15])=[O:14])[CH:4]=1
Reactant: CN(C)C(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: c1c[nH]c(-c2ccsc2)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN(C)C(=O)c1ccc(-n2ccnc2-c2ccsc2)c([N+](=O)[O-])c1
Temperature: 100 °C

Procedure:
4-Fluoro-N,N-dimethyl-3-nitrobenzamide 1.06 g, 2-(3-thienyl)-1H-imidazole as synthesized in above Production Example 2, 747 mg, potassium carbonate 1.37 g and N,N-dimethylacetamide 10 mL were mixed, and its outside temperature was heated to 100° C. for 6.5 hours. The reaction liquid was poured into brine and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. Distilling the solvent off, 1.30 g of the title compound was obtained.
Reaction SMILES: C(O[C@H:5]1[C@H:10]([NH:11][C:12]([NH:14][CH3:15])=[S:13])[C@@H:9]([O:16][C:17](=[O:19])[CH3:18])[C@H:8]([O:20][C:21](=[O:23])[CH3:22])[C@@H:7]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[O:6]1)(=O)C.Cl[Sn](Cl)(Cl)Cl>C(Cl)Cl>[C:21]([O:20][C@@H:8]1[C@@H:7]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[O:6][CH:5]2[CH:10]([N:11]=[C:12]([NH:14][CH3:15])[S:13]2)[C@H:9]1[O:16][C:17](=[O:19])[CH3:18])(=[O:23])[CH3:22]
Reactant: CNC(=S)N[C@H]1[C@H](OC(C)=O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: CNC1=NC2C(O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O)S1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.4 %

Procedure:
(2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-(3-methylthioureido)-tetrahydro-2H-pyran-2,4,5-triyl triacetate (0.457 g, 1.09 mmol) was added to dry DCM, and SnCl4 (1.13 g, 4.33 mmol) was added dropwise. The reaction was stirred at room temperature overnight (16 h). The reaction was quenched with saturated aqueous NaHCO3 until the solution was basic and no more gas was evolved. The aqueous layer was extracted three times with DCM and the combined organic layers were dried with MgSO4, filtered and concentrated. The crude material was purified by flash chromatography (silica gel, EtOAc), providing (5R,6S,7R)-5-(acetoxymethyl)-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diyl diacetate (22) as an oil (0.30 g, 77% yield). 1H NMR (500 MHz, CDCl3) δ 2.05 (s, 3H), 2.06 (s, 3H), 2.08 (s, 3H), 2.90 (s, 3H), 3.84 (m, 1H), 4.12 (m, 2H), 4.34 (dd, 1H, J=4.3, 6.2 Hz), 4.90 (ddd, 1H, J=0.8, 2.8, 9.6 Hz), 5.39 (dd, 1H, J=2.9, 4.1 Hz), 6.21 (d, 1H, J=6.5 Hz). 13 C NMR (125 MHz, CDCl3) δ 21.00, 21.10, 21.23, 31.19, 63.40, 68.67, 69.40, 72.24, 73.01, 90.03, 161.21, 169.72, 169.90, 170.89.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:14])[CH3:13])=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.[H-].[Na+].I[CH3:18].O>C1COCC1>[CH3:18][N:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[N:4]2)[C:12](=[O:14])[CH3:13]
Reactant: CC(=O)Nc1ccc2nccnc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N(C)c1ccc2nccnc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.9 %

Procedure:
To a solution of N-(quinoxalin-6-yl)acetamide (8.0 g, 0.043 mol) in THF (120 mL) was added sodium hydride (60% wt in mineral oil, 3.42 g, 0.086 mol). The mixture was stirred at room temperature for 10 min. Then iodomethane (7.28 g, 0.051 mol) was added. The mixture was stirred at room temperature for 2 h. Water (60 mL) was added carefully. The mixture was extracted with EtOAc (3×150 mL). The extracts were dried over sodium sulfate, concentrated to give N-methyl-N-(quinoxalin-6-yl)acetamide as a brown solid (8.04 g, yield 93%). ESI MS: m/z 202.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([CH2:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])[C:3]=1[CH3:23].[CH3:24][C:25]1([CH3:40])[C:29]2=[N:30][CH:31]=[C:32]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:33]=[C:28]2[NH:27][CH2:26]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>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].C1(C)C=CC=CC=1>[CH3:24][C:25]1([CH3:40])[C:29]2=[N:30][CH:31]=[C:32]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:33]=[C:28]2[N:27]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=3[F:12])[N:5]=[C:4]([CH2:14][C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[C:18]#[N:19])[C:3]=2[CH3:23])[CH2:26]1
Reactant: CC1(C)CNc2cc(N3CCOCC3)cnc21
Reactant: Cc1c(Cc2cccc(C#N)c2)nc2cc(F)cc(F)c2c1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(Cc2cccc(C#N)c2)nc2cc(F)cc(F)c2c1N1CC(C)(C)c2ncc(N3CCOCC3)cc21

Procedure:
3-((4-Chloro-5,7-difluoro-3-methylquinolin-2-yl)methyl)benzonitrile (42.3 mg, 0.129 mmol), 4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-morpholine (30 mg, 0.129 mmol), Pd2dba3 (11.8 mg, 0.013 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (12.3 mg, 0.026 mmol), sodium tert-butoxide (37.1 mg, 0.386 mmol), and toluene (1.29 mL) were stirred at 105° C. for 2 h. The reaction mixture was then concentrated and the resulting residue partitioned between EtOAc and saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine and water, then dried (MgSO4) and concentrated. Purification of the crude product by reverse-phase HPLC (0-70% acetonitrile in water) gave 3-((4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-5,7-difluoro-3-methyl-2-quinolinyl)-methyl)benzonitrile. 1H NMR (400 MHz, chloroform-d) δ ppm 7.55-7.63 (2H, m), 7.47-7.53 (2H, m), 7.38-7.46 (1H, m), 7.24 (1H, br. s.), 6.91-7.03 (1H, m), 5.53-5.59 (1H, m), 4.39-4.47 (2H, m), 3.77-3.82 (1H, m), 3.68-3.77 (4H, m), 3.58 (1H, d, J=9.0 Hz), 2.89-3.02 (4H, m), 2.19-2.26 (3H, m), 1.39-1.58 (6H, m). Mass Spectrum (ESI) m/e=526.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][C:8]2[CH:20]=[CH:19][C:11]([O:12][CH:13]([CH3:18])[C:14]([O:16]C)=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:23]([NH2:27])[CH2:24][CH2:25][CH3:26]>CO>[CH2:23]([NH:27][C:14](=[O:16])[CH:13]([O:12][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][O:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:22][CH:21]=2)=[CH:20][CH:19]=1)[CH3:18])[CH2:24][CH2:25][CH3:26]
Reactant: COC(=O)C(C)Oc1ccc(COc2ccc(Cl)cc2)cc1
Reactant: CCCCN
Solvent: CO
Product: CCCCNC(=O)C(C)Oc1ccc(COc2ccc(Cl)cc2)cc1
Yield: 38.8 %

Procedure:
6.4 gm of methyl 2-[4-(4-chlorophenoxy-methyl)-phenoxy]-propionate were dissolved in 60 ml of methanol, 6.0 gm of n-butylamine were added to the solution, and the mixture was heated in an autoclave for 4 hours at a pressure of 15-16 atmospheres gauge. After cooling, the solvent was distilled off in vacuo, and the residue was recrystallized from ethanol, yielding 2.8 gm (39% of theory) of the amide named in the heading, which had a melting point of 98° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][CH:11]=[C:10]([C:13]([O:15]C)=[O:14])[C:9]=2[CH3:17])=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:3]=1.[OH-].[Na+].C(O)=O>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][CH:11]=[C:10]([C:13]([OH:15])=[O:14])[C:9]=2[CH3:17])=[C:4]([C:18]([F:21])([F:19])[F:20])[CH:3]=1
Reactant: COC(=O)c1c[nH]c(-c2ccc(Cl)cc2C(F)(F)F)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: CO
Product: Cc1c(C(=O)O)c[nH]c1-c1ccc(Cl)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 3 h
Yield: 93.7 %

Procedure:
To a solution of methyl 5-[4-chloro-2-(trifluoromethyl)phenyl]-4-methyl-1H-pyrrole-3-carboxylate (0.39 g, 1.3 mmol) in methanol (5.0 ml) was added 5N NaOH (5.0 ml) and the mixture was stirred at 80° C. for 3.0 h. The reaction mixture was cooled to room temperature and added formic acid (3.0 ml). The mixture was concentrated on a rotary evaporator. To the residue was added water and triturated. The solid was filtered and dried to give the title compound (0.37 g, 93%) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH:6]=[CH:7][CH2:8][N:9]([CH2:11][CH2:12][NH:13][S:14]([C:17]2[C:18]3[CH:19]=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH3:10])=[CH:4][CH:3]=1.[N:29]1([CH2:35][CH2:36]O)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][CH2:8][N:9]([CH2:11][CH2:12][N:13]([CH2:36][CH2:35][N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[S:14]([C:17]2[C:18]3[CH:19]=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:15])=[O:16])[CH3:10])=[CH:27][CH:28]=1
Reactant: CN(CC=Cc1ccc(Cl)cc1)CCNS(=O)(=O)c1cccc2cnccc12
Reactant: OCCN1CCCCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(CC=Cc1ccc(Cl)cc1)CCN(CCN1CCCCC1)S(=O)(=O)c1cccc2cnccc12
Yield: 74.9 %

Procedure:
To a solution of 0.39 g of the amorphous compound obtained in Example 190, 0.145 g of 1-piperidinethanol and 0.369 g of triphenylphosphine in 5 ml of tetrahydrofuran, was added dropwise a solution of 0.245 g of diethyl azodicarboxylate in 2 ml of tetrahydrofuran with stirring under ice cooling. The mixture was stirred for 2 hours and evaporated to remove the solvent under a reduced pressure, and resulting residue dissolved in 30 ml of ethyl acetate and extracted three times with 10 ml of 1N hydrochloric acid. The aqueous layer was alkallized with sodium bicarbonate and extracted three times with 10 ml of ehtyl acetate, and the organic extract was dried over magnesium sulfate and evaporated to remove the solvent at a reduced pressure. The resulting residue was applied to a silica gel column and eluted with 2% methanol in chloroform, to obtain 0.37 g of the title compound as a colorless oil.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][C:11]([O:13][CH2:14]C)=[O:12].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[I:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: Oc1cccc(I)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)COc1cccc(I)c1
Yield: 99.7 %

Procedure:
3-Iodophenol (4.00 g, 18.2 mmol), ethyl bromoacetate (2.98 g, 18.2 mmol) and potassium carbonate (2.51 g, 18.2 mmol) were refluxed in acetone (40 ml) for 2 hours. The reaction mixtute was poured into water and extracted with ethyl acetate. The organic layer was dried, and filtered. The filtrate was concentrated and the residue was purified with silica gel chromatography to give the subject compound (5.30 g, 99%).
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([S:11][CH3:12])[C:5]=2[S:4][CH:3]=1.[CH3:13][S:14]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)(=[O:16])=[O:15].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[CH3:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([C:2]2[C:6]3[N:7]=[CH:8][N:9]=[C:10]([S:11][CH3:12])[C:5]=3[S:4][CH:3]=2)=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: CSc1ncnc2c(Br)csc12
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CSc1ncnc2c(-c3ccc(S(C)(=O)=O)cc3)csc12
Temperature: 100 °C
Reaction time: 4 h
Yield: 77.3 %

Procedure:
7-bromo-4-methylsulfanylthieno[3,2-d]pyrimidine (270 mg, 1.0 mmol) was added to 1,4-dioxane (10 mL), and 4-methanesulfonyl-phenylboronic acid (310 mg, 1.6 mmol), tetrakis(triphenylphosphine)palladium(0) (71 mg, 0.062 mmol), and 2N aqueous sodium carbonate (3.1 mL, 3.1 mmol) were sequentially added thereto. The air present in the reaction mixture was removed using a nitrogen balloon, and the reaction mixture was heated to 100° C. and stirred for 4 hours. The reaction was terminated by addition of sodium bicarbonate, and the reaction mixture was extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a foamy residue. The residue was crystallized in the presence of diethyl ether to obtain the title compound (260 mg) as a yellowish solid.
Reaction SMILES: [OH:1][C:2]1[CH2:6][S:5][C:4](=[O:7])[C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=1>C(O)C.[Pd]>[NH2:14][C:10]1[CH:9]=[C:8]([C:3]2[C:4](=[O:7])[S:5][CH2:6][C:2]=2[OH:1])[CH:13]=[CH:12][CH:11]=1
Reactant: O=C1SCC(O)=C1c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(C2=C(O)CSC2=O)c1
Reaction time: 0.17 h
Yield: 66.9 %

Procedure:
A solution of 4-hydroxy-3-(3-nitrophenyl)-2(5H)-thiophenone (0.36 g, 1.5 mmol) in ethanol (70 ml) was hydrogenated at 40 psi using a palladium on carbon catalyst (200 mg, 55% (w /w)), for 10 min. The catalyst was filtered off and the solvent evaporated in vacuo. The brown residue was triturated with ether (10 ml) and methanol (0.5 ml). 3-(3-Aminophenyl)-4-hydroxy-2(5H)-thiophenone (208 mg, 67%) was isolated as a beige solid. mp 252°-254° C. (dec.). 1H NMR (360MHz, D6 -DMSO) δ3.88 (2H, s), 6.56 (1H, d, J=8Hz), 7.05 (1H, dd, J=8 and 8Hz), 7.13 (1H, d, J =8Hz), 7.21 (1H, s).