Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:12][CH2:11][CH2:10]2)[C:5]([N+:13]([O-])=O)=[C:4]([Cl:16])[N:3]=1>CC(O)=O.[Fe]>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:10][CH2:11][CH2:12]2)[C:5]([NH2:13])=[C:4]([Cl:16])[N:3]=1
Reactant: O=[N+]([O-])c1c(Cl)nc(Cl)nc1NC1CCC1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1c(Cl)nc(Cl)nc1NC1CCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Fe powder (631 mg, 11.3 mmol) was added to a solution of 2,6-dichloro-N-cyclobutyl-5-nitropyrimidin-4-amine (crude, 5.65 mmol) in HOAc (5 mL) and the mixture was stirred at rt for 30 min. The mixture was filtered through Celite® and the volatiles were removed under reduced pressure. The resulting residue was diluted with EtOAc (80 mL) and washed with water (80 mL), sat. NaHCO3 (80 mL) and brine (80 mL). The organic layer was dried over Na2SO4 and concentrated to give the title compound as a brown oil which was used without purification. m/z (APCI+) for C8H10Cl2N4 233.15/235.10 (M+H)+.
Reaction SMILES: C([O-])(=[O:3])C.[Na+].C(=O)(O)[O-].[Na+].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:32]=[CH:31][N:30]=[C:29]3[C:25]=2[N:26]=[C:27](Cl)[N:28]3[CH3:33])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>CS(C)=O>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:32]=[CH:31][N:30]=[C:29]3[C:25]=2[NH:26][C:27](=[O:3])[N:28]3[CH3:33])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: Cn1c(Cl)nc2c(N3CCN(C(=O)OC(C)(C)C)CC3)ncnc21
Reactant: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: Cn1c(=O)[nH]c2c(N3CCN(C(=O)OC(C)(C)C)CC3)ncnc21
Temperature: 135 °C
Yield: 53.5 %

Procedure:
Sodium acetate (0.168 g) and sodium bicarbonate (0.100 g) were added to a solution of 4-(8-chloro-9-methyl-9H-purin-6-yl)-piperazine-1-carboxylic acid t-butyl ester (0.353 g) in dimethylsulfoxide (5 mL). This was then heated at 135° C. for 64 hours. The reaction solution was filtered, and was directly loaded onto a column for purification by reverse phase high performance liquid chromatography to give the title compound (0.179 g).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[CH:8][C:9]2[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=2)[O:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:21])[F:20])=[N:17][CH:18]=2)[CH2:4][CH2:3]1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[N:27]=1.C(N(CC)CC)C.O>CS(C)=O>[F:21][C:19]([F:22])([F:20])[C:16]1[N:17]=[CH:18][C:13]([O:12][C:11]2[CH:10]=[C:9]([CH:25]=[CH:24][CH:23]=2)[CH:8]=[C:5]2[CH2:6][CH2:7][N:2]([C:33]([NH:32][C:28]3[N:27]=[N:26][CH:31]=[CH:30][CH:29]=3)=[O:34])[CH2:3][CH2:4]2)=[CH:14][CH:15]=1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)cn1
Reactant: O=C(Nc1cccnn1)Oc1ccccc1
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cccnn1)N1CCC(=Cc2cccc(Oc3ccc(C(F)(F)F)nc3)c2)CC1
Temperature: 25 °C
Yield: 72.5 %

Procedure:
A solution of 5-(3-(piperidin-4-ylidenemethyl)phenoxy)-2-(trifluoromethyl)pyridine hydrochloride (0.100 g), phenyl pyridazin-3-ylcarbamate (0.070 g, 1.2 equiv), and triethylamine (0.083 mL, 2.2 equiv) in dimethyl sulfoxide (2 mL, 0.13 M) was heated to 65° C. for 2 h. The reaction was cooled to room temperature. Water was added and the mixture was extracted with ethyl acetate (3×). The combined organic extracts was washed with water and brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate/dichloromethane) to give the title compound as a white foam (0.089 g, 72% yield). 1H NMR (400 MHz, CDCl3) δ ppm 2.46 (2H, t, J=5.5 Hz), 2.56 (2H, t, J=5.6 Hz), 3.60 (2H, t, J=5.8 Hz), 3.69 (2H, t, J=5.8 Hz), 6.37 (1H, s), 6.92 (2H, m), 7.07 (1H, d, J=7.6 Hz), 7.30-7.46 (3H, m), 7.62 (1H, d, J=8.8 Hz), 8.25 (1H, d, J=8.2 Hz), 8.45 (1H, d, J=2.5 Hz), 8.76 (1H, d, J=1.9 Hz).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[CH:31]=O>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:31][C:22]2[CH:23]=[CH:24][C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:21]=2)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1ccc2ccccc2n1
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1ccc2ccccc2n1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with commercially available quinoline-2-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.63 min.; [M+H]+: 391.16 g/mol.
Reaction SMILES: [C:1]([C:4](C)([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][Si](C(C)(C)C)(C)C)[C:5](OCC)=O)(=[O:3])[CH3:2].[OH-].[Na+].Cl>CO.O>[OH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH:4]([CH3:5])[C:1](=[O:3])[CH3:2]
Reactant: CCOC(=O)C(C)(CCCCCCO[Si](C)(C)C(C)(C)C)C(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)C(C)CCCCCCO
Temperature: 50 °C
Yield: 65.5 %

Procedure:
Ethyl 2-acetyl-8-(tert-butyldimethylsilyloxy)-2-methyloctanoate (13.5 g, 37.65 mmol) was dissolved in 10 mL CH3OH to which 5 g NaOH in 50 mL water was then added. The mixture was then heated to 50° C. overnight. The volume of the reaction mixture was reduced to about 50 mL under reduced pressure and acidified to pH 1 by the addition of 2 M HCl. This resulting mixture was heated to 60° C. for 5 hours. After cooling to room temperature the product was extracted into EtOAc. Concentration gave a yellow oil that was subjected to silica gel chromatography affording a colorless oil (4.25 g, 65.5%). 1H-NMR (300 MHz, CDCl3): δ 3.60 (t, 2H) 2.46 (m, 1H), 2.09 (s, 3H), 1.54 (m, 4H), 1.30 (m, 6H), 1.04 (d, 3H) ppm; MS m/z calculated for C10H20O2 (M+H): 173.2. Found 173.1 (M+H, ESI+).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[Cl:26][C:27]1[C:28]([F:36])=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1>CCCCCCC.CCOC(C)=O>[Cl:26][C:27]1[C:28]([F:36])=[C:29]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: OB(O)c1cccc(Cl)c1F
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1I
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1cccc(Cl)c1F

Procedure:
The title compound was prepared in analogy to example 72, from N-(4-iodo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 98, intermediate a) and 3-chloro-2-fluorophenylboronic acid (CAS RN 352535-82-1) and using a gradient of n-heptane:EtOAc (100:0 to 30:70) for the chromatographic purification. Light yellow oil (64%). MS (ESI): m/z=477.061 [M+H]+.
Reaction SMILES: [Br-].[O:2]1[CH2:7][CH2:6][CH2:5][O:4][CH:3]1[CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH:40]=O.O>C1COCC1>[O:4]1[CH2:5][CH2:6][CH2:7][O:2][CH:3]1[CH2:8]/[CH:9]=[CH:40]/[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][N:34]=1.[O:4]1[CH2:5][CH2:6][CH2:7][O:2][CH:3]1[CH2:8]/[CH:9]=[CH:40]\[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][N:34]=1
Reactant: O=Cc1ccccn1
Reactant: c1ccc([P+](CCC2OCCCO2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: C(=C/c1ccccn1)\CC1OCCCO1
Product: C(=C\c1ccccn1)\CC1OCCCO1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 4.6 g (10.2 mmol) of [2-(1,3-dioxan-2yl)ethyl]triphenylphosphonium bromide (Aldrich Chemical Co.) in 50 mL of THF at 0° C. was added 6.4 mL (10.2 mmol) of n-butyl lithium (1.6M in hexanes) and the resulting red solution was allowed to stir at 0° C. for 0.5 h. To this solution was added 880 μL (9.3 mmol) of 2-pyridinecarboxaldehyde (Aldrich Chemical Co.). The reaction mixture was allowed to stir at room temperature for 1 h and was then poured into water and partitioned with ether. The combined either extracts were dried over MgSO4 and concentrated. Flash chromatography (elution with 3:1 hexane:ethyl acetate) gave 0.43 g of E-3-(1,3-dioxan-2-yl)-1-(2-pyridyl)-1-propene (148) and 1.12 g of Z-3-(1,3-dioxan-2-yl)-1-(2-pyridyl)-1-propene (149). 1H NMRs consistent with structures.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9](F)([C:17]([F:20])([F:19])[F:18])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[CH:6]=[C:5]([CH3:22])[C:4]=1[NH2:23])[CH3:2].[OH-:24].[K+]>C(#N)C.O>[NH2:23][C:4]1[C:5]([CH3:22])=[CH:6][C:7]([C:9]([OH:24])([C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[C:17]([F:20])([F:19])[F:18])=[CH:8][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc(C)c1N
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCc1cc(C(O)(C(F)(F)F)C(F)(F)C(F)(F)F)cc(C)c1N
Temperature: 70 °C
Reaction time: 48 h
Yield: 59.8 %

Procedure:
To a solution of 2-ethyl-4-(1,2,2,3,3,3-hexafluoro-1-trifluoromethylpropyl)-6-methyl-phenylamine (prepared as descriebed in WO 2008/074427) (3.88 g, 11 mmol) in a mixture of acetonitrile (320 ml) and water (80 ml) was added potassium hydroxide (46.2 g, 827 mmol). The reaction mixture was stirred at 70° C. for 2 days. The reaction mixture was diluted with water (200 ml) and the mixture extracted three times with ethyl acetate (200 ml). The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/cyclohexane 1:3) to give 2-(4-amino-3-ethyl-5-methylphenyl)-1,1,1,3,3,4,4,4-octafluorobutan-2-ol (2.31 g, 60% yield). LC-MS (Method 1): RT=1.87, [M−H]−=352.
Reaction SMILES: [C:1]([C:5]1[C:9]([C:10]#[N:11])=[C:8](Cl)[S:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][C:14]1[CH:20]=[C:19]([OH:21])[C:18]([CH3:22])=[CH:17][C:15]=1[NH2:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:16][C:15]1[C:14]([CH3:13])=[CH:20][C:19]([O:21][C:8]2[S:7][N:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:9]=2[C:10]#[N:11])=[C:18]([CH3:22])[CH:17]=1
Reactant: CC(C)(C)c1nsc(Cl)c1C#N
Reactant: Cc1cc(O)c(C)cc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2snc(C(C)(C)C)c2C#N)c(C)cc1N

Procedure:
A suspension of 5.0 g (24.9 mmol) of 3-tert-butyl-5-chloroisothiazole-4-carbonitrile, 3.41 g (24.9 mmol) of 2,5-dimethyl-4-hydroxyaniline and 5.51 g (39.86 mmol) of potassium carbonate in 100 ml of DMF is heated under reflux for 6 h. After cooling, the reaction mixture is poured onto ice-water. After extraction with dichloromethane, the combined organic phases are dried over Na2SO4 and freed from the solvent under reduced pressure.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:44]=[C:43]([F:45])[C:16]([CH2:17][S:18][C:19]2[N:20]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)[C:21]([C:24]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([O:34][CH3:35])[CH:28]=3)([CH3:26])[CH3:25])=[CH:22][N:23]=2)=[C:15]([F:46])[CH:14]=1)(C(C)(C)C)(C)C>CC#N.CC#N.O>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C:24]([C:21]2[N:20]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)[C:19]([S:18][CH2:17][C:16]3[C:15]([F:46])=[CH:14][C:13]([O:12][CH2:11][CH2:10][CH2:9][OH:8])=[CH:44][C:43]=3[F:45])=[N:23][CH:22]=2)([CH3:26])[CH3:25])=[CH:28][C:29]=1[O:34][CH3:35]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCCO[Si](C)(C)C(C)(C)C)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Solvent: CC#N
Solvent: O
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCCO)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Yield: 50.6 %

Procedure:
A solution of 2-(4-(3-(tert-butyldimethylsilyloxy)propoxy)-2,6-difluorobenzylthio)-5-(2-(4-chloro-3-methoxyphenyl)-propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole (785 mg, 1.13 mmol) in CH3CN was treated with 5% HF in CH3CN/H2O (8:2) and purified by chromatography to afford the title compound (330 mg, 50%) as a white solid. MS (EI) m/z 577.4 (MH+).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([O:10]CC)=O)=[C:5]([CH3:7])[N:6]=1.O.[NH2:14][NH2:15]>C(O)C>[CH3:1][C:2]1[S:3][C:4]([C:8]([NH:14][NH2:15])=[O:10])=[C:5]([CH3:7])[N:6]=1
Reactant: CCOC(=O)c1sc(C)nc1C
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1nc(C)c(C(=O)NN)s1
Temperature: 90 °C
Reaction time: 8 h
Yield: 49.8 %

Procedure:
To ethyl 2,4-dimethylthiazole-5-carboxylate (Prep25, 50 g, 0.27 mol) in ethanol (200 mL), hydrazine hydrate (64 g, 1.08 mol) was added. The mixture was stirred at 90° C. overnight. After cooling to room temperature, the solvent was removed under vacuum to afford 41 g of crude product as a solid. The crude was purified by FC to give 23 g pure title compound product (y=50%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]([CH2:17][N:18]2[C@@H:22]([CH3:23])[C@@H:21]([C:24]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=3)[O:20][C:19]2=[O:38])=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1)(=O)=O.[F:41][C:42]1[C:47]([CH:48]([CH3:50])[CH3:49])=[CH:46][C:45](B(O)O)=[C:44]([O:54][CH3:55])[CH:43]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1.CCO.O.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>[F:37][C:34]([F:35])([F:36])[C:26]1[CH:25]=[C:24]([C@H:21]2[O:20][C:19](=[O:38])[N:18]([CH2:17][C:16]3[C:7]([C:45]4[CH:46]=[C:47]([CH:48]([CH3:50])[CH3:49])[C:42]([F:41])=[CH:43][C:44]=4[O:54][CH3:55])=[CH:8][C:9]4[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=4[CH:15]=3)[C@H:22]2[CH3:23])[CH:29]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:27]=1
Reactant: COc1cc(F)c(C(C)C)cc1B(O)O
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc2c(cc1OS(=O)(=O)C(F)(F)F)CCCC2
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: O
Solvent: c1ccccc1
Solvent: CCO
Product: COc1cc(F)c(C(C)C)cc1-c1cc2c(cc1CN1C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]1C)CCCC2
Temperature: 95 °C

Procedure:
A mixture of 3-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate (12.4 mg, 0.0204 mmol), (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (13.0 mg, 0.0614 mmol), and tetrakis(triphenylphosphine)palladium (0) (2.8 mg, 0.00246 mmol), sodium carbonate (18.2 mg, 0.172 mmol) in benzene (1.4 mL), EtOH (0.2 mL) and water (0.6 mL) was heated at 95° C. in a sealed tube overnight. The reaction mixture was cooled to room temperature and water (10 mL) was added. The mixture was extracted with EtOAc (3×20 mL) and the combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 0-20% EtOAc in hexanes gradient) and chiral HPLC (IA column, 20×250 mm, 3% i-PrOH in heptane) to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[3-(4-fluoro-5-isopropyl-2-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. Rf=0.49 (20% EtOAc/hexanes). LCMS calc.=624.2; found=624.2 (M+1)+. 1H NMR (600 MHz, CDCl3, 1:1 mixture of atropisomers): δ 7.83 (s, 1H); 7.67 (s, 1H); 7.65 (s, 1H); 7.17 (s, 0.5H); 7.06 (s, 0.5H); 7.01 (d, J=8.6 Hz, 0.5H); 6.98 (d, J=8.6 Hz, 0.5H); 6.94 (s, 0.5H); 6.91 (s, 0.5H); 6.65 (d, J=9.6 Hz, 0.5H); 6.63 (d, J=9.5 Hz, 0.5H); 5.52 (d, J=8.2 Hz, 0.5H); 5.23 (d, J=8.0 Hz, 0.5H); 4.85 (d, J=15.2 Hz, 0.5H); 4.79 (d, J=15.3 Hz, 0.5H); 3.95 (d, J=15.3 Hz, 0.5H); 3.77-3.71 (m, 4.5H); 3.22-3.14 (m, 1H); 2.84-2.77 (m, 4H); 1.86-1.80 (m, 4H); 1.27-1.21 (m, 4.5H); 1.15 (d, J=7.0 Hz, 1.5H); 0.50 (d, J=6.5 Hz, 1.5H); 0.28 (d, J=6.5 Hz, 1.5H).
Reaction SMILES: C([N:9]([C:17]1[O:18][C@H:19]([C:32]([F:35])([F:34])[F:33])[CH2:20][C@:21]([C:24]2[C:25]([F:31])=[N:26][CH:27]=[C:28]([Br:30])[CH:29]=2)([CH3:23])[N:22]=1)[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].Cl>CO>[Br:30][C:28]1[CH:29]=[C:24]([C@:21]2([CH3:23])[CH2:20][C@@H:19]([C:32]([F:34])([F:33])[F:35])[O:18][C:17]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[N:22]2)[C:25]([F:31])=[N:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)c1ccccc1)C1=N[C@](C)(c2cc(Br)cnc2F)C[C@@H](C(F)(F)F)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(Br)cnc2F)C[C@@H](C(F)(F)F)O1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
The crude product (5i) from step 7 was dissolved in MeOH (15 mL). Potassium carbonate (Aldrich, 0.200 g, 1.445 mmol) was added and the reaction was stirred at room temperature for 40 min. Hydrogen chloride (4M in 1,4-dioxane; 1.1 mL, 4.40 mmol) was added to the reaction mixture and the solvent was removed under the reduced pressure. The residue was diluted with EtOAc and water. The organic layer was washed with brine, and dried over sodium sulfate. The filtrate was concentrated and the residue used in the next step without further purification. MS m/z=400, 402 [M−tBu]+/[M+2−tBu]+; Calculated for C16H18BrF4N0O3: 456.2
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[C:11]([CH:13]=[CH2:14])[N:10]=[C:9]([CH:15]=[CH2:16])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[C:11]([CH2:13][CH3:14])[N:10]=[C:9]([CH2:15][CH3:16])[CH:8]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: C=Cc1cc(C(=O)OC(C)(C)C)cc(C=C)n1
Agent: [Pd]
Solvent: CO
Product: CCc1cc(C(=O)OC(C)(C)C)cc(CC)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.8 %

Procedure:
To a solution of 2,6-divinyl-isonicotinic acid tert-butyl ester (703 mg, 3.04 mmol) in methanol (15 mL), Pd/C (50 mg, 10% Pd) is added and the mixture is stirred under 1 atm of H2 at rt for 15 h. The catalyst is filtered off and the filtrate is evaporated. The remaining residue is purified by CC on silica gel eluting with heptane:EA 5:1 to give 2,6-diethyl-isonicotinic acid tert-butyl ester (635 mg) as a colourless oil; LC-MS: tR=1.05 min, [M+1]+=236.13.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[C:7]([N+:12]([O-:14])=[O:13])[C:6]=1[S:15][C:16](=[O:20])[N:17]([CH3:19])[CH3:18])C.C(OCC)C.B>C1COCC1>[Br:11][C:9]1[CH:8]=[C:7]([N+:12]([O-:14])=[O:13])[C:6]([S:15][C:16](=[O:20])[N:17]([CH3:19])[CH3:18])=[C:5]([CH2:4][OH:3])[CH:10]=1
Reactant: CCOC(=O)c1cc(Br)cc([N+](=O)[O-])c1SC(=O)N(C)C
Agent: B
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C)C(=O)Sc1c(CO)cc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.3 %

Procedure:
5-Bromo-2-dimethylcarbamoylsulfanyl-3-nitro-benzoic acid ethyl ester (3.0 g, 9.4 mmol) is taken up in THF (40 mL)/diethyl ether (10 mL) and cooled to zero with an ice bath. Borane in THF (1M, 20 mL, 2.1 mmol) is added dropwise to the reaction and then the reaction warmed to room temperature. An additional equivalent of borane is added, and the reaction warmed to 45° C. The reaction is stirred at 45° C. for 4 hours and then the reaction cooled to zero and quenched by the slow addition of saturated NH4Cl. The reaction is poured into water and then extracted with ethyl acetate. The combined organic layers were dried filtered and evaporated. The residue is purified on silica gel with DCM/MeOH as the eluent to afford 2.5 g (91%) of the title product. LCMS (ESMS): m/z 336.9 (M+H+).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13](I)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH2:17]1[CH2:21]OCC1.CCN(CC)CC.[CH3:29][Si:30]([C:33]#[CH:34])([CH3:32])[CH3:31]>C(Cl)Cl.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.[Cu]I>[CH3:29][Si:30]([C:33]#[C:34][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([C:21]#[C:17][Si:30]([CH3:32])([CH3:31])[CH3:29])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1)([CH3:32])[CH3:31]
Reactant: C#C[Si](C)(C)C
Reactant: C1CCOC1
Reactant: Ic1ccc(C#Cc2ccc(I)cc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(C#Cc2ccc(C#C[Si](C)(C)C)cc2)cc1

Procedure:
Firstly, a mixture of 4,4′-diiodotolan (171 mg, 0.40 mmol), PdCl2(PPh3)2 (27.9 mg, 0.040 mmol) and CuI (7.6 mg, 0.040 mmol) was added with dist. THF (3 mL), dist. Et3N (3 mL) and trimethylsilylacetylene (140 μL, 0.99 mmol). The resultant mixture was then stirred under a nitrogen atmosphere at 50° C. for 17 hours to obtain a reaction mixture. Subsequently, the reaction mixture was diluted with CH2Cl2. After that, an organic layer was washed with sat. NaCl, and the washed organic layer was then dried with MgSO4. The dried organic layer was filtered and concentrated to obtain a crude product (I). The obtained crude product (I) was separated and purified by silica gel column chromatography (hexane/EtOAc=10/1) to obtain 4,4′-bis(trimethylsilylethynyl)tolan.
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:11]=[CH:10][CH:9]=2.N>C(O)(=O)C>[CH3:5][CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[C:15]([F:17])([F:16])[F:18])[NH:7]1
Reactant: Cc1cc2c(C(F)(F)F)cccc2[nH]1
Agent: N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CC1Cc2c(cccc2C(F)(F)F)N1
Temperature: 15 °C
Reaction time: 16 h
Yield: 92.4 %

Procedure:
209 mg of 95% sodium cyanoborohydride are added to a solution of 210 mg of 2-methyl-4-trifluoromethyl-1H-indole in 8 ml of acetic acid, cooled to 15° C. The reaction mixture is stirred for 16 hours at ambient temperature and then poured into an aqueous ammonia solution (pH=9). The aqueous phase is extracted with methylene chloride and the combined organic phases are washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure, so as to give 196 mg of 2-methyl-4-trifluoromethyl-2,3-dihydro-1H-indole in the form of a pale yellow liquid, which is used in the next step.
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH2:23]([NH2:26])[CH2:24][CH3:25]>>[CH3:22][C:3]1[C:2]([NH:26][CH2:23][CH2:24][CH3:25])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:4]=1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: CCCN
Product: CCCNc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2nc1C
Temperature: 100 °C
Yield: 57 %

Procedure:
Prepared similarly to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 50 mg, 0.169 mmol) and propan-1-amine (41.6 μl, 0.506 mmol, Aldrich), heating at 100° C. for 2 h. Purification by silica gel (100% DCM to 5% MeOH/DCM) provided 2-(2-methyl-3-(propylamino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (57% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.07 (t, J=7.34 Hz, 3H) 1.80 (sxt, J=7.39 Hz, 2H) 2.58 (s, 3H) 2.93 (t, J=6.85 Hz, 2H) 3.46-3.57 (m, 4H) 6.98 (br. s., 1H) 7.20 (d, J=2.35 Hz, 1H) 7.34-7.43 (m, 2H) 7.61 (dd, J=8.02, 1.17 Hz, 1H) 7.93 (d, J=7.63 Hz, 1H) 12.19 (br. s., 1H). MS (ESI, pos. ion) m/z: 336.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[S:21])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:4][CH:3]=1.[CH3:22]I>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([S:21][CH3:22])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:6][CH:7]=1
Reactant: CI
Reactant: COc1cc(-c2[nH]c(=S)[nH]c2-c2ccc(F)cc2)ccn1
Solvent: CO
Product: COc1cc(-c2[nH]c(SC)nc2-c2ccc(F)cc2)ccn1

Procedure:
A solution of 24d (1.0 g; 3.3 mmol) and methyl iodide (5.6 g; 39 mmol) in methanol (50 ml) was stirred under reflux for 3 h. The reaction mixture was cooled and filtered. The filtrate was concentrated and the residue was taken up in ethanol. Insoluble components were filtered off and the filtrate was concentrated. The residue was taken up in CH2Cl2/EtOH (9+1). Insoluble components were filtered off, and the filtrate was separated by column chromatography (SiO2 60, CH2Cl2/EtOH 9+1). M.p. 158° C.