Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1.FC(F)(F)C(O)=O.[CH2:20]([C:22]1[S:23][CH:24]=[C:25]([C:27]([N:29]2[CH2:34][C:33]3([CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[O:32][CH2:31][CH2:30]2)=[O:28])[N:26]=1)[CH3:21].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.O>[CH2:20]([C:22]1[S:23][CH:24]=[C:25]([C:27]([N:29]2[CH2:34][C:33]3([CH2:39][CH2:38][N:37]([CH2:2][CH2:3][C:4]4[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=4)[CH2:36][CH2:35]3)[O:32][CH2:31][CH2:30]2)=[O:28])[N:26]=1)[CH3:21]
Reactant: CCc1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reactant: OCCc1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCCC1=O
Solvent: O
Product: CCc1nc(C(=O)N2CCOC3(CCN(CCc4ccc(CCO)cc4)CC3)C2)cs1
Temperature: 75 °C
Reaction time: 4 h

Procedure:
A solution of 2-(4-(2-bromoethyl)phenyl)ethanol [Organometallics 2002, 21(20), 4217] (1.71 g) in NMP (5 mL) was added to a suspension of (2-ethylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate [Example 3, step b] (3.0 g) and cesium carbonate (5.60 g) in NMP (10 mL) and the mixture stirred at 75° C. under nitrogen for 4 hours. More 2-(4-(2-bromoethyl)phenyl)ethanol (0.65 g) was added and the mixture stirred at 75° C. for 18 hours. The mixture was cooled, diluted with water and extracted into ethyl acetate (×3). The combined extracts were washed with 10% brine, 30% brine and saturated brine, dried over magnesium sulfate, filtered and the solvent removed. The crude product was purified by flash silica chromatography, successively eluted with 50% ethyl acetate in isohexane with 5% triethylamine, then 100% ethyl acetate with 5% triethylamine, then 10% methanol in ethyl acetate with 5% triethylamine. Fractions containing the product were evaporated to dryness to afford the subtitled compound as a yellow oil. Yield 1.90 g.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]([CH2:12][C:13](OCC)=O)[C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=3[CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Na+].CC[O:32]CC>>[CH:1]1[C:11]2[CH:10]([CH:12]([OH:32])[CH3:13])[C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=3[CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CC1c2ccccc2COc2ccccc21
Reactant: CCOCC
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Product: CC(O)C1c2ccccc2COc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
27 g. (0.096 mol) ethyl 6,11-dihydrodibenz[b,e]-oxepin-11-yl-acetate were added dropwise, with cooling, to a suspension of 3.8 g. (0.1 mol) lithium aluminum hydride in 300 ml. ether. The reaction mixture was subsequently stirred for 2 hours at ambient temperature, decomposed by the addition of a saturated aqueous solution of sodium chloride and the precipitated hydroxides were filtered off with suction and the filtrate was evaporated. The residue consisted of practically pure 6,11-dihydrodibenz[b,e]oxepin-11-yl-ethanol in a yield of 22.4 g. (97.5% of theory). 10 g. of this product were distilled in a high vacuum. There were obtained 9.0 g. of the product with a boiling point of 158° - 159°C./0.2 mm.Hg.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=3)[N:9]=2)=[C:5]([CH3:7])[N:6]=1.[Cl:24][CH2:25][C:26](Cl)=[O:27].N1C=CC=CC=1.CC#N>CN(C=O)C.C(O)(C(F)(F)F)=O>[Cl:24][CH2:25][C:26]([NH:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=3)[N:9]=2)=[C:5]([CH3:7])[N:6]=1)=[O:27]
Reactant: Cc1nc(N)sc1-c1ccnc(Nc2cccc([N+](=O)[O-])c2)n1
Reactant: O=C(Cl)CCl
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1nc(NC(=O)CCl)sc1-c1ccnc(Nc2cccc([N+](=O)[O-])c2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of [4-(2-amino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl]-(3-nitro-phenyl)-amine (0.33 g, 1.0 mmol) in dry DMF (3 mL) was cooled on an ice-water bath. Chloroacetyl chloride (0.22 g, 2.0 mmol) and pyridine (80 μL) were added. After stirring at room temperature for 18 h, the product was isolated as a brown solid by preparative RP-HPLC (Vydac 218TP1022, 9 mL/min) using a gradient from 10-70% MeCN in 0.1% aq CF3COOH over 40 min. Anal. RP-HPLC: tR=20.62 min (Vydac 218TP54, 0-60% MeCN in 0.1% aq CF3COOH over 20 min, 1 mL/min, 25° C., purity >97%). 1H-NMR (DMSO-d6) δ: 2.45 (s, 3H, CH3), 4.12 (s, 2H, CH2), 7.03(d, 1H, J=5.2 Hz, pyrimidinyl-H), 7.42 (m, 1H, Ph-H), 7.63 (m, 1H, Ph-H), 8.01 (m, 1H, Ph-H), 8.41 (d, 1H, J=5.2 Hz, pyrimidinyl-H), 8.64 (s, 1H, Ph-H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[N:9]=[CH:10][C:11]3[CH2:17][CH2:16][C@H:15]([C:18]([OH:20])=O)[O:14][C:12]=3[N:13]=2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Si:45]([O:52][CH2:53][C@H:54]([C:56]1[CH:61]=[CH:60][C:59]([Cl:62])=[C:58]([F:63])[CH:57]=1)[NH2:55])([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46].CCN(C(C)C)C(C)C.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C(Cl)Cl>[Si:45]([O:52][CH2:53][C@@H:54]([NH:55][C:18]([C@@H:15]1[O:14][C:12]2[N:13]=[C:8]([NH:7][CH:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)[N:9]=[CH:10][C:11]=2[CH2:17][CH2:16]1)=[O:20])[C:56]1[CH:61]=[CH:60][C:59]([Cl:62])=[C:58]([F:63])[CH:57]=1)([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H](N)c1ccc(Cl)c(F)c1
Reactant: O=C(O)[C@H]1CCc2cnc(NC3CCOCC3)nc2O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H](NC(=O)[C@H]1CCc2cnc(NC3CCOCC3)nc2O1)c1ccc(Cl)c(F)c1
Reaction time: 18 h
Yield: 48.4 %

Procedure:
A vial was charged 408 (0.050 g, 0.15 mmol), HATU (0.069 g, 0.18 mmol), 68 (0.055 g, 0.18 mmol), DIPEA (1 mL), DCM (2 mL) and DMF (1 mL) and stirred for 18 h. To the solution was added satd. aq. Na2CO3 (5 mL), and the mixture stirred for 5 min. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography (SNAP 25) eluting with DCM/MeOH (95:5) to afford 0.041 g (43%) of (R)—N—((S)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-2-(tetrahydro-2H-pyran-4-ylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine-7-carboxamide (410): MS m/z (APCI-pos) M+1=565.0.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:20][CH:21]([F:31])[O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=O>>[F:20][CH:21]([F:31])[O:22][C:23]1[CH:24]=[C:25]([CH2:26][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)[CH:28]=[CH:29][CH:30]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1cccc(OC(F)F)c1
Product: FC(F)Oc1cccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-(difluoromethoxy)benzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[[3-(difluoromethoxy)phenyl]methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([C@H:20]3[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]3)=[C:13]3[C:17]=2[C:16](=[O:18])[N:15]([CH3:19])[CH2:14]3)[C:5]([C:27]([F:30])([F:29])[F:28])=[CH:4][N:3]=1.[NH2:31][C:32]1[N:37]=[CH:36][C:35]([CH2:38][P:39](=[O:46])([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42])=[CH:34][C:33]=1[O:47][CH3:48].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[OH:26][C@H:23]1[CH2:24][CH2:25][C@H:20]([C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6]3[C:5]([C:27]([F:30])([F:29])[F:28])=[CH:4][N:3]=[C:2]([NH:31][C:32]4[N:37]=[CH:36][C:35]([CH2:38][P:39](=[O:46])([O:40][CH2:41][CH3:42])[O:43][CH2:44][CH3:45])=[CH:34][C:33]=4[O:47][CH3:48])[N:7]=3)=[C:17]3[C:13]=2[CH2:14][N:15]([CH3:19])[C:16]3=[O:18])[CH2:21][CH2:22]1
Reactant: CN1Cc2c(c(Nc3nc(Cl)ncc3C(F)(F)F)ccc2[C@H]2CC[C@H](O)CC2)C1=O
Reactant: CCOP(=O)(Cc1cnc(N)c(OC)c1)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CCOP(=O)(Cc1cnc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](O)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Temperature: 25 °C

Procedure:
To a suspension of 7-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-4-(trans-4-hydroxycyclohexyl)-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 308C, 130.0 mg, 0.29 mmol), diethyl [(6-amino-5-methoxypyridin-3-yl)methyl]phosphonate (Compound 308A, 80.9 mg, 0.29 mmol), Pd(OAc)2 (3.31 mg, 0.015 mmol), Xantphos (17.1 mg, 0.029 mmol), and Cs2CO3 (192.2 mg, 0.59 mmol) in dry dioxane (1.2 mL) was bubbled nitrogen for 2 min. This mixture was then irradiated at 160° C. for 40 min in a CEM microwave reactor. After cooled to room temperature, the reaction mixture was filtered and the filtrate was concentrated and purified by silica gel chromatography (1-5% MeOH in DCM) to give 1.9 mg of the title compound (yield: 1%). 1H NMR (CDCl3, 400 MHz): δ=1.29 (t, J=7.2 Hz, 6 H), 1.45 (m, 2 H), 1.63 (m, 2 H), 1.90 (m, 2 H), 2.16 (m, 2 H), 2.50 (m, 1 H), 3.18 (d, J=21.2 Hz, 2 H), 3.22 (s, 3 H), 3.77 (m, 1 H), 3.94 (s, 3 H), 4.04-4.10 (m, 4 H), 4.39 (s, 2 H), 7.41 (d, J=8.4 Hz, 1 H), 8.04 (s, 1 H), 8.45 (s, 1 H), 9.33 (d, J=8.0 Hz, 1 H), 10.86 (s, 1 H). MS (ES+): m/z 679.23 [MH+]. HPLC: tR=1.21 min (UPLC TOF, polar—3 min).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([N:14]1[N:18]=[C:17]2[CH:19]=[CH:20][CH:21]=[C:22]([Cl:23])[C:16]2=[N:15]1)[CH2:11][C:12]#[CH:13]>>[Cl:23][C:22]1[C:16]2[C:17](=[N:18][N:14]([CH2:10][CH2:11][C:12]#[C:13][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=3)[N:15]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: FCc1cccc(Br)n1
Reactant: C#CCCn1nc2cccc(Cl)c2n1
Product: FCc1cccc(C#CCCn2nc3cccc(Cl)c3n2)n1
Yield: 34 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (30 mg, 0.16 mmol) and 2-(but-3-ynyl)-4-chloro-2H-benzo[d][1,2,3]triazole (30 mg, 0.15 mmol, Example 146(B)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 16-mg (51 μmol, 35%) of 4-chloro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]([I:12])[C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:16])=O>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]([I:12])[C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=C(O)c1c(I)ccc(Cl)c1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cl)c1c(I)ccc(Cl)c1Cl
Reaction time: 2 h

Procedure:
DMF (one drop) was added to a stirred solution of 2,3-dichloro-6-iodobenzoic acid (1.53 g, 4.83 mmol) and oxalyl chloride (2 ml) in ethyl acetate (20 ml). After 2 hours, the solution was evaporated and the product was used immediately.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([OH:10])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C[O-].[Na+].[I-].[K+].Br[CH:17]([C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[CH:24][CH:23]=1)[C:18]([O:20][CH3:21])=[O:19]>CO.C1C=CC=CC=1.O>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][CH:17]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]4[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=4)=[CH:24][CH:23]=3)[C:18]([O:20][CH3:21])=[O:19])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Oc1ccc2c(c1)CCC2
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: C[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)C(Oc1ccc2c(c1)CCC2)c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
To a solution of 3.36 g of 5-indanol, 1.19 g of sodium methoxide and 50 mg of potassium iodide in 40 ml of methanol is added 7.11 g of methyl α-bromo-α-[p-(p-chlorophenoxy)phenyl]acetate in 10 ml of benzene. The mixture is refluxed overnight and added to 100 ml of water. The mixture is then extracted with 2 × 75 ml of ether and the combined extracts are washed with 50 ml of 5% NaOH, 50 ml of water, 50 ml of saturated brine and dried (MgSO4). Evaporation of the solvent yields a yellow oil. Chromatography on 100 g of silica gel (benzene, 400 ml) yields a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH2:24][C:25]2[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[C:27]([F:33])[C:26]=2[F:34])=[CH:17][C:3]=1[NH:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([O:14][CH3:15])[N:8]=[C:7](Cl)[N:6]=1.Cl.[CH3:36][NH:37][CH3:38].C(N(CC)C(C)C)(C)C>C(#N)C.O>[Cl:1][C:2]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH2:24][C:25]2[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[C:27]([F:33])[C:26]=2[F:34])=[CH:17][C:3]=1[NH:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([O:14][CH3:15])[N:8]=[C:7]([N:37]([CH3:38])[CH3:36])[N:6]=1
Reactant: COc1cc(Cl)c(Nc2nc(Cl)nc(OC)c2[N+](=O)[O-])cc1OCc1c(OC)ccc(F)c1F
Reactant: CNC
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc(Cl)c(Nc2nc(N(C)C)nc(OC)c2[N+](=O)[O-])cc1OCc1c(OC)ccc(F)c1F
Temperature: 60 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
A mixture of 2-chloro-N-(2-chloro-6-methoxy-5-nitropyrimidin-4-yl)-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyaniline (0.1 g), dimethylamine hydrochloride (41 mg) and N,N-diisopropylethylamine (0.13 mL) in acetonitrile (2 mL) was stirred at 60° C. for 2 hours. The reaction mixture was diluted with water, and the precipitated crystals were collected by filtration. The crystals were washed with water and diethyl ether, and dried under reduced pressure to give 2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-N-(6-methoxy-2-dimethylamino-5-nitropyrimidin-4-yl)-4-methoxyaniline (86 mg). The title compound was prepared in a similar manner to that described in Example 171 using this material instead of ethyl 2-[4-chloro-2-(2-fluoro-6-methoxybenzyloxy)-4-(6-methoxy-2-methoxymethyl-5-nitropyrimidin-4-ylamino)phenoxy]acetate.
Reaction SMILES: C(OC([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17](OS(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(=O)=O)[CH:18]=2)[NH:13][C:12]=1C)=O)C1C=CC=CC=1.C([N:40](CC)CC)C.CN(CC#C)C.C(OCC)(=O)C.CO.C(N(CC)CC)C>C1COCC1.[Cu]I.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[C:12]1[NH2:40]
Reactant: Cc1[nH]c2ccc(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2c1C(=O)OCc1ccccc1
Reactant: CCN(CC)CC
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cc2ccccc2[nH]1
Temperature: 80 °C
Reaction time: 48 h
Yield: 62.3 %

Procedure:
2-Methyl-5-(nonafluorobutane-1-sulfonyloxy)-1H-indole-3-carboxylic acid benzyl ester (0.480 g, 0.85 mmol, 1 eq, Example 52, Step A) was dissolved in dry THF (10 mL) under Ar. Triethylamine (0.223 mL, 1.6 mmol, 2.0 eq) was added followed by the addition of copper (1) iodide (0.008 g, 0.04 mmol, 5 mol %), dichloropalladium (II) bis-diphenylphosphinoferrocene (0.016 g, 0.02 mmol, 2 mol %), and N,N-dimethylpropargylamine (0.184 mL, 1.6 mmol, 2 eq). The reaction mixture was stirred at 80° C. and followed by TLC (ethyl acetate/methanol/triethylamine 87/10/3). After 48 hours, the reaction was loaded on silica gel and chromatographed, (ethyl acetate/methanol/triethylamine 87/10/3). The resulting product was contaminated with bis-alkyne side product, and was further purified using reverse-phase prep-HPLC 10%-1 00% Acetonitrile/water, 0.1% TFA. 0.070 g (18% yield) of the indole-amine was obtained as a brown semisolid: LC/MS (ESI+) 347 (M+1).
Reaction SMILES: [CH:1]12[CH2:18][CH:8]([CH2:9][N:10]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:11]1)[C:7]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]2=1.[Cl:19][S:20](O)(=[O:22])=[O:21]>>[F:14][C:13]([F:15])([F:16])[C:12]([N:10]1[CH2:11][CH:1]2[CH2:18][CH:8]([C:7]3[CH:6]=[CH:5][C:4]([S:20]([Cl:19])(=[O:22])=[O:21])=[CH:3][C:2]=32)[CH2:9]1)=[O:17]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(N1CC2CC(C1)c1ccccc12)C(F)(F)F
Product: O=C(N1CC2CC(C1)c1cc(S(=O)(=O)Cl)ccc12)C(F)(F)F
Reaction time: 0.08 h
Yield: 86.2 %

Procedure:
1-(10-Aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone (530 mg, 2.1 mmol) was added to chlorosulfonic acid (2 mL, 30 mmol) and stirred for 5 minutes. The mixture was quenched with ice, extracted with ethyl acetate, dried (Na2SO4), filtered and concentrated to provide an oil (640 mg, 87%). (TLC 30% ethyl acetate/hexanes Rf 0.15).
Reaction SMILES: Cl.[CH:2]1([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([C:16]3[CH:17]=[CH:18][C:19]4[C:20]5[CH2:29][NH:28][CH2:27][CH2:26][C:21]=5[N:22]([CH3:25])[C:23]=4[CH:24]=3)[C:12](=[O:30])[CH:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:31](N(CC)CC)C.C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO>[CH:2]1([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([C:16]3[CH:17]=[CH:18][C:19]4[C:20]5[CH2:29][N:28]([CH3:31])[CH2:27][CH2:26][C:21]=5[N:22]([CH3:25])[C:23]=4[CH:24]=3)[C:12](=[O:30])[CH:11]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CCN(CC)CC
Reactant: Cn1c2c(c3ccc(-n4ccc(OCC5CCCCC5)cc4=O)cc31)CNCC2
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: CO
Product: CN1CCc2c(c3ccc(-n4ccc(OCC5CCCCC5)cc4=O)cc3n2C)C1
Temperature: 25 °C
Yield: 69.2 %

Procedure:
To a solution of 4-(cyclohexylmethoxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one hydrochloride (110 mg, 0.26 mmol) in CH3OH (5 mL) was added triethylamine (90 μL, 2.5 mmol), formaldehyde (30 μL, 0.39 mmol) and NaBH(OAc)3 (110 mg, 0.52 mmol). The reaction was stirred at room temperature until complete. The solvent was removed under reduced pressure, and the residue was dissolved in CH2Cl2. The organic solution was washed with H2O and 5% aqueous LiCl and dried over Na2SO4. After filtration and concentration, the residue was purified by flash column chromatography (silica gel, 10% CH3OH in CH2Cl2) to give 4-(cyclohexylmethoxy)-1-(2,5-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one as a white solid (73 mg, 69%). The free base was converted to the HCl salt to give the title compound (84 mg, 100%) as a white powder: mp 270-272° C.; 1H NMR (500 MHz, DMSO-d6) δ 10.53 (s, 1H), 7.53 (d, J=7.5 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.50 (d, J=1.5 Hz, 1H), 7.00 (dd, J=8.5, 1.5 Hz, 1H), 6.04 (dd, J=7.5, 2.5 Hz, 1H), 5.85 (d, J=3.0 Hz, 1H), 4.64 (d, J=13 Hz, 1H), 4.30 (dd, J=14, 7.5 Hz, 1H), 3.82 (d, J=6.0 Hz, 2H), 3.80-3.78 (m, 1H), 3.69 (s, 3H), 3.51-3.47 (m, 1H), 3.18 (t, J=5.5 Hz, 2H), 2.98 (d, J=4.5 Hz, 3H), 1.80-1.65 (m, 6H), 1.30-1.01 (m, 5H); ESI MS m/z 406 [M+H]+; HPLC (Method A)>99% (AUC), tR=14.4 min.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[C:8]1[C:9]([CH:14]=[O:15])=[N:10][N:11]([CH3:13])[CH:12]=1.[F:16][C:17]1[C:22]([F:23])=[C:21]([F:24])[CH:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])O.[Na+]>CCO.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:13][N:11]1[CH:12]=[C:8]([C:20]2[CH:19]=[CH:18][C:17]([F:16])=[C:22]([F:23])[C:21]=2[F:24])[C:9]([CH:14]=[O:15])=[N:10]1
Reactant: OB(O)c1ccc(F)c(F)c1F
Reactant: Cn1cc(Br)c(C=O)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CCO
Product: Cn1cc(-c2ccc(F)c(F)c2F)c(C=O)n1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
Potassium carbonate (0.418 mL, 0.836 mmol), Pd(OAc)2 (2.82 mg, 0.013 mmol) was added to a stirred, room temperature mixture of 4-bromo-1-methyl-1H-pyrazole-3-carbaldehyde (79 mg, 0.418 mmol) and (2,3,4-trifluorophenyl)boronic acid (96 mg, 0.543 mmol) in EtOH (0.7 mL) and the mixture was stirred at 90° C. for 24 hours. The mixture was cooled, aqueous sodium hydrogen carbonate (saturated, 10 mL) was added and the mixture was extracted with ethyl acetate (2×15 mL). The combined organic fractions were washed with water, dried (MgSO4) and filtered. The solvent was evaporated under reduced pressure to give the crude intermediate which was used in the next step.
Reaction SMILES: [C:1]([NH2:4])(=[S:3])[CH3:2].Br.Br[CH2:7][C:8]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=O.[OH-].[NH4+]>CO.O>[CH3:2][C:1]1[S:3][CH:7]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:4]=1
Reactant: O=C(CBr)c1cccnc1
Reactant: CC(N)=S
Agent: Br
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nc(-c2cccnc2)cs1
Reaction time: 1 h
Yield: 77.2 %

Procedure:
A solution of thioacetamide (5 g) in methanol (25 ml) was added dropwise to a stirred suspension of 3-bromoacetylpyridine hydrobromide (17,75 g) in methanol (89 ml) at room temperature over ten minutes. After about one hour, the hydrobromide of the product crystallized out. The mixture was diluted with ether (100 ml) and the product was isolated by filtration. The solid was dissolved in water and the solution was basified with ammonium hydroxide. The product was extracted into ether and the extract was washed with saturated salt solution, then evaporated to give 2-methyl-4-(pyridin-3-yl)-thiazole as a crystalline solid (8,6 g) Mp 81° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:16][C@H:15]3[C@H:10]([NH:11][CH2:12][CH2:13][CH2:14]3)[CH2:9]2)=[N:6][CH:7]=1.[C:17](=O)([O-])[O-].[K+].[K+].IC>C(#N)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:16][C@H:15]3[C@H:10]([N:11]([CH3:17])[CH2:12][CH2:13][CH2:14]3)[CH2:9]2)=[N:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Brc1ccc(N2C[C@@H]3CCCN[C@@H]3C2)nc1
Agent: [K+]
Solvent: CC#N
Solvent: CI
Solvent: O
Product: CN1CCC[C@H]2CN(c3ccc(Br)cn3)C[C@H]21
Temperature: 25 °C
Yield: 64.2 %

Procedure:
Compound 23a (600 mg, 2.13 mmol) was dissolved in acetonitrile. Potassium carbonate (590 mg, 4.26 mmol) and iodomethane (652 mg, 3.20 mmol) were added. The resulting mixture was allowed to react overnight at 80° C. and monitored by TLC. After the reaction completed, it was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phase was washed with saturated saline solution, and dried over anhydrous sodium sulfate. Column chromatography afforded 405 mg of white solid (compound 23b), yield 64%.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[N:7]1([CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3([C:28]#[N:29])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1.[OH-].[Na+].[ClH:32]>CCOCC.C(Cl)Cl.O1CCOCC1>[ClH:32].[ClH:32].[N:7]1([CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3([CH2:28][NH2:29])[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[CH:18][CH:17]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: N#CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCOCC
Product: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Temperature: 7.5 °C
Yield: 81 %

Procedure:
To a stirred suspension of LiAlH4 (1.81 g, 47.7 mmol, 5 eq) in Et2O/DCM (1:1, 30 mL) at 0 to 5° C. under a nitrogen atmosphere was added 4-[4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-carbonitrile (3 g, 9.55 mmol) in Et2O/DCM (1:1, 30 mL) over 15 minutes maintaining the temperature at 5 to 10° C. The reaction mixture was allowed to warm up to ambient temperature and stirred until complete. Sodium hydroxide (2N, 15 mL) was added dropwise and the resulting solids were filtered, washed with Et2O/DCM (1:1, 6×50 mL) and concentrated in vacuo at 40° C. A portion of the crude product from the above reaction (0.5 g, 1.57 mmol) was dissolved in dioxane (5 mL) and 4M HCl in dioxane (1.18 mL) added under N2. The reaction was stirred for 3 hours and filtered under a blanket of N2 (hygroscopic), washed with TBME and dried in the oven at 40° C. to give the title compound as a white solid (0.5 g, 81%). 1H NMR (400 MHz, DMSO-d6) δ11.24 (br s, 1H), 8.00 (br s, 3H), 7.33 (d, 2H), 6.98 (d, 2H), 4.08 (t, 2H), 3.76-3.63 (m, 2H), 3.60-3.46 (m, 2H), 3.45-3.18 (m, 4H), 3.07-2.87 (m, 4H), 2.25-1.77 (m, 10H).