Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:23])[N:4]([CH:20]([CH3:22])[CH3:21])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8].[CH3:24]OC(OC)N(C)C.C(O)(=O)C.[C:36]([C:38]1[CH:47]=[CH:46][C:41]([C:42]([NH:44][NH2:45])=O)=[CH:40][CH:39]=1)#[N:37]>CN(C)C=O.O>[CH:20]([N:4]1[C:3](=[O:23])[C:2]([N:1]2[CH:24]=[N:45][N:44]=[C:42]2[C:41]2[CH:46]=[CH:47][C:38]([C:36]#[N:37])=[CH:39][CH:40]=2)=[C:7]([CH3:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:16])[F:18])[CH:10]=2)[C:5]1=[O:19])([CH3:21])[CH3:22]
Reactant: Cc1c(N)c(=O)n(C(C)C)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: N#Cc1ccc(C(=O)NN)cc1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(-n2cnnc2-c2ccc(C#N)cc2)c(=O)n(C(C)C)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-isopropyl-6-methyl-5-nitro-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 195) (1.68 g) in ethyl acetate/methanol (20.0 ml/20.0 ml) was added palladium hydroxide (500.0 mg) and the resulting mixture was performed catalytic hydrogenation at room temperature for four and a half hours. The reaction mixture was degassed and then filtered through Celite (trade mark) and then concentrated under reduced pressure to afford the residue (897.0 mg) containing 5-amino-3-isopropyl-6-methyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione. A solution of the resulting residue (150.0 mg), dimethylformamide dimethylacetal (340 μl) and acetic acid (7 μl) in N,N-dimethy formamide (4.0 ml) was stirred at 110° C. for forty-five minutes and then cooled to room temperature, and thereto were added 4-cyanobenzohydrazide (221.4 mg) and acetic acid (690 μl) and the resulting mixture was stirred at 130° C. for two hours. To the reaction mixture was added water (30 ml) and the resulting mixture was extracted with ethyl acetate (30 ml×2). The organic layer was washed with water (30 ml×2) and saturated saline (30 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) and aminosilica gel column chromatography (eluent: ethyl acetate/methanol) to afford 4-(4-(3-isopropyl-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)benzonitrile (64.1 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.CN(C)[CH:9]=[CH:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)=O>C(O)(=O)C>[F:20][C:19]([F:21])([F:22])[C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:11]2[N:3]3[N:4]=[CH:5][CH:6]=[C:2]3[N:1]=[CH:9][CH:10]=2)[CH:14]=1
Reactant: Nc1cc[nH]n1
Reactant: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1
Solvent: CC(=O)O
Product: FC(F)(F)c1cccc(-c2ccnc3ccnn23)c1

Procedure:
A mixture of 8.31 g. of 3-aminopyrazole, 24.32 g. of 3-dimethylamino-3'-(trifluoromethyl)acrylophenone and 100 ml. of glacial acetic acid is refluxed for 8 hours and evaporated in vacuo to an oil. This oil is treated as described in Example 1, giving the desired product, m.p. 103°-104.5° C.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]1=2)=[O:4].[N:21]1([CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C(OCC)(=O)C>[N:21]1([CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][N:30]([CH2:2][C:3]([N:5]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[C:9](=[O:16])[NH:8][C:7]4[CH:17]=[CH:18][CH:19]=[CH:20][C:6]3=4)=[O:4])[CH2:29]2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: C1CCN(CC2CCCNC2)CC1
Reactant: O=C1Nc2ccccc2N(C(=O)CCl)c2ccccc21
Solvent: CCOC(C)=O
Product: O=C1Nc2ccccc2N(C(=O)CN2CCCC(CN3CCCCC3)C2)c2ccccc21

Procedure:
The title compound is prepared analogously to Example 35 from 5-(chloroacetyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one and 3-[(1-piperidinyl)methyl]piperidine to give colorless crystals, mp. 150°-152° C. (ethyl acetate).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[NH2:16][C:17]([NH2:19])=[S:18]>>[CH3:1][O:2][C:3]([C:4]1[N:16]=[C:17]([NH2:19])[S:18][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[O:15]
Reactant: NC(N)=S
Reactant: COC(=O)C(=O)C(Cl)c1ccc(F)cc1
Product: COC(=O)c1nc(N)sc1-c1ccc(F)cc1

Procedure:
prepared by reaction of 3-chloro-3-(4-fluoro-phenyl)-2-oxo-propionic acid methyl ester with thiourea. LC-MS: tR=0.75 min; [M+H]+=253.2.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:5]([NH2:10])=[CH:6][CH:7]=[CH:8][CH:9]=1.[N:11]([O-])=O.[Na+].[CH3:15][O:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1>C1(C)C(C)=CC=CC=1>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[N:11][C:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21]([NH:20][CH2:19][CH2:18][CH2:17][O:16][CH3:15])=[CH:22][CH:23]=1
Reactant: COc1ccccc1N
Reactant: COCCCNc1cccc2ccccc12
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: COCCCNc1ccc(N=Nc2ccccc2OC)c2ccccc12
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To a three liter flask was charged 200 grams of ice and 1.25 moles of hydrochloric acid. 63.6 grams of o-anisidine was added. At a temperature of 0°-3° C. was added 35 gm of sodium nitrite as a 40% solution. Once the o-anisidine was fully diazotized, 100 gm. of methoxypropyl alpha naphthylamine and 100 gm of xylene were added. The pH was then raised to between 3.5 and 4.0 with a mineral alkaline buffering agent. The coupling temperature was maintained at between 8°-12° C. while the mixture was stirred for 4 hours until a negative coupling test was achieved. The reaction was heated to 70°C. An organic layer was separated from an aqueous phase. Xylene was stripped under vacuum. The non-volatile tarry substance was dissolved in an aromatic high flash solvent which is 50% product/50% viscosity depressant, which solution is stable at -20° C. indefinitely.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([CH3:19])=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][NH:13][C:14]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:23]>>[CH2:1]([O:8][C:9]1[C:18]([CH3:19])=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][N:13]=[C:14]2[Cl:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc2c(=O)[nH]ccc2c1OCc1ccccc1
Product: Cc1ccc2c(Cl)nccc2c1OCc1ccccc1

Procedure:
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 5-(benzyloxy)-6-methyl-1,2-dihydroisoquinolin-1-one (100 mg, 0.38 mmol, 1.00 equiv) and POCl3 (10 mL). The resulting solution was heated to reflux for 3 h in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 250 mL of ethyl acetate. The resulting mixture was washed with 2×150 mL of water and 2×150 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20). This resulted in 70 mg (96%) of 5-(benzyloxy)-1-chloro-6-methylisoquinoline as an off-white solid. MS (ESI) m/z 284 ([M+H]+).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:20])(=[O:19])[NH:13][C:14]2[S:15][CH:16]=[CH:17][N:18]=2)=[CH:8][C:7]=1[CH3:21])=O.[OH-].[Na+].Cl>O>[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:13][C:14]2[S:15][CH:16]=[CH:17][N:18]=2)(=[O:20])=[O:19])=[CH:8][C:7]=1[CH3:21]
Reactant: Cc1cc(S(=O)(=O)Nc2nccs2)ccc1NC(=O)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(S(=O)(=O)Nc2nccs2)ccc1N
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 31.4 %

Procedure:
Synthesized according to general procedure 71. A solution of 2,2,2-trifluoro-N-(2-methyl-4-(N-thiazol-2-ylsulfamoyl)phenyl)acetamide (1 g, 2.74 mmol), NaOH (1.09 g, 27.4 mmol), and H2O (5 mL) was stirred at RT for 1 h, then cooled to 0° C. 1 N hydrochloric acid (27.4 mL, 27.4 mmol) was added, and the reaction was stirred at 0° C. for 20 min. The formed precipitate was filtered off and dried under vacuum to give 4-amino-3-methyl-N-(thiazol-2-yl)benzenesulfonamide (232 mg, 31%).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:29](O)=[O:30])[CH2:20][CH:21](C(C)(C)C)[C:22]([OH:24])=[O:23])=[O:17])[C:11]3C(=CC=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CN1CCOCC1.ClC(O[CH2:43][CH:44]([CH3:46])[CH3:45])=O.[BH4-].[Na+].[CH2:49]1[CH2:53]OC[CH2:50]1>CO>[C:44]([O:24][C:22](=[O:23])[CH2:21][CH2:20][C@H:19]([NH:18][C:16]([O:15][CH2:14][CH:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:53]2[C:11]1=[CH:10][CH:9]=[CH:50][CH:49]=2)=[O:17])[CH2:29][OH:30])([CH3:46])([CH3:45])[CH3:43]
Reactant: CC(C)COC(=O)Cl
Reactant: C1CCOC1
Reactant: CC(C)(C)C(C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: CO
Product: CC(C)(C)OC(=O)CC[C@@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of N-(9-fluorenylmethoxycarbonyl)-γ-t-butyl glutamic acid (8.51 g, 20.0 mmol) and NMM (2.42 mL, 1.1 eq) in dry THF (110 mL) under N2 at 0° C. was added isobutyl chloroformate (2.72 mL, 1.05 eq). After 20 min., the reaction e was filter-added to a solution of NaBH4 (1.5 g) in THF (120 mL)-MeOH (30 mL) at −78° C. under N2 and rinsed with dry THF (20 mL). After stirring for 2.5 h at −78° C., the reaction was quenched with acetic acid (13 mL). After concentrating to ˜50 mL, the residue was dissolved in ethyl acetate-hexanes (200 mL, 1:1), washed with water (150 mL×2). Aqueous layer was re-extracted with ethyl acetate-hexanes (150 mL, 1:1). Combined extract was washed with sat'd NaHCO3 (150 mL×2), dried (anhydrous Na2SO4), filtered and concentrated to give 8.30 g of the title compound as glasslike solid. The crude alcohol was used directly.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([SH:11])[N:3]=1.C(N(CC)CC)C.Cl[CH2:20][CH:21]([OH:44])[CH2:22][N:23]1[CH2:28][CH2:27][N:26]([CH:29]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:25][CH2:24]1>CN(C=O)C>[OH2:44].[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([S:11][CH2:20][CH:21]([OH:44])[CH2:22][N:23]2[CH2:24][CH2:25][N:26]([CH:29]([C:37]3[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=3)[C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)[CH2:27][CH2:28]2)[N:3]=1.[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([S:11][CH2:20][CH:21]([OH:44])[CH2:22][N:23]2[CH2:24][CH2:25][N:26]([CH:29]([C:37]3[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=3)[C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)[CH2:27][CH2:28]2)[N:3]=1
Reactant: OC(CCl)CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: Nc1nc(S)c2[nH]cnc2n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1nc(SCC(O)CN2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c2[nH]cnc2n1
Product: O
Reaction time: 0.08 h
Yield: 81.3 %

Procedure:
To 2-amino-6-mercaptopurine (10 mmol, 1.67 g) in DMF (25 mL) was added triethylamine (10 mmol, 1.4 mL). After stirring about 5 min, 1-(1-chloro-2-hydroxy-3-propanyl)-4-(4,4'-difluorobenzhydryl)piperazine (10 mmol, 3.81 g) in DMF (20 mL) was added dropwise over 5 min. under nitrogen. After one week, the DMF was removed in vacuo and the resultant crude solid was flash chromatographed over silica gel using 5% MeOH: CH2Cl2 to give the desired product (2.82 g, 55.1%) as a white solid, mp 118°-122° C. (dec.). MS DCI (M+1) 512; (400 MHz) 1H NMR (CDCl3) δ: 7.9 (s, 1H); 7.3 (m, 4H), 6.95 (m, 4H), 4.2 (s, 1H), 4.15 (m, 1H), 3.3 (m, 2H), 2.3-2.6 (m, 10H).
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14]Br)=[CH:7][CH:6]=1.[CH3:17][N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([CH:27]=[N:28][OH:29])=[C:19]1[CH3:30].[OH-].[Na+]>>[CH3:17][N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](/[CH:27]=[N:28]/[O:29][CH2:14][CH2:13][CH2:12][O:11][C:8]2[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:2])=[O:16])=[CH:6][CH:7]=2)=[C:19]1[CH3:30]
Reactant: Cc1c(C=NO)c2ccccc2n1C
Reactant: COC(=O)Cc1ccc(OCCCBr)cc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(/C=N/OCCCOc2ccc(CC(=O)O)cc2)c2ccccc2n1C
Temperature: 25 °C
Yield: 48.1 %

Procedure:
To a solution [4-(3-bromo-propoxy)-phenyl]-acetic acid methyl ester (0.47 g, 1.64 mmol) and 1,2-dimethyl-1H-indole-3-carbaldehyde oxime (0.32 g, 1.73 mmol) in 10/5/3 tetrahydrofuran/ethanol/water (21 mL) was added 2.5 M sodium hydroxide solution (6 mL). This mixture was heated to reflux for 2.5 hours and then allowed to cool back to room temperature. The mixture was partitioned between ethyl acetate and water. The aqueous layer was acidified to approximately pH 5 using 1 N hydrochloric acid. The layers were then separated. The aqueous layer was extracted with one additional portion of ethyl acetate. The organics were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography through silica gel using ethyl acetate/hexanes (20/80 with 1% formic acid) to give {4-[3-({[(1E)-(1,2-dimethyl-1H-indol-3-yl)methylidene]amino}oxy)propoxy]phenyl}acetic acid (0.30 g, 48%) as a white solid. mp=106.5-107.5° C. 1H NMR (400 MHz, DMSO-d6); δ 12.20 (bs, 1H), 8.45 (s, 1H), 7.95 (d, 1H), 7.43 (d, 1H), 7.16 (t, 1H), 7.14 (d, 2H), 7.07 (t, 1H), 6.88 (d, 2H), 4.23 (t, 2H), 4,09 (t, 2H), 3.67 (s, 3H), 3.46 (s, 2H), 2.47 (s, 3H), 2.13 (m, 2H). Mass spec; (ES+) m/z 381.2 Elemental analysis; Calculated for C22H24N2O4: C, 69.46; H, 6.36; N, 7.36. Found: C, 69.25; H, 6.23; N, 7.27.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:9]1[C:10]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]([CH:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:23][CH:22]=3)[CH:17]=2)=[N:11][C:12](Br)=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH3:55][C:56]([C:60]1[CH:65]=[C:64](B2OC(C)(C)C(C)(C)O2)[CH:63]=[CH:62][N:61]=1)([CH3:59])[C:57]#[N:58]>C1(C)C=CC=CC=1.O>[C:1]([O:5][C:6]([N:8]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:9]1[C:10]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]([CH:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:23][CH:22]=3)[CH:17]=2)=[N:11][C:12]([C:64]2[CH:63]=[CH:62][N:61]=[C:60]([C:56]([C:57]#[N:58])([CH3:59])[CH3:55])[CH:65]=2)=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C#N)c1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1-c1cc(-c2ccc(CN(C(=O)OC(C)(C)C)C3CCOCC3)cc2)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(-c2ccnc(C(C)(C)C#N)c2)nc1-c1cc(-c2ccc(CN(C(=O)OC(C)(C)C)C3CCOCC3)cc2)no1
Temperature: 70 °C
Yield: 68.1 %

Procedure:
A mixture of tert-butyl N-[[4-[5-[3-[bis(tert-butoxycarbonyl)amino]-6-bromo-pyrazin-2-yl]isoxazol-3-yl]phenyl]methyl]-N-tetrahydropyran-4-yl-carbamate (110.0 g, 151 mmol), K2CO3 (41.6 g, 301 mmol), and 2-methyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]propanenitrile (41.0 g, 151 mmol) in toluene (770 mL) and water (220 mL) is stirred and degassed with N2 for 30 min. at 20° C. The catalyst Pd(dtbpf)Cl2 (1.96 g, 3.01 mmol) is added and the mixture is degassed for an additional 10 min. The mixture is heated at 70° C. until the reaction is complete. The mixture is cooled to ambient temperature, diluted with water (220 mL), and filtered through a bed of Celite. The organic phase is concentrated to remove most of the solvent. The concentrate is diluted with i-PrOH (550 mL). The resultant suspension is stirred for at least 1 h and then the solid is collected by filtration to afford a tan powder. The solid is dissolved in toluene (990 mL) and stirred with Biotage MP-TMT resin (18.6 g) for 2 h at ambient temperature. The resin is removed by filtration. The filtrate is concentrated then diluted with i-PrOH (550 mL) and then re-concentrated. Add i-PrOH (550 mL) and stir for 1 h at ambient temperature. Cool the suspension to 5° C. and collect the solid by filtration then dry to afford tert-butyl N-[[4-[5-[3-[bis(tert-butoxycarbonyl)amino]-6-[2-(1-cyano-1-methyl-ethyl)-4-pyridyl]pyrazin-2-yl]isoxazol-3-yl]phenyl]methyl]-N-tetrahydropyran-4-yl-carbamate (Compound I-1) (81.9 g; 68%, yield, 98.7 area % purity by HPLC) as a cream-colored powder.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.Cl.Cl.[F:52][C:53]([F:64])([F:63])[C:54]1[CH:55]=[CH:56][C:57]([CH2:60][CH2:61][NH2:62])=[N:58][CH:59]=1.C(N(CC)CC)C>ClCCCl>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([C:18](=[O:20])[NH:62][CH2:61][CH2:60][C:57]3[CH:56]=[CH:55][C:54]([C:53]([F:64])([F:52])[F:63])=[CH:59][N:58]=3)=[CH:21][CH:22]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Reactant: NCCc1ccc(C(F)(F)F)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(C(F)(F)F)cn4)cc3)c(C#N)cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47.7 %

Procedure:
A mixture of 4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid (20 mg, 0.0566 mmol), 1-(3-(dimethylamino)propyl)-3-ethyl-carbodiimide hydrochloride (12.85 mg, 0.0670 mmol), 1-hydroxybenzotriazole monohydrate (10.26 mg, 0.0670 mmol), and 1,2-dichloroethane (1 mL) was stirred at ambient temperature for 20 minutes. 2-(5-(Trifluoromethyl)pyridin-2-yl)ethanamine dihydrochloride (19.23 mg, 0.0731 mmol) and triethylamine (84.91 μl, 0.6092 mmol) were added to the activated acid and the mixture was stirred for 18 hours at ambient temperature. The reaction mixture was purified on silica gel (MeOH in dichloromethane gradient) to provide 14.2 mg of the title compound as a thin film (48%).
Reaction SMILES: [C@H:1]1([NH:11][CH:12]=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(OC(=O)C)(=[O:16])C>>[O:16]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C@H:1]([NH:11][CH:12]=[O:13])[CH2:2][CH2:3]1
Reactant: O=CN[C@@H]1CCCc2ccccc21
Reactant: CC(=O)OC(C)=O
Product: O=CN[C@@H]1CCC(=O)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (R)—N-(1,2,3,4-tetrahydronaphthalen-1-yl)formamide (4.01 g, 22.9 mmol) in 40 mL of acetic anhydride at 0° C. was added Chomium(VI) oxide (6.00 g, 60.0 mmol). The solution was stirred at 0° C. for 1 h. The solution was filtered, extracted with EtOAc, washed with brine, dried over Na2SO4 and evaporated to dryness. flash chomatograph (SiO2, EtOAc/hexane=1:1 to 2:1 to pure EtOActo EtOAc/MeOH=10:1 to 10:2) afforded (R)—N-(4-oxo-1,2,3,4-tetrahydro-naphthalen-1-yl)formamide as a white solid.
Reaction SMILES: C1(Cl)C(Cl)=C(Cl)C(=O)C(=O)C=1Cl.[Br:13][C:14]1[N:15]=[C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][CH:25]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)[CH2:24][CH2:23]3)=[N:18][N:17]2[C:33]=1[CH:34]1[CH:39]=[CH:38][N:37](C(OCC)=O)[N:36]=[CH:35]1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.ClCCl>[Br:13][C:14]1[N:15]=[C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][CH:25]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)[CH2:24][CH2:23]3)=[N:18][N:17]2[C:33]=1[C:34]1[CH:39]=[CH:38][N:37]=[N:36][CH:35]=1
Reactant: CCOC(=O)N1C=CC(c2c(Br)nc3ccc(N4CCC(N5CCCC5)CC4)nn23)C=N1
Agent: O=C1C(=O)C(Cl)=C(Cl)C(Cl)=C1Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Brc1nc2ccc(N3CCC(N4CCCC4)CC3)nn2c1-c1ccnnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.4 %

Procedure:
0.101 g of ortho-chloranil (0.41 mmol) in solution in 1 ml of toluene is added to a mixture of 0.16 g (0.32 mmol) of ethyl 4-[2-bromo-6-(4-pyrrolidin-1-ylpiperidin-1-yl)imidazo[1,2-b]pyridazin-3-yl]-4H-pyridazine-1-carboxylate in 4 ml of chloroform. The mixture is stirred at ambient temperature for 1 hour and then diluted with 40 ml of dichloromethane. The solution is washed with 2 ml of a 2N aqueous solution of sodium hydroxide and then with a saturated solution of sodium chloride. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure after the addition of silica gel. The evaporation residue is loaded onto a silica gel column and the product is purified by chromatography on a silica gel column, elution being carried out with a mixture of 0 to 10% of methanol in dichloromethane. 0.080 g of product is thus isolated.
Reaction SMILES: CN(C)CCN.C(N(CC)C(C)C)(C)C.[C:16]1([S:22]([O-:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Na+].C(OC([N:33]1[CH2:37][CH2:36][CH:35]2[C:38]3[CH:39]=[C:40](I)[CH:41]=[CH:42][C:43]=3[O:44][CH2:45][CH:34]12)=O)(C)(C)C>CS(C)=O.[Cu]I.O>[C:16]1([S:22]([C:40]2[CH:41]=[CH:42][C:43]3[O:44][CH2:45][CH:34]4[CH:35]([C:38]=3[CH:39]=2)[CH2:36][CH2:37][NH:33]4)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S([O-])c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC2c3cc(I)ccc3OCC21
Agent: [Cu]I
Agent: CN(C)CCN
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: O=S(=O)(c1ccccc1)c1ccc2c(c1)C1CCNC1CO2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83.7 %

Procedure:
Copper(I) iodide (19 mg, 0.10 mmol) was added to a stirring solution of N,N-dimethyl-1,2-ethanediamine (21 μL, 0.20 mmol) in DMSO (2 mL). The reaction was stirred at RT for 10 minutes. N,N-diisopropylethylamine (130 μL, 0.75 mmol), sodium benzenesulfinate (245 mg, 1.5 mmol) and tert-butyl-8-iodo-1,3a,4,9b-tetrahydrochromeno[3,4-b]pyrrole-3(2H)-carboxylate (P05, enantiomer 1,200 mg, 0.5 mmol) were then added sequentially. The reaction was stirred at 100° C. for 18 h. After cooling to RT, water (24 mL) was added and the resulting suspension was extracted with DCM (3×). The combined organic layers were washed with water (2×) and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting oil was stirred in TFA:DCM (1:1, 2 mL) for 30 min and the solvent was evaporated. This crude product was purified by preparative LC/MS. The resulting material was suspended in DCM, washed with 1N aqueous sodium hydroxide (3×) and water (3×) and the solvent evaporated. The product was converted to the HCl salt by dissolving the free base in a small amount of DCM, adding 1.0 N HCl in diethyl ether and evaporating the solvent to provide 132 mg of 8-(phenylsulfonyl)-1,2,3,3a,4,9b-hexahydrochromeno[3,4-b]pyrrole, Enantiomer 1. MS m/z 316 [M+H]+. 1H-NMR (400 MHz, DMSO-d6): δ 1.91-1.97 (m, 1H), 2.53-2.60 (m, 1H), 2.98-3.02 (m, 1H), 3.19-3.22 (m, 1H), 3.72-3.77 (m, 1H), 4.09 (bs, 1H), 4.24-4.32 (m, 2H), 7.09 (d, J=2.1 Hz, 1H), 7.59-7.74 (m, 4H), 7.94-7.99 (m, 3H), 9.13 (bs, 1H), 9.79 (bs, 1H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]1[CH2:14][NH:13][C:12](=[O:15])[CH2:11]1.[H-].[Na+].[CH3:18]I>>[CH3:18][N:13]1[CH2:14][CH:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)[CH2:11][C:12]1=[O:15]
Reactant: O=C1CC(c2cc3ccccc3o2)CN1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CN1CC(c2cc3ccccc3o2)CC1=O
Yield: 81 %

Procedure:
The compound is prepared from 4-(2-benzofuryl)-pyrrolidin-2-one, sodium hydride and methyl iodide, as described in Example 5. B.p.(0.3 mm Hg)=172° C. M.p. 73° C. Yield: 81%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:12][CH2:13]Cl.[CH3:21][NH2:22]>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@H:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:12][CH2:13][NH:22][CH3:21]
Reactant: ClCCC(c1ccccc1)n1ccc2c(Cl)cccc21
Reactant: CN
Product: CNCC[C@@H](c1ccccc1)n1ccc2c(Cl)cccc21

Procedure:
4-chloro-1-(3-chloro-1-phenyl-propyl)-1H-indole (0.228 g) was reacted with methylamine following the procedure of step 3 of Example 11 to afford 0.135 g of (S)-[3-(4Chloro-indol-1-yl)-3-phenyl-propyl]-methyl-amine, (M+H=300).