Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:43])[C@H:4]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]2[C:40]([Cl:41])=[CH:39][CH:38]=[CH:37][C:36]=2[Cl:42])=[O:34])=[CH:28][CH:27]=1)[NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=2)=[O:15])=[CH:10][C:9]=1[Cl:24])=[O:7].[OH-].[Li+]>CO.O1CCCC1>[Cl:24][C:9]1[CH:10]=[C:11]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=2)=[O:15])[CH:12]=[CH:13][C:8]=1[C:6]([NH:5][C@H:4]([C:3]([OH:43])=[O:2])[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([NH:32][C:33]([C:35]2[C:36]([Cl:42])=[CH:37][CH:38]=[CH:39][C:40]=2[Cl:41])=[O:34])=[CH:30][CH:31]=1)=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)c1ccc(C(=O)Nc2cccc(O)c2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1cccc(O)c1)c1ccc(C(=O)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.3 %

Procedure:
A solution of N-[[2-chloro-4-[[(3-hydroxyphenyl)amino]carbonyl]phenyl]carbonyl]-4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester (35 mg; 0.053 mmol) in methanol (0.35 mL) and tetrahydrofuran (0.35 mL) was treated with an aqueous 1N lithium hydroxide solution (0.16 mL) and the mixture was stirred at room temperature under argon for 90 minutes. The solution was concentrated under reduced pressure, then was diluted with water (5 mL) and extracted with diethyl ether (2×5 mL). The separated aqueous layer was acidified with 1 N HCl (0.18 mL) and the resulting colorless solid was filtered off, washed with water, and dried to give 29 mg of N-[[2-chloro-4-[[(3-hydroxyphenyl)amino]carbonyl]phenyl]carbonyl]-4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine. FAB HRMS: (C31H24Cl3N3O6) Obs. Mass 640.0821 Calcd. Mass 640.0809 (M+H).
Reaction SMILES: [CH:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([CH2:12][CH2:13]S(C)(=O)=O)[CH2:4]1)=[O:2].[Cl:18][C:19]1[CH:27]=[C:26]2[C:22]([C:23]([C:28]3[CH2:29][CH2:30][NH:31][CH2:32][CH:33]=3)=[CH:24][NH:25]2)=[CH:21][CH:20]=1>CC(C)=O>[Cl:18][C:19]1[CH:27]=[C:26]2[C:22]([C:23]([C:28]3[CH2:29][CH2:30][N:31]([CH2:13][CH2:12][CH:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[N:3]([CH:1]=[O:2])[CH2:4]4)[CH2:32][CH:33]=3)=[CH:24][NH:25]2)=[CH:21][CH:20]=1
Reactant: Clc1ccc2c(C3=CCNCC3)c[nH]c2c1
Reactant: CS(=O)(=O)CCC1CN(C=O)c2ccccc21
Solvent: CC(C)=O
Product: O=CN1CC(CCN2CC=C(c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
From 19b and 6-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole. Mp 183-5° C. (from acetone). 1H NMR (DMSO-d6, the spectrum shows hindered rotation which is eliminated by heating above 100° C.) δ 1.60-1.80 (m, 1H), 1.95-2.10 (m, 1H), 2.35-2.55 (m, 4H), 2.70 (t, 2H), 3.15 (s, 2H), 3.35-3.55 (m, 1H), 3.65 (dd, 0.76H), 3.90 (dd, 0.24H), 4.10 (t, 0.76H), 4.30 (t, 0.24H), 6.15 (s, 1H), 6.95-7.15 (m, 2H), 7.25 (t, 1H), 7.35 (d, 1H), 7.40-7.50 (m, 3H), 7.80 (d, 0.76H), 7.90 (d, 0.24H), 8.50 (s, 0.24H), 9.05 (s, 0.76H), 11.20 (s, 1H). MS m/z (%): 406 (MH+, 100%), 377 (5%), 244 (15%).
Reaction SMILES: CC1C=CC(S(OCC2(C)CC3C=C(Cl)C=C(C4C=CC=CC=4)C=3O2)(=O)=O)=CC=1.[N-]=[N+]=[N-].[Na+].[N:34]([CH2:37][C:38]1([CH3:54])[CH2:42][C:41]2[CH:43]=[C:44]([Cl:53])[CH:45]=[C:46]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:40]=2[O:39]1)=[N+]=[N-].[N-]=[N+]=[N-]>[Pt]>[Cl:53][C:44]1[CH:45]=[C:46]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:40]2[O:39][C:38]([CH2:37][NH2:34])([CH3:54])[CH2:42][C:41]=2[CH:43]=1
Reactant: CC1(CN=[N+]=[N-])Cc2cc(Cl)cc(-c3ccccc3)c2O1
Agent: [Pt]
Agent: Cc1ccc(S(=O)(=O)OCC2(C)Cc3cc(Cl)cc(-c4ccccc4)c3O2)cc1
Agent: [N-]=[N+]=[N-]
Product: CC1(CN)Cc2cc(Cl)cc(-c3ccccc3)c2O1
Yield: 64 %

Procedure:
Treatment of (±)-(5-chloro-2-methyl-7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (5.00 g, 10.0 mmol) with phenylboronic acid (1.83 g, 15.0 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.82 g, 1.0 mmol), and potassium carbonate (2.76 g, 20.0 mmol) generally according to the procedure described for Intermediate 35 gave (±)-(5-chloro-2-methyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. Treatment of (±)-(5-chloro-2-methyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (4.1 g, 9.5 mmol) with sodium azide (3.9 g, 60.0 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-2-(azidomethyl)-5-chloro-2-methyl-7-phenyl-2,3-dihydro-1-benzofuran. Treatment of the azide with sulfided platinum on carbon (0.350 g, 5 wt. %) generally according to the procedure described for Example 1 provided 2.0 g (64%) of (±)-1-(5-chloro-2-methyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine as a white solid, hydrochloride salt. mp 222-225° C.; Anal. calcd. for C16H16ClNOHCl: C, 61.95; H, 5.52; N, 4.52. Found: C, 60.82; H, 5.67; N, 4.37.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:19][C:8]2[C:9]3[CH:10]=[CH:11][C:12]([C:16](O)=[O:17])=[CH:13][C:14]=3[S:15][C:7]=2[C:6]=1[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:4].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:39]1([NH2:45])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:19][C:8]2[C:9]3[CH:10]=[CH:11][C:12]([C:16](=[O:17])[NH:45][CH:39]4[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]4)=[CH:13][C:14]=3[S:15][C:7]=2[C:6]=1[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:4]
Reactant: CCOC(=O)COc1c(C(=O)OC)sc2c1sc1cc(C(=O)O)ccc12
Reactant: NC1CCCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(=O)COc1c(C(=O)OC)sc2c1sc1cc(C(=O)NC3CCCCC3)ccc12
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 14.6 %

Procedure:
1-ethoxycarbonylmethoxy-3,8-dithia-cyclopenta[a]indene-2,6-dicarboxylic acid 2-methyl ester (49 mg, 0.13 mmol) and carbonyldiimidazole (25 mg, 0.15 mmol) were dissolved in THF (6 ml). After stirring for 1.5 hr at 60° C., the reaction was cooled to RT. Cyclohexylamine (25 gl, 0.22 mmol, 1.7 mmol). Stirred for 3 hr. Removal of solvent followed by column chromatography yielded 9mg (15%) of 6-cyclohexylcarbamoyl-1-ethoxycarbonylmethoxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:21])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([NH2:19])=O)=[CH:13][N:12]=1)[CH2:9][CH3:10].N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:21])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:19])=[CH:13][N:12]=1)[CH2:9][CH3:10]
Reactant: CCN(Cc1cc(Br)ccc1O)c1ccc(C(N)=O)cn1
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: CCN(Cc1cc(Br)ccc1O)c1ccc(C#N)cn1
Temperature: 25 °C
Yield: 62.9 %

Procedure:
2-[N-(5-Bromo-2-hydroxybenzyl)-N-ethylamino]pyridine-5-carboxamide (example 4) (1.93 g, 5.5 mmol) was suspended in THF (30 ml) and treated with pyridine (1.15 g, 14.25 mmol, 1.15 ml) followed by trifluoroacetic anhydride (3.4 g, 16 mmol) whilst stirring at ambient temperature. The white solid dissolved and there was a slight exotherm. The resultant solution was left overnight at ambient temperature. The mixture was then evaporated to low volume, a saturated aqueous solution of sodium bicarbonate was added and the mixture stirred at ambient temperature for 30 minutes. The mixture was again evaporated to low volume and the white solid that precipitated was filtered, washed with water and sucked dry (1.68 g). The solid was purified by MPLC on silica to give 2-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino]-5-cyanopyridine as a white solid (1.15 g, 63%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][C@H:12]([NH:16][C@@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]3[NH:23][C:24]3[CH:29]=[C:28]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32](OC(F)(F)F)[CH:31]=4)[CH:27]=[CH:26][N:25]=3)[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:41][C:42]([F:54])([F:53])[O:43]C1C=CC(B(O)O)=CC=1>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][C@H:12]([NH:16][C@@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]3[NH:23][C:24]3[CH:29]=[C:28]([C:30]4[CH:31]=[CH:32][C:33]([O:43][C:42]([F:54])([F:53])[F:41])=[CH:34][CH:35]=4)[CH:27]=[CH:26][N:25]=3)[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(N2CCC[C@H](N[C@@H]3CCCC[C@H]3Nc3cc(-c4cccc(OC(F)(F)F)c4)ccn3)C2)cc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: O=[N+]([O-])c1ccc(N2CCC[C@H](N[C@@H]3CCCC[C@H]3Nc3cc(-c4ccc(OC(F)(F)F)cc4)ccn3)C2)cc1

Procedure:
(1R,2R)—N1-((S)-1-(4-Nitrophenyl)piperidin-3-yl)-N2-(4-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)cyclohexane-1,2-diamine (1.4 mg, 0.003 mmol, 6.0% yield) was synthesized as described in General Procedure I using Intermediate A from Example 23 (20 mg, 0.04 mmol) and 4-(trifluoromethoxy)phenylboronic acid (12.2 mg, 0.04 mmol). The desired fraction from RP prep-HPLC method D was concentrated to give the title compound as a pale yellow solid. Anal. Calcd. for C29H32F3N5O3 m/z 555.2, found: 556.2 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 8.11 (d, J=5.6 Hz, 1H), 8.01 (d, J=9.2 Hz, 2H), 7.57 (d, J=4.4 Hz, 2H), 7.30 (d, J=8 Hz, 2H), 6.78 (d, J=5.6 Hz, 1H), 6.66 (d, J=9.3 Hz, 2H), 6.51 (s, 1H), 4.7 (bs, 1H), 3.72 (m, 1H), 3.62 (m, 2H), 3.54 (m, 1H), 3.05 (m, 1H), 2.9 (m, 2H), 2.53 (m, 1H), 2.14 (m, 3H), 1.96 (m, 1H), 1.78 (m, 4H), 1.27 (m, 6H).
Reaction SMILES: C[N:2]([C:12]([CH3:20])([CH3:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])=[O:4].CC(N)(C)C1C=CC=CC=1.[OH-].[Na+].C1(S(Cl)(=O)=O)C=CC=CC=1>>[CH3:20][C:12]([NH:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:4])=[O:5])([CH3:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CN(C(C)(C)c1ccccc1)S(=O)(=O)c1ccccc1
Agent: CC(C)(N)c1ccccc1
Agent: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Product: CC(C)(NS(=O)(=O)c1ccccc1)c1ccccc1
Yield: 67 %

Procedure:
The N-(α,α-dimethylbenzyl)benzenesulfonamide used as a starting compound in the above procedure could be prepared in the following manner. A two-layered mixture consisting of 33.8 g (0.25 mole) of α,α-dimethylbenzylamine and 120 ml of a 10% aqueous solution of sodium hydroxide was stirred at below 40° C., and 44.1 g of benzenesulfonyl chloride was added dropwise. Stirring the mixture for an additional 1.5 hours afforded a white precipitate. The solid precipitate was collected by filtration, and recrystallized from methanol to afford N-(α,α-dimethylbenzyl)benzenesulfonamide having melting point of 114° to 115° C. in a yield of 67%.
Reaction SMILES: [CH2:1]([CH:3]1[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][N:4]1[CH3:17])=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)[CH3:2].N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH:35]=[C:36]([C:38]1[CH:43]=[CH:42][C:41]([F:44])=[C:40]([F:45])[CH:39]=1)[CH3:37]>CN(C=O)C.[Cu]I>[F:45][C:40]1[CH:39]=[C:38](/[C:36](/[CH3:37])=[CH:35]/[N:9]2[C:10]3[C:15](=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)[C:7]3[CH2:6][CH2:5][N:4]([CH3:17])[CH:3]([CH2:1][CH3:2])[C:8]2=3)[CH:43]=[CH:42][C:41]=1[F:44]
Reactant: CC(=CBr)c1ccc(F)c(F)c1
Reactant: CCC1c2[nH]c3ccc(C)cc3c2CCN1C
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CCC1c2c(c3cc(C)ccc3n2/C=C(\C)c2ccc(F)c(F)c2)CCN1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 18.3 %

Procedure:
1-ethyl-2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (82 mg, 0.36 mmol) was dissolved in DMF (6 mL). To this solution was added CuI (8 mg, 0.036 mmol), L-proline (9 mg, 0.086 mmol), K3PO4 (183 mg, 0.86 mmol). The reaction mixture was stirred for 10 min at room temperature followed by addition of 4-(1-bromoprop-1-en-2-yl)-1,2-difluorobenzene (100 mg, 0.43 mmol). The reaction mixture was heated at 80° C. for 18 h. Solvent was evaporated under reduced pressure, the residue was diluted with brine and extracted with ethyl acetate. Organic layer was dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to obtain 25 mg of (E)-9-(2-(3,4-difluorophenyl)prop-1-enyl)-1-ethyl-2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole. 1H NMR (DMSO) OXALATE SALT 7.80 (m, 1H), 7.56 (m, 2H), 7.38 (s, 1H), 7.20 (s, 1H), 7.05 (m, 2H), 3.80 (m, 3H), 3.18 (s, 3H), 3.0 (m, 2H), 2.80 (m, 2H), 2.40 (s, 3H), 1.82 (s, 3H), 0.95 (t, 3H).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([NH:13][CH:14]3[CH2:19][CH:18]([CH2:20][C:21]4[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=4[F:28])[CH2:17][N:16]([CH3:29])[CH2:15]3)=[O:12])[CH:9]=2)[N:4]([C:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:57][C:58]1[CH:63]=[C:62](B2OC(C)(C)C(C)(C)O2)[CH:61]=[CH:60][N:59]=1>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:27][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]([F:28])[C:21]=1[CH2:20][CH:18]1[CH2:17][N:16]([CH3:29])[CH2:15][CH:14]([NH:13][C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]([C:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[N:3]=[C:2]3[C:62]2[CH:61]=[CH:60][N:59]=[C:58]([CH3:57])[CH:63]=2)=[O:12])[CH2:19]1
Reactant: CN1CC(Cc2c(F)cccc2F)CC(NC(=O)c2ccc3c(c2)c(Br)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Product: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)NC4CC(Cc5c(F)cccc5F)CN(C)C4)cc23)ccn1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
3-bromo-N-(5-(2,6-difluorobenzyl)-1-methylpiperidin-3-yl)-1-trityl-1H-indazole-5-carboxamide (0.050 g, 0.0716 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (0.0052 g, 0.00716 mmol), Potassium phosphate tribasic (0.046 g, 0.215 mmol) and 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.018 g, 0.0788 mmol) was added into a flask. After purging the reaction vessel with nitrogen gas, dioxane (0.215 mL) and water (0.043 mL) was added. The reaction was allowed to stir at 80° C. for 16 hrs. The reaction was quenched with water (1 mL) and extracted with dichloromethane (3×1 mL). The extracts were combined, dried using sodium sulfate, filtered through celite, and concentrated under vacuo. The crude product was progressed to the next step without further purification. LC-MS found 718.2, calcd M+H 718.3.
Reaction SMILES: [F:1][CH:2]1[C:7](=O)[CH2:6][CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[O:10])[CH2:3]1.[C:20]([CH:25]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:22][CH2:23][CH3:24])=[O:21]>C1(C)C=CC=CC=1>[CH2:23]([O:22][C:20](=[O:21])/[CH:25]=[C:7]1\[CH:2]([F:1])[CH2:3][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:6]\1)[CH3:24]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(COC(=O)N2CCC(=O)C(F)C2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C1/CCN(C(=O)OCc2ccc(C)cc2)CC1F
Reaction time: 1 h
Yield: 81.5 %

Procedure:
To a solution of (±)-4-methylbenzyl 3-fluoro-4-oxopiperidine-1-carboxylate (40 g, 150 mmol) in toluene (200 mL) at RT was added (carbethoxymethylene)triphenylphosphorane (63.0 g, 181 mmol) and the reaction mixture stirred for 1 h. The reaction mnixture was concentrated and purified by silica gel chromatography (gradient elution: 10% to 20% EtOAc in hexanes) to give the olefins (±)-4-methylbenzyl (E)-4-(2-ethoxy-2-oxoethylidene)-3-fluoropiperidine-1-carboxylate and (±)-4-methylbenzyl (Z)-4-(2-ethoxy-2-oxoethylidene)-3-fluoropiperidine-1-carboxylate (41.0 g, 78% yield, 3 steps) as a 3:1 E:Z mixture. This mixture was utilized directly in the next step. A small sample of the mixture was separated by silica gel chromatography for characterization purposes.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=1.[OH-].[NH4+:15]>O1CCCC1.C(N(CC)CC)C>[NH2:15][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=1
Reactant: CCOC(=S)c1cnc(C)nc1Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=S)c1cnc(C)nc1N
Reaction time: 16 h
Yield: 94 %

Procedure:
A solution of ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate (1450 g, 6.23 mole) (Aldrich Chemical Co., Milwaukee, Wis., USA) in 2987 mL of tetrahydrofuran was cooled to 5-10° C. and treated slowly with a mixture of 2407 mL of a 37% solution of ammonium hydroxide in 2978 mL triethylamine. After stirring for 16 hours, the reaction mixture was concentrated in vacuo to approximately 5L and filtered. The filter cake was washed with hexanes and dried in a vacuum oven at 60-65° C. The filtrate was evaporated under reduced pressure to give 1314 g (94%) of ethyl 4-amino-2-methylthiopyrimidine-5-carboxylate as a white solid. m.p. 130.1-130.7° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]2[N:20]=[C:19]([C:21]3[N:28]4[C:24]([S:25][CH:26]=[CH:27]4)=[N:23][C:22]=3[C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]4[N:39]=[C:38]([CH3:40])[O:37][N:36]=4)[CH:30]=3)[CH:18]=[CH:17][N:16]=2)[CH2:9]1)=O)(C)(C)C.Cl>C(OCC)(=O)C>[CH3:40][C:38]1[O:37][N:36]=[C:35]([C:31]2[CH:30]=[C:29]([C:22]3[N:23]=[C:24]4[N:28]([C:21]=3[C:19]3[CH:18]=[CH:17][N:16]=[C:15]([NH:14][C@@H:10]5[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]5)[N:20]=3)[CH:27]=[CH:26][S:25]4)[CH:34]=[CH:33][CH:32]=2)[N:39]=1
Reactant: Cc1nc(-c2cccc(-c3nc4sccn4c3-c3ccnc(N[C@@H]4CCCN(C(=O)OC(C)(C)C)C4)n3)c2)no1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cccc(-c3nc4sccn4c3-c3ccnc(N[C@@H]4CCCNC4)n3)c2)no1
Yield: 109.4 %

Procedure:
((R)-3-(4-{6-[3-(5-Methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-imidazo[2,1-b]thiazol-5-yl}-pyrimidin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.15 g, 0.269 mmol) was dissolved in 2 mL of ethyl acetate and treated with 2 ml of 3.0 M HCl in ethyl acetate at room temperature (RT) overnight. Solid product was filtered, washed ethyl acetate and dried under vacuum overnight to provide 0.135 g (100%) of the title compound as a yellow solid. M.p.=203-207° C. 400 MHz 1H NMR (DMSO-d6 at 60° C.) δ: 9.35 (br. s, 1H), 8.21 (s, 1H), 8.12 (d, J=6.0 Hz, 1H), 8.0 (d, J=7.6 Hz, 1H), 7.82-7.80 (m, 1H), 7.67 (t, J=8.2 Hz, 1H), 7.54 (s, 1H), 6.90 (bs, 1H), 6.48 (d, J=5.6 Hz, 1H), 4.2 (br. s, 1H), 3.40 (d, J=10.8 Hz, 1H), 3.13 (d, 1H), 2.92-2.87 (m, 2H), 2.65 (s, 3H), 2.00-1.97 (m, 1H), 1.96-1.89 (m, 1H), 1.89-1.80 (bs, 1H), 1.64-1.57 (m, 1H); LCMS: 459 [M+H]. calc. for C23H22N8OS.2.3HCl: C, 50.93; H, 4.52; N, 20.66. Found C, 50.93; H, 4.42; N, 19.30.
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:20]=[CH:19][C:6]2[C:7](=[O:18])[C:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:9][O:10][C:5]=2[CH:4]=1.[CH3:23][O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28](I)[CH:27]=1.[Cl-].[NH4+]>CN(C)C=O>[C:25]([C:26]1[CH:27]=[C:28]([C:3]2[CH:20]=[CH:19][C:6]3[C:7](=[O:18])[C:8]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:9][O:10][C:5]=3[CH:4]=2)[CH:29]=[CH:30][CH:31]=1)([O:24][CH3:23])=[O:33]
Reactant: C[Sn](C)(C)c1ccc2c(=O)c(Cc3ccccc3)coc2c1
Reactant: COC(=O)c1cccc(I)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2ccc3c(=O)c(Cc4ccccc4)coc3c2)c1
Temperature: 25 °C
Yield: 100.4 %

Procedure:
To a stirred solution of the compound of step F (7.0 g, 17.5 mmole) in dimethylformamide (DMF) (35 mL) was added Pd(PPh3)2C12 (490 mg, 0.7 mmole), 3 crystals of BHT and methyl-3-iodobenzoate (5.0 g, 19.1 mmole). The mixture was stirred at reflux for 1.5 hours, cooled to room temperature and poured into 150 mL of saturated aqueous ammonium chloride solution. The mixture was extracted with 3×150 mL of diethyl ether, and the combined extract was washed with 2×100 mL of water, and then brine. The solution was dried over sodium sulfate, filtered and evaporated in vacuo to afford a yellow oil. Chromatography over silica gel (4:1 hexane: ether elution) afforded 6.51 g of the title compound as a viscous oil.
Reaction SMILES: C(ON=O)(C)(C)C.N[C:9]1[N:13]([C:14]2[C:19]([F:20])=[C:18]([F:21])[C:17]([C:22]([F:25])([F:24])[F:23])=[C:16]([F:26])[C:15]=2[F:27])[N:12]=[CH:11][C:10]=1[N+:28]([O-:30])=[O:29].C(Br)(Br)[Br:32]>>[Br:32][C:9]1[N:13]([C:14]2[C:19]([F:20])=[C:18]([F:21])[C:17]([C:22]([F:25])([F:24])[F:23])=[C:16]([F:26])[C:15]=2[F:27])[N:12]=[CH:11][C:10]=1[N+:28]([O-:30])=[O:29]
Reactant: BrC(Br)Br
Reactant: Nc1c([N+](=O)[O-])cnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F
Agent: CC(C)(C)ON=O
Product: O=[N+]([O-])c1cnn(-c2c(F)c(F)c(C(F)(F)F)c(F)c2F)c1Br
Yield: 89.9 %

Procedure:
21.6 ml (0.18 mol) of t-butylnitrite are added dropwise to 20.6 g (0.06 mol) of 5-amino-4-nitro-1-(2,3,5,6-tetrafluoro-4-trifluoromethyl-phenyl)-pyrazole in 100 ml (1.125 mol) of bromoform in the course of 10 minutes, while stirring, whereupon the temperature of the reaction mixture rises to 50° C. When the addition has ended, the mixture is stirred at the reflux temperature for a further two hours and is concentrated in vacuo, the residue is taken up in methylene chloride, the mixture is washed several times with saturated sodium bicarbonate solution, 2n-hydrochloric acid and water and dried over sodium sulphate and the solvent is stripped off in vacuo. 22 g (89.9% of theory) of 5-bromo-4-nitro-1-(2,3,5,6-tetrafluoro-4-trifluoromethyl-phenyl)-pyrazole are obtained as a brown oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9](=[O:16])OCC(Cl)(Cl)Cl)[O:4][N:3]=1.[F:17][C:18]1[CH:19]=[C:20]([C:24]2[N:25]=[C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[S:27][CH:28]=2)[CH:21]=[CH:22][CH:23]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9]([N:32]2[CH2:33][CH2:34][N:29]([C:26]3[S:27][CH:28]=[C:24]([C:20]4[CH:21]=[CH:22][CH:23]=[C:18]([F:17])[CH:19]=4)[N:25]=3)[CH2:30][CH2:31]2)=[O:16])[O:4][N:3]=1
Reactant: Fc1cccc(-c2csc(N3CCNCC3)n2)c1
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: Cc1noc(NC(=O)N2CCN(c3nc(-c4cccc(F)c4)cs3)CC2)c1C
Temperature: 70 °C
Reaction time: 4 h
Yield: 42.8 %

Procedure:
A mixture of 2,2,2-trichloroethyl (3,4-dimethylisoxazol-5-yl)carbamate (300 mg, 1.04 mmol), 1-[4-(3-fluorophenyl)-1,3-thiazol-2-yl]piperazine (250 mg, 0.949 mmol) and diisopropylethylamine (0.330 ml, 1.90 mmol) in dimethylsulfoxide (3.2 ml) was stirred at 70° C. for 4 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) and recrystallized from a mixed solvent of hexane and ethyl acetate to give the desired product (163 mg, 42.7%) as a solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[S:8][C:9]([CH2:12][NH2:13])=[CH:10][CH:11]=2)[N:6]=1.C(N(CC)CC)C.[C:21]([O:24][CH2:25][C:26](Cl)=[O:27])(=[O:23])[CH3:22]>C(Cl)(Cl)Cl>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[S:8][C:9]([CH2:12][NH:13][C:26](=[O:27])[CH2:25][O:24][C:21](=[O:23])[CH3:22])=[CH:10][CH:11]=2)[N:6]=1
Reactant: CC(=O)OCC(=O)Cl
Reactant: NCc1ccc(-c2csc(N)n2)s1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)OCC(=O)NCc1ccc(-c2csc(N)n2)s1
Temperature: 25 °C

Procedure:
To a suspension of 2-amino-4-(5-aminomethyl-2-thienyl) thiazole in 150 ml of chloroform is added 10 ml of triethylamine, and 3.1 g of acetoxyacetylchloride is added dropwise with stirring at room temperature (10°-35° C.). The whole mixture is stirred at room temperature for an hour, and then washed with water. The organic layer is separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is recrystallized from ethanol to give 2-amino-4-(5-acetoxyacetylaminomethyl-2-thienyl) thiazole, melting at 149°-150° C. The corresponding maleate melts at 153°-154° C. with decomposition.