Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br[CH2:6][C:7]([CH:9]1[CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:24])[CH:19]=3)[N:14]=[CH:13][C:12]=2[O:11][CH2:10]1)=O.N>C(O)C>[CH3:24][O:23][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][C:12]1[O:11][CH2:10][CH:9]([C:7]3[N:1]=[C:2]([NH2:4])[S:3][CH:6]=3)[CH2:22][C:21]2=1
Reactant: COc1ccc2ncc3c(c2c1)CC(C(=O)CBr)CO3
Reactant: NC(N)=S
Agent: N
Solvent: CCO
Product: COc1ccc2ncc3c(c2c1)CC(c1csc(N)n1)CO3
Yield: 7.7 %

Procedure:
Thiourea (190 mg, 2.5 mmol, 1.0 eq) is added at room temperature to a stirred solution of 2-bromo-1-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-yl)-ethanone (850 mg, 2.5 mmol, 1.0 eq) in ethanol (200 mL) and the resulting suspension is heated to reflux for 15 minutes. Then pH of the reaction mixture is adjusted to 8-10 by the addition of a 30% aqueous ammonia solution. Solvent was removed to give the crude product that is purified by preparative HPLC to afford 4-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-yl)-thiazol-2-ylamine as a white solid (60 mg, 13% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[C:5]2[C:10]([O:32][CH3:33])=[N:11][N:12]([C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]=2[CH:3]=1.[C:34]1([C@H:40]([NH:42][C:43]([NH2:45])=[O:44])[CH3:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH:8]([C:6]1[C:5]2[C:10]([O:32][CH3:33])=[N:11][N:12]([C:13]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:4]=2[CH:3]=[C:2]([NH:45][C:43]([NH:42][C@@H:40]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH3:41])=[O:44])[N:7]=1)=[O:9]
Reactant: C[C@@H](NC(N)=O)c1ccccc1
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C=O)c12
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)nc(C=O)c12

Procedure:
In a manner similar to that described previously (e.g. Scheme 3/Method A and Example 40), 6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carbaldehyde (Intermediate 11B) was reacted with converted to (R)-1-(1-phenylethyl)urea (BrettPhos PreCatalyst, cesium carbonate, dioxane, 90° C. for 4 hrs) to provide (R)-1-(4-formyl-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. MS: [M+H]+ m/z 582.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[CH:10]=2)=[CH:6][CH:5]=[C:4]([N+:21]([O-])=O)[N:3]=1>[Pd].CCOC(C)=O.CO>[NH2:21][C:4]1[N:3]=[C:2]([CH3:1])[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[CH:10]=2)=[CH:6][CH:5]=1
Reactant: Cc1nc([N+](=O)[O-])ccc1Oc1ccnc(NC(=O)C2CC2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1nc(N)ccc1Oc1ccnc(NC(=O)C2CC2)c1
Yield: 88.4 %

Procedure:
A solution of N-(4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide (0.50 g, 1.591 mmol) in 2:1 EtOAc/MeOH (30 mL) was treated with palladium on carbon (50% wet, 0.188 g, 0.159 mmol) and hydrogenated (1 atm) for 2 days. The solids were removed via filtration through diatomaceous earth, washed well with MeOH and the filtrate was concentrated to dryness to afford N-(4-((6-amino-2-methylpyridin-3-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide (400 mg, 88%). 1H NMR (400 MHz, DMSO-d6): δ 10.77 (s, 1H), 8.13 (d, J=5.7 Hz, 1H), 7.52 (d, J=2.4 Hz, 1H), 7.14 (d, J=8.7 Hz, 1H), 6.58 (dd, J=5.7, 2.4 Hz, 1H), 6.32 (d, J=8.7 Hz, 1H), 5.92 (s, 2H), 2.03 (s, 3H), 1.95 (m, 1H), 0.76 (s, 4H); MS (ESI) m/z: 285.1 (M+H+).
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[C:6]1[CH:7]=[C:8]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][C:19]([NH2:21])=[CH:20][C:14]=3[CH:13]=2)[CH:9]=[N:10][CH:11]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][C:24]=1[C:32]([F:35])([F:34])[F:33]>O1CCCC1.C(OCC)(=O)C>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:21][C:19]2[CH:18]=[CH:17][C:15]3[S:16][C:12]([C:8]4[CH:9]=[N:10][CH:11]=[C:6]([C:5]5[N:1]=[N:2][NH:3][N:4]=5)[CH:7]=4)=[CH:13][C:14]=3[CH:20]=2)=[O:31])=[CH:25][C:24]=1[C:32]([F:33])([F:34])[F:35]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1ccc2sc(-c3cncc(-c4nn[nH]n4)c3)cc2c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Nc1ccc2sc(-c3cncc(-c4nn[nH]n4)c3)cc2c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
The reaction mixture of 2-(5-(2H-tetrazol-5-yl)pyridin-3-yl)benzo[b]thiophen-5-amine (44.1 mg, 0.15 mmol, 1 eq) and 4-chloro-3-(trifluoromethyl)phenyl isocyanate (33.2 mg, 1 eq) in anhydrous tetrahydrofuran (1.5 mL) under nitrogen atmosphere was stirred at room temperature for 45 minutes. The reaction was then diluted with ethyl acetate, washed with aqueous ammonium chloride, brine, and dried with anhydrous sodium sulfate. The upper clear solution was decanted and concentrated. The soft solid was wrapped with silica gel and chromatographed (EtOAc to MeOH-EtOAc 1:4) to give 1-[4-chloro-3-(trifluoromethyl)phenyl]-3-{2-[5-(2H-tetrazol-5-yl)pyridin-3-yl]-1-benzothien-5-yl}urea as a yellow powder in the amount of 26 mg.
Reaction SMILES: C([O:5][C:6](=[O:8])[CH3:7])(C)(C)C.[CH3:9][C:10]([CH3:38])([CH3:37])[C:11](=[O:36])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:25]2[S:29][C:28]([S:30]([NH2:33])(=[O:32])=[O:31])=[C:27]([CH3:34])[CH:26]=2)([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][C:15]=1[CH3:35]>Cl.O1CCOCC1>[C:6]([OH:8])(=[O:5])[CH3:7].[CH3:38][C:10]([CH3:9])([CH3:37])[C:11](=[O:36])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:25]2[S:29][C:28]([S:30]([NH2:33])(=[O:32])=[O:31])=[C:27]([CH3:34])[CH:26]=2)([CH2:21][CH3:22])[CH2:23][CH3:24])=[CH:16][C:15]=1[CH3:35]
Reactant: CC(=O)OC(C)(C)C
Agent: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc(C)c(S(N)(=O)=O)s1
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)O

Procedure:
A solution of (5-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-thiophene-2-sulfonylamine)-acetic acid tert-butyl ester (320 mg, 0.57 mmol) in 4N HCl/dioxane (10 ml) is stirred at RT overnight. The reaction is concentrated and chromatographed (Hex to 0.5% AcOH in 50% EtOAc/Hex) to give the title compound (250 mg, 87%).
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[C@H:13]2[CH2:16][CH2:17][CH2:18][C@H:12]2[NH:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CI.[C:27](=O)([O-])O.[Na+]>CN(C)C=O.O>[CH2:1]([N:8]1[C:14](=[O:15])[C@H:13]2[CH2:16][CH2:17][CH2:18][C@H:12]2[N:11]([CH3:27])[C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1[C@H]2CCC[C@H]2Nc2ccccc2N1Cc1ccccc1
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CN1c2ccccc2N(Cc2ccccc2)C(=O)[C@H]2CCC[C@H]21
Temperature: 80 °C
Reaction time: 13 h
Yield: 82 %

Procedure:
To a solution of (3aR*,10aS*)-9-benzyl-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]-diazepin-10(1H)-one (2.93 g, 10 mmol) in N,N-dimethylformamide (20 mL) were added sodium hydride (60% liquid paraffin dispersion, 0.41 g, 10 mmol) and methyl iodide (1.3 mL, 21 mmol). The mixture was stirred for 13 hours at 80° C. To the reaction mixture were added water and, then, a saturated aqueous solution of sodium hydrogencarbonate. The mixture was subjected extraction with ethyl acetate three times. Organic layers were combined and washed with water and, then, with a saturated aqueous solution of sodium hydrogencarbonate, which was dried over sodium sulfate, followed by filtration and concentration under reduced pressure. The concentrate was purified by silica-gel column chromatography (hexane-ethyl acetate 10:1) to give 2.52 g (yield 82%) of the titled compound. The sample for analytical experiment was prepared by recrystallization from methanol. m.p. 123°-125° C.
Reaction SMILES: [N:1](=[C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[C:5]([CH3:16])([CH3:15])[S:4]1)[OH:2].[CH3:17][N:18]=[C:19]=[O:20]>>[CH3:17][NH:18][C:19]([O:2][N:1]=[C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[C:5]([CH3:16])([CH3:15])[S:4]1)=[O:20]
Reactant: CN=C=O
Reactant: CC1(C)SC(=NO)N=C1c1ccc(Cl)cc1
Product: CNC(=O)ON=C1N=C(c2ccc(Cl)cc2)C(C)(C)S1

Procedure:
2-oxo-4-(p-chlorophenyl)-5,5-dimethyl-3-thiazoline-oxime was reacted with methyl isocyanate as described in Example 4 to yield 2-oxo-4-(p-chlorophenyl)-5,5-dimethyl-3-thiazoline-O-(methylcarbamoyl)-oxime, m.p. 147°-149° C. The 2-oxo-4-(p-chlorophenyl)-5,5-dimethyl-3-thiazoline-oxime starting material melts at 205°-207° C.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]([CH2:10][NH2:11])=[N:6][CH:7]=[CH:8][N:9]=1.C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.[CH2:31]([O:38][C:39]([N:41]1[CH2:46][CH2:45][CH:44]([C:47](O)=[O:48])[CH2:43][CH2:42]1)=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[Cl:3][C:4]1[C:5]([CH2:10][NH:11][C:47]([CH:44]2[CH2:45][CH2:46][N:41]([C:39]([O:38][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[O:40])[CH2:42][CH2:43]2)=[O:48])=[N:6][CH:7]=[CH:8][N:9]=1
Reactant: NCc1nccnc1Cl
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1nccnc1Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of C-(3-Chloropyrazin-2-yl)methylamine bis-hydrochloride (2.00 g, 0.0107 mol) and N,N-diisopropylethylamine (2.2 g, 0.017 mol) in DCM (27.0 mL) was treated with and N-(3-dimethylaminopropyl)-Al-ethylcarbodiimide hydrochloride (3.2 g, 0.017 mol), 1-hydroxybenzotriazole (1.5 g, 0.011 mol) and 1-[(benzyloxy)carbonyl]-4-piperidine carboxylic acid (3.8 g, 0.014 mol). The mixture was stirred at rt overnight then diluted with DCM (30 mL), washed with sat. NaHCO3 (20 mL) and brine (20 mL), then dried over Na2SO4 and concentrated in vacuo. The crude material thus obtained was chromatographed over silica gel eluting with EtOAc:hexane 1:1 yielding 3.38 g of the title compound. 1H NMR (400 MHz, CDCl3): δ 1.68-1.78 (m, 2H), 1.91-1.94 (m, 2H), 2.44 (m, 1H), 2.89-2.92 (m, 2H), 4.24-4.26 (m, 2H), 4.70 (d, J=4.8 Hz, 2H), 5.14 (s, 2H), 6.85 (br, 1H), 7.30-7.37 (m, 5H), 8.34 (d, J=2.8 Hz, 1H), 8.45 (d, J=2.8 Hz, 1H). MS (ES+): m/z 389.17 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:25]([CH2:31][CH3:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27]>CC(=O)CC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH:25]([CH2:31][CH3:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:16][C:11]=3[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Br)CC
Reactant: Oc1ccc2c(-c3ccc(Cl)cc3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(CC)Oc1ccc2c(-c3ccc(Cl)cc3)noc2c1
Reaction time: 5 h

Procedure:
A mixture of 6.5 g of 3-(4-chlorophenyl)-6-hydroxy-1,2-benzisoxazole, 7.5 g of potassium carbonate, 5.16 g of ethyl 2-bromobutyrate and 100 ml 2-butanone is heated under reflux with stirring for 5 hr. The reaction mixture is poured into ice/dil hydrochloric acid. The oil, which solidified on scratching, was collected and dried in vacuo. Recrystallization from isopropyl ether (decolorizing carbon) gives ethyl 2-{[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl]oxy}butyrate, mp 73° C.
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([C:9]2[S:13][C:12]([S:14]([NH:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=[O:16])=[O:15])=[CH:11][CH:10]=2)[N:3]=1.[CH:26]1([C:29]2[NH:33][N:32]=[C:31]([NH2:34])[CH:30]=2)[CH2:28][CH2:27]1>C(O)CCC>[Cl:8][C:7]1[C:2]([NH:34][C:31]2[CH:30]=[C:29]([CH:26]3[CH2:28][CH2:27]3)[NH:33][N:32]=2)=[N:3][C:4]([C:9]2[S:13][C:12]([S:14]([NH:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=[O:16])=[O:15])=[CH:11][CH:10]=2)=[N:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NNS(=O)(=O)c1ccc(-c2ncc(Cl)c(Br)n2)s1
Reactant: Nc1cc(C2CC2)[nH]n1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)NNS(=O)(=O)c1ccc(-c2ncc(Cl)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Yield: 11.8 %

Procedure:
A mixture of tert-butyl 2-(5-(4-bromo-5-chloropyrimidin-2-yl)thiophen-2-ylsulfonyl)hydrazinecarboxylate (179 mg, 0.38 mmol, 1.0 eq) and 5-cyclopropyl-1H-pyrazol-3-amine (92 mg, 0.76 mmol, 2.0 equiv.) in n-butanol was refluxed for 2 h, The reaction was cooled down and extracted with EA and the combined layers were dried (Na2SO4), filtered and purified by silica gel chromatography (EA/PE 1:2) to afford tert-butyl 2-(5-(5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophen-2-ylsulfonyl)hydrazinecarboxylate (23 mg, 12%). LC-MS (m/z)=512 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([C:23]1[C:32]2[O:31][CH2:30][C:29](=[O:33])[NH:28][C:27]=2[CH:26]=[C:25]([OH:34])[CH:24]=1)[CH2:3][NH:4][C:5]1([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13]([CH3:21])([CH3:20])[O:12][CH:11]2[OH:22])[CH2:7][CH2:6]1.[H][H]>CO.[Pd]>[OH:1][CH:2]([C:23]1[C:32]2[O:31][CH2:30][C:29](=[O:33])[NH:28][C:27]=2[CH:26]=[C:25]([OH:34])[CH:24]=1)[CH2:3][NH:4][C:5]1([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13]([CH3:21])([CH3:20])[O:12][C:11]2=[O:22])[CH2:6][CH2:7]1
Reactant: CC1(C)OC(O)N(CCC2(NCC(O)c3cc(O)cc4c3OCC(=O)N4)CC2)c2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC1(C)OC(=O)N(CCC2(NCC(O)c3cc(O)cc4c3OCC(=O)N4)CC2)c2ccccc21

Procedure:
1-(2-{1-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-cyclopropyl}-ethyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-ol 590 mg (1.06 mmol) 1-(2-{1-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxy-ethylamino]-cyclopropyl}-ethyl)-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one are dissolved in 30 mL methanol and hydrogenated in the presence of palladium on charcoal (10%) at ambient temperature and 3 bar hydrogen pressure. Yield: 180 mg (36%); mass spectroscopy: [M+H]+=468.
Reaction SMILES: C([N:3]1[CH2:21][CH2:20][C@@:10]23[C:11]4[CH:12]=[C:13]([O:18][CH3:19])[CH:14]=[CH:15][C:16]=4[CH2:17][C@@H:4]1[C@:5]2([O:23][CH3:24])[CH2:6][CH2:7][C:8](=[O:22])[CH2:9]3)#N.[ClH:25]>>[ClH:25].[CH3:19][O:18][C:13]1[CH:14]=[CH:15][C:16]2[CH2:17][C@H:4]3[NH:3][CH2:21][CH2:20][C@@:10]4([C:11]=2[CH:12]=1)[C@@:5]3([O:23][CH3:24])[CH2:6][CH2:7][C:8](=[O:22])[CH2:9]4
Reactant: COc1ccc2c(c1)[C@]13CCN(C#N)[C@H](C2)[C@]1(OC)CCC(=O)C3
Agent: Cl
Product: COc1ccc2c(c1)[C@]13CCN[C@H](C2)[C@]1(OC)CCC(=O)C3

Procedure:
3,14-Dimethoxymorphinan-6-one hydrochloride (6b) was prepared by refluxing 17-cyano-3,14-dimethoxymorphinan-6-one (5) (0.385 g, 1.18 mmol) in 25 ml of 2 N hydrochloric acid for 4 hours. The solution was concentrated under reduced pressure to give 0.360 g (91% theory) of (6b) as a white solid which was used without further purification in the preparation of the N-cyclobutyl derivative.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[N:13]=[C:14]([NH2:17])[S:15][CH:16]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:3])[CH3:2].[C:18]([N:26]=[C:27]=[S:28])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[C:1]([NH:4][CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[N:13]=[C:14]([NH:17][C:27]([NH:26][C:18](=[O:25])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[S:28])[S:15][CH:16]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCc1cccc(-c2csc(N)n2)c1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: CC(=O)NCc1cccc(-c2csc(NC(=S)NC(=O)c3ccccc3)n2)c1
Yield: 88.6 %

Procedure:
A suspension of 4-(3-acetylaminomethylphenyl)-2-aminothiazole (2.0 g) and benzoyl isothiocyanate (1.32 g) in acetone (40 ml) was refluxed for 5 hours. The resulting precipitate was collected by filtration to afford 4-(3-acetylaminomethylphenyl)-2-(3-benzoyl-2-thioureido)thiazole (2.94 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:12][CH2:13][CH2:14]O)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:35]N1C(=O)CCC1=O.O>C(Cl)Cl>[Br:35][CH2:14][CH2:13][CH2:12][C:4]1[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:10])[F:9])=[C:2]([F:1])[CH:3]=1
Reactant: OCCCc1ccc(C(F)(F)F)c(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: Fc1cc(CCCBr)ccc1C(F)(F)F
Yield: 79 %

Procedure:
Compound 68-2 (2.83 g) was dissolved in methylene chloride (42 ml), triphenylphosphine (3.67 g) and N-bromosuccinimide (2.56 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride and washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.87 g) as a colorless oil.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.[CH2:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26]([O:28][CH3:29])=[O:27])[CH:24]=2)[CH2:19][CH2:18][NH:17]1.[C:30]([C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1)#[N:31].C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)C>[C:30]([C:32]1[CH:39]=[CH:38][C:35]([CH2:36][N:17]2[CH2:18][CH2:19][C:20]3[C:25](=[CH:24][C:23]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)[CH2:16]2)=[CH:34][CH:33]=1)#[N:31]
Reactant: COC(=O)c1ccc2c(c1)CNCC2
Reactant: N#Cc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)c1ccc2c(c1)CN(Cc1ccc(C#N)cc1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium triacetoxyborohydride (2.2 g, 10.4 mmol) was added to a solution of methyl 1,2,3,4-tetrahydroisoquinoline-7-carboxylate hydrochloride (1.0 g, 4.4 mmol) and 4-cyanobenzaldehyde (0.83 g, 6.3 mmol) in dichloromethane (10 mL). The resulting reaction mixture was allowed to stir at room temperature overnight, poured over saturated sodium bicarbonate solution (75 mL) and extracted with dichloromethane (3×30 mL). The combined organic layer was washed with water (2×30 mL), dried (MgSO4), filtered and concentrated to give a foamy residue. Column chromatography (30% ethyl acetate/hexanes) provided methyl 2-(4-cyanobenzyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylate as a white crystalline solid upon trituration with ethyl ether (1.30 g, 97%). 1H NMR (CDCl3) δ 7.85 (1H, d, J=7.7 Hz); 7.72-7.58 (5H, m); 7.23 (1H, d, J=8.0 Hz); 4.00-3.98 (2H, m); 3.92 (3H, s); 3.83 (2H, br s); 3.08 (2H, br s); 2.97 (2H, br s). MS (M+H)+=307.
Reaction SMILES: C[O:2][C:3](=[O:25])[C@@H:4]([N:11]1[CH2:15][C:14]2=[CH:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[O:23][CH:13]2[C:12]1=[O:24])[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+].CCOCC>C1COCC1.O>[CH:6]1([CH2:5][C@H:4]([N:11]2[CH2:15][C:14]3[CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=4[O:23][C:13]=3[C:12]2=[O:24])[C:3]([OH:25])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@H](CC1CCCC1)N1CC2=Cc3ccccc3OC2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: O=C(O)[C@H](CC1CCCC1)N1CC2=C(Oc3ccccc3C2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To a magnetically stirred mixture of (S)-3-Cyclopentyl-2-(3-oxo-3,3a-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-propionic acid methyl ester (0.64 g, 1.88 mmol) in THF (9 mL) and water (3 mL) was added lithium hydroxide (0.102 g, 2.44 mmol). After addition was complete the mixture was stirred at 25° C. for 2 hours. The reaction mixture was poured into water and ether and the layers separated. The aqueous layer was made acidic with 2N HCl and extracted with three portions of ethyl acetate. The combined ethyl acetate fractions were washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to afford (S)-3-Cyclopentyl-2-(3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-propionic acid as a white solid, 500 mg (81% yield). ESI-LRMS m/e calcd for C19H21NO4 [M+] 327, found 328 [M+H+]. (Note: The double bond isomerizes during the course of the reaction based on NMR spectrum)
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([O:16][CH3:17])[C:13]([O-:15])=[O:14])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[K+].S(=O)(=O)(O)O.O.[C:25]([O-])(O)=O.[Na+]>CO>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH:12]([O:16][CH3:17])[C:13]([O:15][CH3:25])=[O:14])=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COC(C(=O)[O-])c1ccc(-n2cccn2)cc1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)C(OC)c1ccc(-n2cccn2)cc1
Temperature: 80 °C
Yield: 47 %

Procedure:
To a stirred solution of potassium 2-(4-(1H-pyrazol-1-yl)phenyl)-2-methoxyacetate (˜7.55 mmol) in dry MeOH under argon was added sulfuric acid (2.0 mL) dropwise. The mixture was heated at 80° C. for 17 hours. After cooling to room temperature, water was added then the mixture made basic with saturated aqueous NaHCO3 addition. The aqueous phase was extracted with EtOAc and the combined organics were washed with water and brine then dried over Na2SO4 and concentrated in vacuo. Purification by chromatography (20-35% EtOAc-hexanes) provided methyl 2-(4-(1H-pyrazol-1-yl)phenyl)-2-methoxyacetate as a colorless oil (0.88 g, 47% yield for two steps).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]3=[N:10][C:9]=2[C:18]2[CH:19]=[CH:20][C:21]([O:35][CH3:36])=[C:22]([CH:34]=2)[C:23]([NH:25][C:26]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=2[F:33])=[O:24])[CH:5]=[CH:4][N:3]=1.[CH3:37][O:38][C:39]1[CH:45]=[C:44]([N:46]2[CH2:51][CH2:50][CH:49]([CH2:52][CH2:53][S:54]([CH3:57])(=[O:56])=[O:55])[CH2:48][CH2:47]2)[CH:43]=[CH:42][C:40]=1[NH2:41].Cl.O1CCOCC1.C[O-].[Na+]>FC(F)(F)CO.CO.C(Cl)Cl.CCCCCC>[F:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=1[NH:25][C:23](=[O:24])[C:22]1[CH:34]=[C:18]([C:9]2[N:10]=[C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:41][C:40]3[CH:42]=[CH:43][C:44]([N:46]4[CH2:51][CH2:50][CH:49]([CH2:52][CH2:53][S:54]([CH3:57])(=[O:56])=[O:55])[CH2:48][CH2:47]4)=[CH:45][C:39]=3[O:38][CH3:37])[N:7]=2)[CH:19]=[CH:20][C:21]=1[O:35][CH3:36]
Reactant: COc1ccc(-c2nc3cc(F)ccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: COc1cc(N2CCC(CCS(C)(=O)=O)CC2)ccc1N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: OCC(F)(F)F
Solvent: C1COCCO1
Product: COc1cc(N2CCC(CCS(C)(=O)=O)CC2)ccc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3cc(F)ccn23)n1
Temperature: 170 °C
Yield: 77.3 %

Procedure:
To 5-[3-(2-chloro-4-pyrimidinyl)-7-fluoroimidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluoro-phenyl)-2-(methyloxy)benzamide (Example 197, step A) (126 mg, 0.25 mmol) and 2-(methyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperidinyl}aniline (Example 200, step B) (70 mg, 0.22 mmol) in 2,2,2-trifluoroethanol (1.0 mL) was added 4 M HCl in dioxane (112 μL, 0.45 mmol). The mixture was stirred and heated on a microwave at 170° C. for 45 min, then cooled to rt. The mixture was neutralized with 0.5M sodium methoxide in MeOH. The mixture was concentrated under vacuum and the residue purified by silica gel chromatography to give a yellow oil. The oil was dissolved in minimal DCM, then hexane was added until a precipitate was formed. The slurry was cooled at −10° C. for 30 min, then poured through a Teflon filter, washing the solids with cold hexanes. The solids were dried under vacuum to give the title compound (135 mg, 0.17 mmol, 77%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): 6 ppm 9.80 (s, 1H), 9.40-9.53 (m, 1H), 8.50 (s, 1H), 8.21 (d, J=5.1 Hz, 1H), 8.11 (d, J=1.3 Hz, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.59 (dd, J=9.5, 2.4 Hz, 1H), 7.33-7.46 (m, 2H), 7.30 (d, J=8.6 Hz, 1H), 7.20 (t, J=8.1 Hz, 2H), 6.97-7.07 (m, 1H), 6.70 (d, J=1.6 Hz, 1H), 6.45-6.58 (m, 2H), 4.00 (s, 3H), 3.81 (s, 3H), 3.70-3.75 (m, 2H), 3.14-3.22 (m, 2H), 2.97 (s, 3H), 2.64 (t, J=11.4 Hz, 2H), 1.74-1.85 (m, 2H), 1.62-1.72 (m, 2H), 1.46-1.58 (m, 1H), 1.21-1.37 (m, 2H). MS (ESI): 785 [M+H]+.