Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]3[C:39]([CH3:40])=[N:38][N:37]([CH:41]4[CH2:46][CH2:45][CH2:44][CH2:43][O:42]4)[C:18]=3[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:24][C:23]=3[F:36])[CH:21]=2)=O)[CH:10]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B.CSC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:16]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:24][C:23]=3[F:36])[N:19]=[C:18]3[N:37]([CH:41]4[CH2:46][CH2:45][CH2:44][CH2:43][O:42]4)[N:38]=[C:39]([CH3:40])[C:17]=23)[CH:10]([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OCc4ccccc4)cc3F)cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3c3ccccc3)c12
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OCc4ccccc4)cc3F)cc(CN3CCN(C(=O)OC(C)(C)C)CC3c3ccccc3)c12
Yield: 51.3 %

Procedure:
To a solution of 529 mg of 4-[6-(4-benzyloxy-2-fluoro-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-3-phenyl-piperazine-1-carboxylic acid tert-butyl ester in 15 ml of dry THF 6 ml of borane-dimethylsulfide complex (1 M in DCM) was added slowly at r.t., and the reaction was heated to reflux for 30 min. The reaction was quenched by the addition of 3.75 ml of methanol, and the solvents were evaporated. The residue was purified by preparative HPLC (C18 column, acetonitrile/water gradient) yielding 266 mg (51%) of the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[O:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1.[CH3:26][O:27][CH2:28][CH2:29][NH2:30]>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:30][CH2:29][CH2:28][O:27][CH3:26])=[C:3]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:16][C:14]=3[N:15]=2)[CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)c(-c2nc3cc(-c4ccccc4)ccc3o2)c1
Reactant: COCCN
Product: COCCNc1ccc([N+](=O)[O-])cc1-c1nc2cc(-c3ccccc3)ccc2o1

Procedure:
Prepared by the method of Example 54a), from 2-(2-fluoro-5-nitrophenyl)-5-phenylbenzoxazole (200 mg, 0.60 mmol), and 2-methoxyethylamine (3 ml) the subtitle compound was obtained (216 mg, 93%). MS 390 m/z (M+H)+.
Reaction SMILES: [CH2:1]([C@:3]1([OH:9])[CH2:7][CH2:6][NH:5][C@H:4]1[CH3:8])[CH3:2].[F:10][C:11]1[CH:18]=[C:17](F)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14].C(=O)([O-])[O-].[Li+].[Li+]>>[CH2:1]([C@:3]1([OH:9])[CH2:7][CH2:6][N:5]([C:17]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([F:10])[CH:18]=2)[C@H:4]1[CH3:8])[CH3:2]
Reactant: CC[C@]1(O)CCN[C@H]1C
Reactant: N#Cc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@]1(O)CCN(c2ccc(C#N)c(F)c2)[C@H]1C

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-3-ethyl-2-methylpyrrolidin-3-ol 0.5 oxalate (257 mg), 2,4-difluorobenzonitrile (411 mg) and lithium carbonate (218 mg), the title compound was obtained as a colorless solid (yield: 250 mg, yield: 68%).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[O:9]=[C:10]1[CH2:15][CH2:14][CH2:13][CH:12]([C:16]([O:18][CH3:19])=[O:17])[CH2:11]1>CS(C)=O.O>[O:9]1[C:10]2([CH2:15][CH2:14][CH2:13][CH:12]([C:16]([O:18][CH3:19])=[O:17])[CH2:11]2)[CH2:2]1
Reactant: COC(=O)C1CCCC(=O)C1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)C1CCCC2(CO2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
To a solution of trimethylsulfoxonium iodide (53.3 g, 242 mmol) in dry DMSO (300 mL) under N2, was added sodium hydride (9.69 g, 242 mmol) portionwise over 30 min. This light yellow mixture was stirred at RT for 1 h. The reaction mixture was then cooled in an ice bath and treated with methyl 3-oxocyclohexanecarboxylate (29.0 g, 186 mmol) dropwise while maintaining a temperature at or below 27° C. The resulting reaction mixture was allowed to warm slowly to RT and stir overnight. The reaction was diluted with water and extracted with DCM. The combined organics were washed with water, dried over MgSO4, filtered, and concentrated to provide methyl 1-oxaspiro[2.5]octane-5-carboxylate (31.8 g, 85% yield) which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 3.66 (s, 3H), 2.71 (m, 1H), 2.65 (d, J=1.76 Hz, 2H), 2.00 (dd J=11.8, 13.6 Hz, 2H), 1.74-1.85 (m, 2H), 1.60-1.74 (m, 1H), 1.40-1.56 (m, 2H), 1.17-1.32 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:30])[N:7]2[CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[CH:22]=2)[CH2:17][CH2:16]1.Cl>C(O)C.[C].[Pd]>[NH2:27][C:23]1[CH:22]=[C:21]([N:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][CH2:12][N:7]3[C:8]4[C:3](=[C:2]([Cl:1])[CH:11]=[CH:10][CH:9]=4)[CH2:4][CH2:5][C:6]3=[O:30])[CH2:16][CH2:17]2)[CH:26]=[CH:25][CH:24]=1
Reactant: O=C1CCc2c(Cl)cccc2N1CCCN1CCN(c2cccc([N+](=O)[O-])c2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1cccc(N2CCN(CCCN3C(=O)CCc4c(Cl)cccc43)CC2)c1
Yield: 89.6 %

Procedure:
5-Chloro-1-{3-[4-(3-nitrophenyl)-1-piperazinyl]propyl}-3,4-dihydrocarbostyril (3 g) was dissolved in 100 ml of ethanol, 2 ml of concentrated hydrochloric acid was added, and catalytic reduction was carried out at 3 atmospheres in the presence of 1.5 g of 5% palladium-carbon. The catalyst was then filtered off, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give 2.5 g of 1-{3-[4-(3-aminophenyl)-1-piperazinyl]propyl}-5-chloro-3,4-dihydrocarbostyril as colorless needles.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.[CH3:19][O:20][C:21](=[O:25])[C@H:22]([CH3:24])[NH2:23].CN(C)CCCN=C=NCC.[CH2:37]([C:40]1([C:55](O)=[O:56])[CH2:44][CH2:43][CH2:42][N:41]1[C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46])[CH:38]=[CH2:39]>CN(C=O)C>[CH3:19][O:20][C:21](=[O:25])[C@H:22]([CH3:24])[NH:23][C:55](=[O:56])[C:40]1([CH2:37][CH:38]=[CH2:39])[CH2:44][CH2:43][CH2:42][N:41]1[C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46]
Reactant: COC(=O)[C@H](C)N
Reactant: C=CCC1(C(=O)O)CCCN1C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C=CCC1(C(=O)N[C@@H](C)C(=O)OC)CCCN1C(=O)OCc1ccccc1
Reaction time: 18 h
Yield: 83.2 %

Procedure:
HOBT (7.7 g), N-methylmorpholine (6.6 g), L-alanine methyl ester hydrochloride (4.5 g) and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide (5.7 g) was added to (RS)-2-allyl-N-(benzyloxycarbonyl)proline (6.5 g) in DMF (30 ml) and the mixture was stirred for 18 hours and then evaporated. The residue was partitioned between ether and water, filtered to remove HOBt and the organic layer separated. The organic layer was evaporated and the residue was purified by chromatography on silica using a gradient of 20% ethyl acetate in hexane increasing to 50% ethyl acetate in hexane. The appropriate fractions were combined and evaporated to dryness to give [(RS)-2-allyl-N-(benzyloxycarbonyl)prolyl]-(S)-alanine methyl ester (7 g); NMR (d6-DMSO (373K)): some doubling of peaks due to the mixture of diastereoisomers, 1.25 and 1.3 (2d, 3H), 1.75 (m, 2H), 2.2 (m,2H), 2.65 (m, 1H), 2.9 (m, 1H), 3.4 (m, 1H), 3.65 (2s, 3H), 3.7 (m, 1H), 4.3 (2q, 1H), 5.0 (m, 4H), 5.7 (m,1H), 7.3 (m, 5H), 7.4 and 7.5 (bs, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([Br:12])=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O>C(O)C>[Br:12][C:9]1[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]2[N:11]([CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:1]=2)[CH:10]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: COC(=O)c1cc(N)ncc1Br
Solvent: CCO
Product: COC(=O)c1cc2nc(-c3ccccc3)cn2cc1Br
Reaction time: 8 h
Yield: 55.9 %

Procedure:
A 40 mL pressure rated scintillation vial was charged with methyl 2-amino-5-bromoisonicotinate (500 mg, 2.16 mmol) and 2-bromo-1-phenylethanone (474 mg, 2.38 mmol). The mixture was partially dissolved in ethanol (10.8 mL) and the reaction vessel was placed in a reaction block preheated to 100° C. The reaction mixture was let stir overnight. After heating for 18 hours, LCMS showed complete conversion of the starting material to a major peak with the desired mass (m/z=332 [M+H]+). The mixture was allowed to come to ambient temperature. After several hours a red precipitate had formed and was filtered. The solid was dried in open air overnight. Methyl 6-bromo-2-phenylimidazo[1,2-a]pyridine-7-carboxylate (400 mg, 1.208 mmol, 55.8% yield) was collected as a red solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.12 (1H, s), 8.58 (1H, s), 8.18 (1H, s), 8.01 (2H, dd, J=8.28, 1.25 Hz), 7.53 (2H, t, J=7.53 Hz), 7.41-7.47 (1H, m), 3.93 (3H, s). Mass found 332 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[C:19]1([C:25]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:26]2[CH:30]=[C:29]([CH2:31][CH2:32][CH2:33]O)[N:28]=[CH:27]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:41]1([C:25]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:26]2[CH:30]=[C:29]([CH2:31][CH2:32][CH2:33][N:4]3[C:3](=[O:8])[C:2]([CH3:1])([C:9]4[C:18]5[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=5)[CH:12]=[CH:11][CH:10]=4)[NH:6][C:5]3=[O:7])[N:28]=[CH:27]2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC1(c2cccc3ccccc23)NC(=O)NC1=O
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(c2cccc3ccccc23)NC(=O)N(CCCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)C1=O
Reaction time: 24 h
Yield: 79.2 %

Procedure:
0.60 g(2.5 mmol) of 5-methyl-5-naphthalen-1-yl-imidazolidin-2,4-dione prepared in Preparation 1, 1.02 g(2.76 mmol) of 3-(1-triphenylmethyl-imidazol-4-yl)-propanol and 0.87 g(3.3 mmol) of triphenylphosphine (Ph3P) were dissolved in 50 ml of tetrahydrofuran. 0.52 ml(3.3 mmol) of diethylazodicarboxylate[DEAD] was added thereto and the resulting solution was stirred for 24 hours. Tetrahydrofuran was removed under reduced pressure and the residue was subjected to chromatography using ethyl acetate the eluent to obtain 1.17 g(Yield: 80%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10]3[C:11]4[C:36](=[O:37])[NH:35][C:34](=[O:38])[C:12]=4[C:13]4[C:14]5[C:19]([N:20]([C@@H:22]6[O:30][C@H:29]([CH2:31][OH:32])[C@@H:27]([OH:28])[C@H:25](O)[C@H:23]6[OH:24])[C:21]=4[C:9]=3[NH:8][C:6]=2[CH:7]=1)=[CH:18][C:17]([F:33])=[CH:16][CH:15]=5.CS(Cl)(=O)=O>N1C=CC=CC=1>[C@@H:22]1([N:20]2[C:21]3[C:9]4[NH:8][C:6]5[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=5[C:10]=4[C:11]4[C:36](=[O:37])[NH:35][C:34](=[O:38])[C:12]=4[C:13]=3[C:14]3[C:19]2=[CH:18][C:17]([F:33])=[CH:16][CH:15]=3)[O:30][C@@H:29]2[CH2:31][O:32][C@@H:25]([C@@H:27]2[OH:28])[C@H:23]1[OH:24]
Reactant: O=C1NC(=O)c2c1c1c3ccc(F)cc3[nH]c1c1c2c2ccc(F)cc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: O=C1NC(=O)c2c1c1c3ccc(F)cc3[nH]c1c1c2c2ccc(F)cc2n1[C@@H]1O[C@@H]2CO[C@H]([C@H]1O)[C@@H]2O
Reaction time: 6 h

Procedure:
2,10-Difluoro-12,13-dihydro-12-[β-D-glucopyranosyl]-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (1.0 g, 1.91 mmol) was dissolved in dry pyridine under nitrogen at room temperature and treated with flame-dried, powdered 4A molecular sieves (0.60 g). The mixture was cooled to −20° C. for 15 min before methanesulfonyl chloride (0.26 mL, 3.34 mmol, 1.75 eq.) was added neat. The flask was sealed and stored at 0° C. for 6 h prior to concentration in vacuo. Purification of the residue by flash chromatography on silica gel (elution with tetrahydrofuran/dichloromethane/methanol, 68:30:2) gave an enriched fraction (280 mg, 24%) containing the title compound as well as a small amount of other closely-spaced by-products which was carried on directly. Potassium phthalimide (0.45 g, 2.43 mmol) was added in one portion to a stirred solution of 2,10-difluoro-12,13-dihydro-12-[6-O-(methylsulfonyl)-β-D-glucopyranosyl]-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (200 mg, 0.33 mmol) in anhydrous dimethylformamide (10 mL) before the mixture was heated to 130°0 C. for 3 h, cooled to ambient temperature, and concentrated down in vacuo overnight. The residue was then taken up in ethyl acetate (some tetrahydrofuran was added) and washed with 0.1N hydrochloric acid and brine. Following drying and solvent concentration, the residue was purified by flash chromatography on silica gel (elution with 7% methanol in chloroform) to yield 2,10-difluoro-12,13-dihydro-12-[6-deoxy-6-(phthalimido)-β-D-glucopyranosyl]-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (46 mg, 21%) as a yellow solid as well as the title compound (22 mg, 13%, 2 steps) also as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17]Br)=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:8]=2[CH:26]=1)([O-:3])=[O:2].[CH2:27]([NH2:30])[C:28]#[CH:29].[I-].[K+]>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17][NH:30][CH2:27][C:28]#[CH:29])=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:8]=2[CH:26]=1)([O-:3])=[O:2]
Reactant: C#CCN
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CBr)n1-2
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCNCc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Preparation 19, 8 -nitro-1-(bromomethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in dimethylformamide is reacted at room temperature with propargylamine in the presence of potassium iodide to give 8-nitro-1-[[(2-propynyl)amino] methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 25 8 -Chloro-1-[[(cyclopropylmethyl)amino]methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:23])[N:12]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:7][N:6]=1)=O.[CH3:24][NH2:25]>CCO>[CH3:24][NH:25][C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:23])[N:12]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:7][N:6]=1)=[O:2]
Reactant: COC(=O)c1ncc2ccc(=O)n(Cc3ccccc3)c2c1O
Reactant: CN
Solvent: CCO
Product: CNC(=O)c1ncc2ccc(=O)n(Cc3ccccc3)c2c1O
Temperature: 80 °C

Procedure:
A mixture of 1-benzyl-8-hydroxy-2-oxo-1,2-dihydro-[1,6]naphthyridine-7-carboxylic acid methyl ester (15 mg, 0.048 mmol) and methylamine (1 mL, 2 M in THF) in 2 mL of EtOH was heated in a sealed tube at 80° C. for 16 h. Solvent was evaporated in vacuo, and the residue was purified by silica gel chromatography (0-5% MeOH/CH2Cl2) to give 9.1 mg of the title compound as a pale yellow solid. MS: (+) m/z 310.27 (M+1).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[CH:11][C:12]([O:16][CH3:17])=[C:13]([CH:15]=2)[NH2:14])[CH2:3]1.CN1CCOCC1.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[C:28]([CH3:36])[CH:27]=1>ClCCl>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:14][C:13]2[CH:15]=[C:9]([N:4]3[CH2:3][C@H:2]([CH3:1])[NH:7][C@H:6]([CH3:8])[CH2:5]3)[CH:10]=[CH:11][C:12]=2[O:16][CH3:17])(=[O:34])=[O:33])=[C:28]([CH3:36])[CH:27]=1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1N
Reactant: Cc1cc(Br)ccc1S(=O)(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)aniline (D4) (1.20 g, 5.1 mmol) in dichloromethane (35 ml) was treated with morpholinomethyl-polystyrene HL resin (2.43 g, 4.2 mmol/g loading, 10.2 mmol) followed by 4-bromo-2-methylbenzenesulfonyl chloride (2.75 g, 10.2 mmol). The resulting solution was stirred at room temperature overnight, the resin filtered off, the solvent evaporated in vacuo and the residue passed through an SCX column eluting first with methanol and then 2M ammonia in methanol. The basic fractions were combined and solvent evaporated in vacuo to afford a crude product which was purified further by chromatography on silica gel using a Flashmaster and an elution gradient of 0 to 10% methanol in dichloromethane. The relevant fractions were combined and the solvent evaporated in vacuo to afford the title compound (E102). MS (ES+) m/e 468/470 [M+H]+.
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=1)[C@H:10]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:11][O:12][Si](C(C)(C)C)(C)C)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([O:7][CH2:8][C@H:9]([C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][CH:28]=1)[C@H:10]([C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:11][OH:12])(=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)[C@H](CO[Si](C)(C)C(C)(C)C)[C@H](COC(=O)C(C)(C)C)c1ccc(C(F)(F)F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@H](CO)[C@H](COC(=O)C(C)(C)C)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 89.6 %

Procedure:
(2S,3S)-3-(Tert-butoxycarbonyl)-4-(tert-butyldimethylsilyloxy)-2-(4-(trifluoromethyl)phenyl)butyl pivalate (2.2 g, 4.0 mmol) was taken up in 40 mL of THF and chilled to 0° C. TBAF, 1 M in THF (6.0 mL, 6.0 mmol) was added slowly. After 20 minutes, the mixture was warmed to room temperature and stirred for 1 hour. 0.5 mL of additional TBAF was added, and the mixture was stirred for 20 minutes. The mixture was quenched with 20 mL of aq NH4Cl. The mixture was then diluted with 40 mL of water and extracted twice with 50 mL of EtOAc. The combined organic extracts were washed with 50 mL of brine and dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (5% to 40% EtOAc/hexanes) afforded (2S,3S)-3-(tert-butoxycarbonyl)-4-hydroxy-2-(4-(trifluoromethyl)phenyl)butyl pivalate (1.5 g, 86% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.59 (d, J=8.22 Hz, 2H) 7.37 (d, J=8.02 Hz, 2H) 4.57 (d, J=6.4 Hz, 1H) 4.45-4.35 (m, 2H) 4.06 (s, 1H) 3.70 (s, 2H) 3.51-3.41 (m, 1H), 1.75 (broad s, 1H) 1.33 (s, 9H) 1.08 (s, 9H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]([C:18]2[N:19]=[CH:20][C:21]3[N:26]=[C:25]([NH:27][C:28](=[O:30])[CH3:29])[S:24][C:22]=3[N:23]=2)[CH:15]2[CH2:17][CH2:16]2)[CH:9]=1)(C)(C)C.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[NH2:7][C:8]1[CH:9]=[C:10]([N:14]([CH:15]2[CH2:17][CH2:16]2)[C:18]2[N:19]=[CH:20][C:21]3[N:26]=[C:25]([NH:27][C:28](=[O:30])[CH3:29])[S:24][C:22]=3[N:23]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC(=O)Nc1nc2cnc(N(c3cccc(NC(=O)OC(C)(C)C)c3)C3CC3)nc2s1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(=O)Nc1nc2cnc(N(c3cccc(N)c3)C3CC3)nc2s1
Yield: 80 %

Procedure:
A solution of the above-mentioned crude product of tert-butyl(3-{[2-(acetylamino)[1,3]thiazolo[5,4-d]pyrimidin-5-yl](cyclopropyl)amino}phenyl)carbamate and anisole (1.5 mL) in trifluoroacetic acid (15 mL) was stirred at 0° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, to the obtained residue was added saturated aqueous sodium hydrogen carbonate solution (60 mL), and the mixture was extracted with ethyl acetate/tetrahydrofuran mixture (9:1, 60 mL, 20 mL). The combined organic layer was washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was washed with ethyl acetate to give the title compound (820 mg, 80%) as a purple solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].C(O[C:13]([S-])=[S:14])C.[K+]>CN(C=O)C>[S:14]=[C:13]1[NH:1][C:2]2[S:3][CH:4]=[CH:5][C:6]=2[C:7](=[O:8])[NH:9]1
Reactant: CCOC(=S)[S-]
Reactant: NC(=O)c1ccsc1N
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1[nH]c(=S)[nH]c2sccc12
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
2-Aminothiophene-3-carboxamide (13 g, 92 mmol) and potassium ethylxanthate (48 g, 275 mmol) were mixed together and added to DMF (300 mL). The resulting mixture was heated to 150° C. for 6 hrs, then cooled to RT and concentrated on the rotovap under reduced pressure at 90° C. The residue was diluted with 300 mL of aqueous citric acid (5%) and cooled to 0° C. and stirred for 30 min. The tan powder was filtered and dried overnight to give (11.5 g) of the title compound MS (ES+): 185 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[CH2:8][CH2:7][NH:6][CH2:5][C@H:4]1[NH:9][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[CH2:18]([N:6]1[CH2:7][CH2:8][C@@H:3]([O:2][CH3:1])[C@H:4]([NH:9][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[CH2:5]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOP(=O)(N[C@@H]1CNCC[C@H]1OC)OCC
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOP(=O)(N[C@@H]1CN(Cc2ccccc2)CC[C@H]1OC)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.7 %

Procedure:
A mixture of diethyl trans-4-methoxypiperidin-3-ylphosphoramidate (1.30 g, 4.88 mmol), benzaldehyde (0.74 mL, 7.32 mmol) and acetic acid (0.56 mL, 9.76 mmol) in methanol (20 mL) was stirred at 0° C. for 30 minutes. NaCNBH3 (0.46 g, 7.32 mmol) was added at 0° C. The resulting solution was warmed to room temperature and stirred at room temperature for 1 hour. The solvent was removed in vacuo and saturated sodium bicarbonate (20 mL) and ethyl acetate (30 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate) and concentrated in vacuo to give diethyl trans-1-benzyl-4-methoxypiperidin-3-ylphosphoramidate (1.70 g, 98%), which was used directly in the next step without purification.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][C:9]([O:11]CC)=[O:10])[O:6][CH2:5][CH2:4][O:3]1.[OH-].[Na+]>CO.O>[CH3:1][C:2]1([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[O:6][CH2:5][CH2:4][O:3]1
Reactant: CCOC(=O)CCC1(C)OCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(CCC(=O)O)OCCO1
Temperature: 25 °C
Reaction time: 17 h
Yield: 65.8 %

Procedure:
A solution of ethyl 3-(2-methyl-1,3-dioxolan-2-yl)propanoate (68.9 g, 366 mmol) in methanol (73 mL) was cooled to approximately 0° C. A warm solution of sodium hydroxide (14.63 g, 366 mmol) in water (73 mL) was added dropwise over a period of three hours. The reaction was then allowed to warm to room temperature and stirred for 17 hours. The methanol was removed under reduced pressure, and the resulting aqueous solution was diluted with water (400 mL) and washed with ethyl acetate (150 mL). The aqueous solution was then cooled to approximately 0° C. and adjusted to pH 2 with the addition of sulfuric acid (180 mL of 1 M). The resulting mixture was extracted with ethyl acetate (2×150 mL), and the combined extracts were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 38.6 g of 3-(2-methyl-1,3-dioxolan-2-yl)propanoic acid as a light yellow oil.