Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([N+:19]([O-:21])=[O:20])[CH:10]=1.[C:22]1([OH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>C(OCC)(=O)C.CN(C)C=O>[N+:19]([C:11]1[CH:10]=[C:9]([CH2:8][O:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14])([O-:21])=[O:20]
Reactant: Oc1ccccc1
Reactant: COC(=O)c1ccc(CBr)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(COc2ccccc2)cc1[N+](=O)[O-]
Reaction time: 10 h
Yield: 101.1 %

Procedure:
0.50 g of potassium carbonate and 0.50 g of methyl 4-(bromomethyl)-2-nitrobenzoate were added to 5 mL of N,N-dimethylformamide solution containing 0.18 g of phenol at room temperature and stirred at the same temperature for 10 hours. Ethyl acetate and 1.0 mol/L hydrochloric acid were added to the reaction mixture. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [eluent; hexane:ethyl acetate=6:1] to obtain 0.53 g of methyl 2-nitro-4-(phenoxymethyl)benzoate as colorless oil.
Reaction SMILES: N1C=CN=C1.[CH2:6]1[CH2:18][O:17][C:8]([CH3:16])([CH2:9][CH2:10][CH2:11][CH:12]([CH3:15])[CH2:13][OH:14])[O:7]1.[Si:19](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[O:14]([CH2:13][CH:12]([CH3:15])[CH2:11][CH2:10][CH2:9][C:8]1([O:7][CH2:6][CH2:18][O:17]1)[CH3:16])[Si:19]([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(CO)CCCC1(C)OCCO1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(CCCC1(C)OCCO1)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Imidazole (26.5 g) is added to a solution of 6,6-ethylenedioxy-2-methyl-heptanol (33.35 g) in dimethylformamide (50 ml). A solution of t-butyldiphenylsilyl chloride (52.2 g) in dimethylformamide (200 ml) is added dropwise to the reaction mixture and allowed to stir for 3 hours at room temperature. The reaction mixtures is extracted with hexane (3X300 ml) and the combined extract is washed with brine and dried (Na2SO4). The solvent is removed in vacuo to give 1-t-butyldiphenylsiloxy-6,6-ethylenedioxy-2-methyl-heptane (75.35 g, 99.6%; nmr (CDCl3,δ), 0.91 (d, 3H, CH3CH), 1.03 [s, (CH3)3C], 1.29 (s, ##STR58## 3.47 (d, CHCH2O), 3.88 (s, OCH2CH2O), 7.2-7.8 (m, 10H, 2φ).
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[NH:16][CH:17]=[CH:18][N:19]=3)=[CH:10][C:8]=2[CH:9]=1)=O.[NH3:20]>C(O)C>[NH:19]1[CH:18]=[CH:17][N:16]=[C:15]1[CH2:14][C:11]1[CH:12]=[CH:13][C:7]2[O:6][C:5]([C:3]([NH2:20])=[O:2])=[CH:9][C:8]=2[CH:10]=1
Reactant: COC(=O)c1cc2cc(Cc3ncc[nH]3)ccc2o1
Reactant: N
Solvent: CCO
Product: NC(=O)c1cc2cc(Cc3ncc[nH]3)ccc2o1

Procedure:
A solution of 5-(1-imidazolylmethyl)benzofuran-2-carboxylic acid methyl ester in a concentrated solution of ammonia in ethanol (25 ml.) was stirred for 18 hours and then evaporated. The residue was crystallized from isopropanol to give 5-(1-imidazolylmethyl)benzofuran-2-carboxamide (0.60 g.), m.p. 174°-176° C.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH:5]=[CH2:6].[Br:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Br)=[CH:10][CH:9]=1.Cl>O1CCCC1>[CH2:12]([C:11]1[CH:14]=[CH:15][C:8]([Br:7])=[CH:9][CH:10]=1)[CH2:6][CH2:5][CH:4]=[CH2:3]
Reactant: C=CCCBr
Reactant: BrCc1ccc(Br)cc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CCCCc1ccc(Br)cc1
Yield: 12.7 %

Procedure:
To a suspension of 970 mg of magnesium in 20 ml of tetrahydrofuran was added dropwise a solution of 5.4 g of 4-bromo-1-butene in 20 ml of tetrahydrofuran while keeping at 50° C. Then, a solution of 10.0 g of 4-bromobenzyl bromide in 20 ml of tetrahydrofuran was added dropwise slowly, and the mixture was refluxed for an hour, made acidic with dilute hydrochloric acid and extracted with n-hexane. The organic layer was washed with water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was chromatographed on silica gel column with n-hexane to give 1.14 g of 4-(4-pentenyl)bromobenzene.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([O:9][C:10](=[O:26])[CH2:11][N:12]=C(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:8].[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[C:32]([Cl:34])=[O:33].Cl>C1COCC1>[ClH:34].[NH2:12][CH:11]([C:32](=[O:33])[C:28]1[S:27][CH:31]=[CH:30][CH:29]=1)[C:10]([O:9][CH2:7][CH3:8])=[O:26]
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)c1cccs1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C(N)C(=O)c1cccs1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
To a stirred solution of potassium tert-butoxide (0.84 g, 7.5 mmol) in dry THF (5.25 mL) under an N2 atmosphere at −78° C. was added a cooled (−78° C.) solution of N-(diphenylmethylene)glycine ethyl ester (2.00 g, 7.5 mmol) in dry THF (3 mL), dropwise. The resulting solution was stirred at −78° C. for 30 minutes when it was added via canula to a stirred solution of 2-thiophene carbonyl chloride (0.80 mL, 7.5 mmol) in dry THF (3 mL) under an N2 atmosphere at −78° C. The resulting mixture was stirred at −78° C. for 1 hour. The reaction was warmed to room temperature, 3N aqueous HCl (7.5 mL) was then added and the mixture stirred for 15 minutes. The resulting mixture was then concentrated in vacuo, diluted with water and washed with Et2O. The aqueous phase was evaporated to dryness to afford ethyl 2-amino-3-oxo-3-(thiophen-2-yl)propanoate hydrochloride (1.345 g) as a pale solid which was used without further purification. LCMS (2) Rt: 1.44 min; m/z (ES+) 214.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=O)=[N:5][C:4]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[N:3]1.[Cl-].[CH3:15][C:16]1[C:17]([CH2:26][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:18][C:19]2[C:24]([N:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2>>[CH3:15][C:16]1[C:17]([CH:26]=[CH:7][C:6]2[N:2]([CH3:1])[N:3]=[C:4]([N:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[N:5]=2)=[N:18][C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:25]=1
Reactant: Cc1nc2ccccc2nc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1nc(N2CCCC2)nc1C=O
Agent: [Cl-]
Product: Cc1nc2ccccc2nc1C=Cc1nc(N2CCCC2)nn1C
Yield: 56.3 %

Procedure:
Was prepared in the same manner as described in General Procedure Example 1g) using 1-methyl-3-(pyrrolidin-1-yl)-1H-1,2,4-triazole-5-carbaldehyde (50 mg, 277 μmol, Eq: 1.00) and ((3-methylquinoxalin-2-yl)methyl)triphenylphosphonium chloride (126 mg, 277 μmol, Eq: 1.00) as starting materials. Chromatography afforded 2-Methyl-3-[2-(2-methyl-5-pyrrolidin-1-yl-2H-[1,2,4]triazol-3-yl)-vinyl]-quinoxaline (50 mg, 56.2%) as light yellow solid. MS: m/z=321.4 (M+H+)
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[ClH:12]>CN(C)C=O.[Cu](Cl)Cl>[Cl:12][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: Cl
Reactant: Cc1cc(N)ncc1[N+](=O)[O-]
Agent: Cl[Cu]Cl
Solvent: CN(C)C=O
Product: Cc1cc(Cl)ncc1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
Copper(II)chloride (10.01 g, 74.5 mmol) was dissolved in N,N-dimethylformamide (75 mL) and the solution was warmed to 60° C. A solution of 2-amino-4-methyl-5-nitropyridine (9.50 g, 62.0 mmol) in N,N-dimethylformamide (145 mL) was added with addition funnel over 0.5 h. The reaction mixture was heated at 110° C. for 16 h. The reaction mixture was cooled to room temperature and poured into 3 N aqueous hydrochloric acid (300 mL), followed by extraction with diethyl ether. The organic extract was dried over sodium sulfate and adsorbed onto silica gel for purification by column chromatography (SiO2, 20:3 hexanes/ethyl acetate). 2-Chloro-4-methyl-5-nitropyridine was obtained as a yellow solid (2.10 g, 20%): 1H NMR (300 MHz, CD3OD) δ2.63 (3H, s), 7.60 (1H, s), 8.96 (1H, s); ESI MS m/z 173 [C6H5ClN2O2+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([B:15]([OH:17])[OH:16])[CH:10]=2)[C:5]([F:18])=[CH:4][N:3]=1.[OH:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>>[F:18][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([B:15]([OH:17])[OH:16])[CH:10]=2)=[N:7][C:2]([NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[C:20]([OH:19])[CH:21]=2)=[N:3][CH:4]=1
Reactant: Nc1cccc(O)c1
Reactant: OB(O)c1cccc(Nc2nc(Cl)ncc2F)c1
Product: OB(O)c1cccc(Nc2nc(Nc3cccc(O)c3)ncc2F)c1

Procedure:
In a like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-dihydroxyborylphenyl)-4-pyrimidineamine and 3-hydroxyaniline were reacted to produce 5-Fluoro-N4-(3-dihydroxyborylphenyl)-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.68 (bs, 1H), 9.35 (bs, 1H), 9.22 (bs, 1H), 8.10 (d, 1H, J=3.9 Hz), 7.88-7.80 (m, 2H), 7.54 (d, 1H, J=7.2 Hz), 7.31 (t, 1H, J=7.2 Hz), 7.08 (d, 1H, J=8.4 Hz), 6.98-6.93 (m, 2H), 6.35 (d, 1H, J=8.4 Hz); LCMS: purity: 96%; MS (m/e): 341(MH+).
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[C:17]2[CH2:16][S:15][C:14](=O)[C:13]=2[CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])[CH3:3].B(F)(F)F.CCOCC>O1CCCC1>[CH3:4][C:2]([NH:5][S:6]([C:9]1[C:17]2[CH2:16][S:15][CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:1])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc2c1CSC2=O
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)NS(=O)(=O)c1cccc2c1CSC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.3 %

Procedure:
A suspension of 8.0 g of 1,3-dihydro-N-(1,1-dimethylethyl)-1-oxobenzo[c]thiophene-4-sulfonamide in a mixture of 15 ml of tetrahydrofuran, 25 ml of boron trifluoride etherate was cooled to 10° under N2, and 56 ml of a 1M solution of borane tetrahydrofuran complex was added dropwise at approximately 10°. The reaction mixture was allowed to warm to ambient temperature as a gas was evolved. When ambient temperature was reached, a slow exotherm to 31° occurred. When the exotherm subsided, the reaction mixture was heated to reflux for two hours, then cooled and allowed to stand overnight. The supernatant was decanted fom some brown solid, and concentrated in vacuo. The resulting yellow oil was cooled to approximately 5°, acidified with 5% hydrochloric acid (gas evolution), and diluted with 150 ml water. The aqueous mixture was extracted with ethyl acetate. The organic solution was washed twice with water, dried over magnesium sulfate, then filtered and the filtrate concentrated in vacuo. The resulting yellow oil was purified by chromatography, using methylene chloride as eluent, to give 3.6 g of 1,3-dihydro-N-(1,1-dimethylethyl)benzo[c]thiophene-4-sulfonamide, m.p. 128.5°-132°.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13][S:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)=[O:6])#[N:2].BrC1C=CC(S)=CC=1.CO.I([O-])(=O)(=O)=[O:33].[Na+]>O>[C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13][S:14]([C:15]1[CH:16]=[CH:17][C:18]([Br:21])=[CH:19][CH:20]=1)=[O:33])=[O:6])#[N:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: N#CCNC(=O)[C@@H]1CCCC[C@H]1CSc1ccc(Br)cc1
Agent: Sc1ccc(Br)cc1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#CCNC(=O)[C@@H]1CCCC[C@H]1CS(=O)c1ccc(Br)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
trans-N-Cyanomethyl-2-(4-bromophenylsulfanylmethyl)cyclohexanecarboxamide (197 mg, 0.536 mmol), prepared as in Example 1 but substituting 4-fluorothiophenol with 4-bromothiophenol, was weighed into a 50 mL round bottom flask fitted with a stirrer and vented cap. Methanol (20 mL) was added to the flask and the reaction mixture was warmed to 50° C. until a clear colorless solution formed. Added sodium periodate (128 mg, 0.599 mmol) solution in water (2.0 mL). A white precipitate slowly formed. The reaction mixture was stirred at 50° C. for 8 h and then concentrated on a rotary evaporator. The residue was triturated in hot water (20 mL) and the reaction mixture was cooled to room temperature. Solids were isolated by filtration, washed thoroughly with water and dried under high vacuum to give trans-N-cyanomethyl-2-(4-bromophenylsulfinylmethyl)cyclohexanecarboxamide as a white solid.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Br)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].[CH:38]([C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1)=[O:39]>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:43]3[CH:44]=[CH:45][C:40]([CH:38]=[O:39])=[CH:41][CH:42]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(Br)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=Cc1ccc(B(O)O)cc1
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(-c4ccc(C=O)cc4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5bromo-2-thienylmethyl)-4-methylbenzene from Example 159-(1) and 4-formylphenylboronic acid were treated in a manner similar to Example 168-(1) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(4-formylphenyl)-2-thienylmethyl)-4-methylbenzene as a colorless solid. APCI-Mass m/Z 640 (M+NH4).
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH:4][CH3:5].[BrH:6].CC1(C)CNC(NN=C(C=CC2C=CC(Cl)=CC=2)C=CC2C=CC(Cl)=CC=2)=NC1.[N:36]1[CH:40]2CC[CH2:43][CH2:44][CH:39]2[NH:38][C:37]=1[NH:45][N:46]=[C:47]([CH:57]=[CH:58][C:59]1[CH:64]=[CH:63][C:62]([Cl:65])=[CH:61][CH:60]=1)[CH:48]=[CH:49][C:50]1[CH:55]=[CH:54][C:53]([Cl:56])=[CH:52][CH:51]=1>>[BrH:6].[NH:36]1[CH2:40][CH2:39][CH2:44][CH2:43][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][N:38]=[C:37]1[NH:45][N:46]=[C:47]([CH:48]=[CH:49][C:50]1[CH:51]=[CH:52][C:53]([Cl:56])=[CH:54][CH:55]=1)[CH:57]=[CH:58][C:59]1[CH:64]=[CH:63][C:62]([Cl:65])=[CH:61][CH:60]=1
Reactant: Clc1ccc(C=CC(C=Cc2ccc(Cl)cc2)=NNC2=NC3CCCCC3N2)cc1
Reactant: C=CC=CC
Agent: Br
Agent: CC1(C)CN=C(NN=C(C=Cc2ccc(Cl)cc2)C=Cc2ccc(Cl)cc2)NC1
Product: Clc1ccc(C=CC(C=Cc2ccc(Cl)cc2)=NNC2=NCCCCCCCCCN2)cc1

Procedure:
The pentadiene in accordance with claim 10, 1,5-bis(p-chlorophenyl)-1,4-pentadiene-3-one 5,5-dimethyl-1,4,5,6-tetrahydropyrimidin-2-ylhydrazone hydrobromide. 13. The pentadiene in accordance with claim 1, 1,5-bis(p-chlorophenyl)-1,4-pentadiene-3-one 3α ,4,5,6,7,7a-hexahydrobenzimidazol-2-yl-hydrazone hydrochloride. 14. The pentadiene in accordance with claim 1, 1,5-bis(p-chlorophenyl)-1,4-pentadien-3-one 3α ,4,5,6,7,7a-hexahydrobenzimidazol-2-yl-hydrazone hydrobromide. 15. The pentadiene in accordance with claim 1, 1,5-bis(p-chlorophenyl)-1,4-pentadiene-3-one 3a,4,5,6,7,7a-hexahydrobenzimidazol-2-yl-hydrazone.
Reaction SMILES: [CH:1]([O-])=[O:2].[Na+].[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([CH3:28])[C:12]2[O:18][C:17]3[C:19]([Cl:24])=[CH:20][C:21]([NH2:23])=[CH:22][C:16]=3[CH2:15][S:14](=[O:26])(=[O:25])[C:13]=2[CH:27]=1)=[O:8]>C(O)=O>[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([CH3:28])[C:12]2[O:18][C:17]3[C:19]([Cl:24])=[CH:20][C:21]([NH:23][CH:1]=[O:2])=[CH:22][C:16]=3[CH2:15][S:14](=[O:26])(=[O:25])[C:13]=2[CH:27]=1)=[O:8]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N)cc(Cl)c1O2
Reactant: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC=O)cc(Cl)c1O2
Temperature: 0 °C

Procedure:
Sodium formate (7.29 g, 0.108 mol) was added to a suspension of compound of Example 1 (20 g, 0.054 mol) in formic acid (200 mL) and refluxed for 1.5 h. The reaction mixture was cooled and poured into ice water (800 mL). The solid precipitated was filtered, washed with water and dried. The crude product was purified by column chromatography (silica gel, 1% methanol in chloroform) to obtain the title compound. Yield: 18 g, (83%); mp 258-262° C. (decomposed); 1H NMR (DMSO-d6, 300 MHz): δ 2.64 (s, 3H, CH3), 3.86 (s, 3H, OCH3), 5.25 (s, 2H, CH2, trans minor isomer), 5.33 (s, 2H, CH2, cis major isomer), 7.33 (d, 1H, Ar, trans minor isomer), 7.50 (d, 1H, Ar, trans minor isomer), 7.69 (d, 1H, Ar, cis major isomer), 7.86 (d, 1H, Ar, cis major isomer), 8.10 (s, 1H, Ar), 8.15 (s, 1H, Ar), 8.30 (s, 1H, CHO, cis major isomer), 8.80 (d, 1H, CHO, trans minor isomer), 10.40 (d, 1H, NH, trans minor isomer), 10.57 (s, 1H, NH, cis major isomer); MS: m/e (ES−) 394 (M−1); analysis: C17H14ClNO6S requires C, 51.54; H, 3.56; N, 3.54; Cl, 8.96; S, 8.10. found: C, 51.96; H, 3.63; N, 3.60; Cl, 9.43; S, 8.50%.
Reaction SMILES: [CH3:1][C:2]1([NH:8][C:9]2[C:10]3[C:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=4[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[F:22][C:23]1[CH:24]=[C:25]([CH:29](OS(C)(=O)=O)[CH3:30])[CH:26]=[CH:27][CH:28]=1>>[F:22][C:23]1[CH:24]=[C:25]([CH:29]([N:5]2[CH2:6][CH2:7][C:2]([NH:8][C:9]3[C:10]4[C:17]5[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=5[S:15][C:11]=4[N:12]=[CH:13][N:14]=3)([CH3:1])[CH2:3][CH2:4]2)[CH3:30])[CH:26]=[CH:27][CH:28]=1
Reactant: CC(OS(C)(=O)=O)c1cccc(F)c1
Reactant: CC1(Nc2ncnc3sc4c(c23)CCCC4)CCNCC1
Product: CC(c1cccc(F)c1)N1CCC(C)(Nc2ncnc3sc4c(c23)CCCC4)CC1

Procedure:
The title compound was prepared (97 mg, 81%) from (4-methyl-piperidin-4-yl)-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-amine(150 mg, 0.28 mmol) and methanesulfonic acid 1-(3-fluoro-phenyl)-ethyl ester (61.1 mg, 0.28 mmol) by following the procedure described for preparation 12. 1H NMR (400 MHz, CDCl3): 6 (ppm) 8.38 (s, 1H), 7.20 (s, 1H), 6.89–6.79 (m, 3H), 3.91 (q, 1H), 2.80–2.74(m, 4H), 2.20–2.09(M, 2H), 1.90 (m, 2H), 1.89–1.85 (m, 4H), 1.55 (m, 4H), 1.31 (s, 3H); MS (SEI): m/z: Calculated: 424.2; Observed: 425.2 (M++1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1.[CH2:16]([O:23][NH:24][CH2:25][CH3:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][N:24]([C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1)[CH2:25][CH3:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCCNc1nc(Cl)nc(NCCC)n1
Reactant: CCNOCc1ccccc1
Product: CCCNc1nc(NCCC)nc(N(CC)OCc2ccccc2)n1
Yield: 38 %

Procedure:
2-Chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) and O-benzyl-N-ethyl-hydroxylamine (LXVII) were reacted as described in Example 13 to afford O-benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-hydroxylamine (LXVIII, 38% yield). 400 MHz 1H NMR (DMSO-d6, ppm) 7.51-7.45 (2H, m), 7.40-7.30 (3H, s), 6.97-6.85 (1H, m), 6.79-6.67 (1H, m), 4.97-4.87 (1H, m), 3.72-3.53 (2H, m), 3.23-3.11 (4H, m), 1.56-1.43 (4H, m), 1.13-1.00 (3H, m), 0.89-0.80 (6H, m). ESI-MS (m/z): 345 [M+H]+.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[C:12]([OH:20])[C:13]3[N:14]([N:16]=[C:17]([CH3:19])[CH:18]=3)[CH:15]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].CS(O[C@H:26]([C@@H:28]1[CH2:32][C:31](=[O:33])[N:30]([C@@H:34]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[CH3:35])[CH2:29]1)[CH3:27])(=O)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C=O)C.C1COCC1>[C:1]([N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[C:12]([O:20][C@@H:26]([C@H:28]3[CH2:29][N:30]([C@@H:34]([C:36]4[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=4)[CH3:35])[C:31](=[O:33])[CH2:32]3)[CH3:27])[C:13]3[N:14]([N:16]=[C:17]([CH3:19])[CH:18]=3)[CH:15]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@H](C)OS(C)(=O)=O)CC2=O)cc1
Reactant: Cc1cc2c(O)cc(-c3cnn(C(C)(C)C)c3)cn2n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(-c4cnn(C(C)(C)C)c4)cn4nc(C)cc34)CC2=O)cc1
Yield: 31.5 %

Procedure:
To a solution of 6-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-methylpyrazolo[1,5-a]pyridin-4-ol (5 mg) in DMF (3 mL) was added (S)-1-((R)-5-oxo-1-((R)-1-phenylethyl)pyrrolidin-3-yl)ethyl methanesulfonate 1.30 (9 mg) and 1 M solution of NaHMDS in THF (0.15 mL) at rt. After 2 h. the reaction mixture was extracted with ethyl acetate. Combined organics were washed with brine, dried, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to provide to provide 3 mg of (R)-4-((R)-1-((6-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-methylpyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one. LCMS [M+H]+: 517.18.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[F:8].[O:12]=[S:13]1(=[O:30])[CH2:18][CH2:17][N:16]2[CH2:19][CH2:20][CH2:21][C@@H:22]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:15]2=[N:14]1.N1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N.C(O[Cu]OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[O:29][C:26]1[CH:25]=[CH:24][C:23]([C@H:22]2[CH:15]3[NH:14][S:13](=[O:30])(=[O:12])[CH2:18][CH2:17][N:16]3[CH2:19][CH2:20][CH2:21]2)=[CH:28][CH:27]=1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: O=S1(=O)CCN2CCC[C@@H](c3ccc(O)cc3)C2=N1
Agent: CC(=O)O[Cu]OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: c1ccncc1
Product: O=S1(=O)CCN2CCC[C@@H](c3ccc(Oc4ccc(F)c(Cl)c4)cc3)C2N1
Temperature: 25 °C
Reaction time: 72 h
Yield: 39.7 %

Procedure:
A mixture of (3-chloro-4-fluorophenyl)boronic acid (933 mg), 4-[(9S)-2,2-dioxido-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazin-9-yl]phenol (500 mg), pyridine (3.60 mL), cesium carbonate (581 mg), diacetoxycopper (648 mg) and powdered 4A MS (4 g) in MeCN (18 mL) was stirred at room temperature for 3 days. The mixture was added with NH silica gel, concentrated in vacuo, and purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) then recrystallized from EtOAc-THF/IPE to give (9S)-9-[4-(3-chloro-4-fluorophenoxy)phenyl]-3,4,6,1,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (290.6 mg) as a white solid.
Reaction SMILES: C(OC(=O)C(C)(C)CC1C=CC(S)=CC=1)C.[CH2:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([C:28]1[CH:33]=[CH:32][C:31]([C:34]([OH:40])([CH3:39])[C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH3:18]>>[CH2:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([C:28]1[CH:33]=[CH:32][C:31]([C@@:34]([OH:40])([CH3:39])[C:35]([F:36])([F:38])[F:37])=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH3:18]
Reactant: CCc1ccccc1S(=O)(=O)c1ccc(C(C)(O)C(F)(F)F)cc1
Agent: CCOC(=O)C(C)(C)Cc1ccc(S)cc1
Product: CCc1ccccc1S(=O)(=O)c1ccc([C@](C)(O)C(F)(F)F)cc1

Procedure:
Using the methods described above in Example 12, but substituting 2-ethylbenzenethiol for 3-(4-mercaptophenyl)-2,2-dimethylpropionic acid ethyl ester in step a, 2-[4-(2-ethylbenzenesulfonyl)phenyl]-1,1,1-trifluoropropan-2-ol was prepared. 1H NMR (CDCl3, 400 MHz) δ 8.19 (dd, J=1.3 Hz, 8.0 Hz, 1H), 7.84 (d, J=8.5 Hz, 2H), 7.73 (d, J=8.5 Hz, 2H), 7.56 (m, 1H), 7.40 (m, 1H), 7.32 (d, J=7.6 Hz 1H), 3.03 (s, 1H), 2.58 (q, J=7.4 Hz, 2H), 1.77 (s, 3H), 1.03 (t, J=7.5 Hz, 3H). The racemic product was resolved by chiral HPLC. The flow rate was 20 mL/min on a Chiralcel OD-H 20 mm i.d.×250 mm, 5μ column (Daciel Chemical Industries LTD), using isopropyl alcohol/hexanes (7/93) as the eluent.