Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([Cl:21])[C:3]=1[C:4](Cl)=[N:5][C:6]1[C:11]([F:12])=[CH:10][N:9]=[CH:8][C:7]=1F.NC(N)=[S:24].N1C=CC=CC=1.CCN(CC)CC>C(O)(C)C>[Cl:1][C:2]1[CH:18]=[C:17]([CH:16]=[C:15]([Cl:21])[C:3]=1[C:4]1[S:24][C:7]2[CH:8]=[N:9][CH:10]=[C:11]([F:12])[C:6]=2[N:5]=1)[C:19]#[N:20]
Reactant: N#Cc1cc(Cl)c(C(Cl)=Nc2c(F)cncc2F)c(Cl)c1
Reactant: NC(N)=S
Solvent: c1ccncc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: N#Cc1cc(Cl)c(-c2nc3c(F)cncc3s2)c(Cl)c1
Temperature: 90 °C
Reaction time: 18 h
Yield: 29.7 %

Procedure:
A stirred suspension of 2,6-dichloro-4-cyano-N-(3,5-difluoropyridin-4-yl)-benzimidoyl chloride (1.5 g, 4.33 mmol), thiourea (1.32 g, 17.34 mmol) and pyridine (1.19 mL, 14.72 mmol) in isopropanol (13 mL) under a nitrogen atmosphere was heated at 90° C. for 4 hours. After cooling to 60° C., Et3N (3.62 mL, 25.98 mmol) was added and heating at 85° C. was continued for 18 hours, then at 90° C. for a further 18 hours. After cooling to room temperature, the volatiles were removed under reduced pressure and the resultant residue was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×2) and the combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The resultant residue was purified by column chromatography on silica gel eluting with 0-90% EtOAc in cyclohexane to afford the title compound as a yellow solid (417 mg, 30%). LCMS (Method D): RT=3.53 min, m/z: 324 [M+H+].
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[C:6]([O:10][C:11](=[O:24])[NH:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[C:14]=1[I:23])([CH3:9])([CH3:8])[CH3:7].C([O-])(O)=O.[Na+].CCOC(C)=O>C(Cl)Cl.C1COCC1>[C:6]([O:10][C:11](=[O:24])[NH:12][C:13]1[C:14]([I:23])=[C:15]([O:21][CH3:22])[CH:16]=[C:17]([O:19][CH3:20])[C:18]=1[Cl:4])([CH3:9])([CH3:7])[CH3:8]
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1cc(NC(=O)OC(C)(C)C)c(I)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(OC)c(I)c(NC(=O)OC(C)(C)C)c1Cl
Temperature: -15 °C
Reaction time: 1 h

Procedure:
A solution of sulfurylchloride (0.92 ml, 11.0 mmol, 1.16 equiv) in DCM (20 mL) is added dropwise (30 min) to a cold (−15° C.) solution of (2-iodo-3,5-dimethoxy-phenyl)-carbamic acid tert-butyl ester (3.6 g, 9.49 mmol) in THF (48 ml), under an argon atmosphere. The reaction mixture is allowed to stir for 1 h at −15° C. and then poured onto a mixture of ice/H2O (100 mL), a saturated aqueous solution of NaHCO3 (80 ml), and EtOAc (100 mL). The layers are separated and the aqueous phase is extracted with EtOAc (2×100 mL). The combined organic phase is washed with H2O (3×60 mL) and brine (60 mL), dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (DCM) followed by crystallization from DCM/Hex to afford the title compound. ESI-MS: 411.9, 413.9 [M-H]+, TLC: Rf=0.18 (DCM/Hex, 7:3).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:47]2[CH2:52][CH2:51][N:50]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:49][CH2:48]2)[CH:5]=[CH:6][C:7]=1[N:8]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:9]1[CH:14]=[C:13]([N:15]([CH3:39])[C:16]([N:18]([C:27]2[C:32]([Cl:33])=[C:31]([O:34][CH3:35])[CH:30]=[C:29]([O:36][CH3:37])[C:28]=2[Cl:38])[CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])=[O:17])[N:12]=[CH:11][N:10]=1.CCN(C(C)C)C(C)C.[C:69](Cl)(=[O:72])[CH:70]=[CH2:71].CCOC(C)=O>C1COCC1.[Cl-].[Na+].O>[C:69]([NH:1][C:2]1[CH:3]=[C:4]([N:47]2[CH2:52][CH2:51][N:50]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:49][CH2:48]2)[CH:5]=[CH:6][C:7]=1[N:8]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:9]1[CH:14]=[C:13]([N:15]([CH3:39])[C:16]([N:18]([C:27]2[C:28]([Cl:38])=[C:29]([O:36][CH3:37])[CH:30]=[C:31]([O:34][CH3:35])[C:32]=2[Cl:33])[CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:24])[CH3:25])=[O:17])[N:12]=[CH:11][N:10]=1)(=[O:72])[CH:70]=[CH2:71]
Reactant: COc1cc(OC)c(Cl)c(N(COCC[Si](C)(C)C)C(=O)N(C)c2cc(N(C(=O)OC(C)(C)C)c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3N)ncn2)c1Cl
Reactant: C=CC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C=CC(=O)Nc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1N(C(=O)OC(C)(C)C)c1cc(N(C)C(=O)N(COCC[Si](C)(C)C)c2c(Cl)c(OC)cc(OC)c2Cl)ncn1
Yield: 45.8 %

Procedure:
Crude tert-butyl 4-(3-amino-4-((tert-butoxycarbonyl)(6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)ureido)pyrimidin-4-yl)amino)phenyl)piperazine 1-carboxylate (95 g, 0.11 mmol) was dissolved in THF (1.5 ml) and stirred over ice bath under nitrogen atmosphere. DIEA (57 μl, 0.30 mmol) followed by acryloyl chloride (13 μl, 0.16 mmol) were added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into EtOAc and brine. The organic. layer was separated, dried over MgSO4 and evaporated. The resulting material was purified by flash chromatography on silica eluting with 30% to 100% EtOAc/Hexane to afford the title compound (47 mg, yield: 47%). 1H-NMR (400 MHz, CDCl3) δ 0.02 (s, 9H) 0.79-1.04 (m, 2H) 1.36 (s, 9H) 1.49 (s, 9H) 3.08 (s, 4H) 3.05 (s, 3H) 3.25 (br. s., 4H) 3.64 (br. s., 4H) 3.86 (s, 6H) 5.27 (s, 1H) 5.67-5.79 (m, 1H) 6.15-6.56 (m, 2H) 6.48 (s, 1H) 7.03-7.14 (m, 1H) 7.87-8.09 (m, 2H) 8.19-8.29 (br. s., 1H) 8.44 (s, 1H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][N:22]3[CH2:26][CH2:25][C@H:24]([NH:27][S:28]([C:31]4[CH:40]=[CH:39][C:38]5[C:33](=[CH:34][C:35]([O:41][CH3:42])=[CH:36][CH:37]=5)[CH:32]=4)(=[O:30])=[O:29])[C:23]3=[O:43])[CH:19]=2)[CH:14]=[CH:13][N:12]=1.Cl>C(Cl)Cl.O>[O:7]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][N:22]3[CH2:26][CH2:25][CH:24]([NH:27][S:28]([C:31]4[CH:40]=[CH:39][C:38]5[C:33](=[CH:34][C:35]([O:41][CH3:42])=[CH:36][CH:37]=5)[CH:32]=4)(=[O:29])=[O:30])[C:23]3=[O:43])[CH:19]=2)[CH:14]=[CH:13][N:12]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4ccc5ccnc(Cl)c5c4)C3=O)cc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc2ccc(S(=O)(=O)NC3CCN(Cc4ccc5ccnc(Oc6ccccc6)c5c4)C3=O)cc2c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
Phenol (6.81 g, 72.4 mmol) and potassium hydroxide ( 0.41 g, 7.31 mmol) are added to 7-methoxynaphthalene-2-sulfonic acid [1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide (1.8 g, 3.6 mmol) and heated to 90° C. until a homogeneous mixture is obtained. The mixture is stirred overnight at 90° C., then cooled to room temperature and diluted with methylene chloride (100 mL) and water. The aqueous layer is neutralized to pH 7 using 1 N HCl, then the two layers are separated and the aqueous layer is extracted with additional methylene chloride. The combined organic layers are washed with brine, dried over MgSO4, filtered and concentrated. The residue is purified by column chromatography eluting with a gradient of 30% EtOAc/hexanes to 60% EtOAc/hexanes to give the product (1.66 g, 3 mmol) as a white solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Cl:34][C:35]1[C:40]([F:41])=[CH:39][CH:38]=[C:37]([Cl:42])[C:36]=1[C@@H:43]([OH:45])[CH3:44].[Br:46][C:47]1[CH:48]=[C:49](O)[C:50]([N+:53]([O-:55])=[O:54])=[N:51][CH:52]=1>C1COCC1>[Br:46][C:47]1[CH:48]=[C:49]([O:45][C@@H:43]([C:36]2[C:37]([Cl:42])=[CH:38][CH:39]=[C:40]([F:41])[C:35]=2[Cl:34])[CH3:44])[C:50]([N+:53]([O-:55])=[O:54])=[N:51][CH:52]=1
Reactant: O=[N+]([O-])c1ncc(Br)cc1O
Reactant: C[C@H](O)c1c(Cl)ccc(F)c1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](Oc1cc(Br)cnc1[N+](=O)[O-])c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.9 %

Procedure:
To a stirred solution of triphenyl phosphine (9.4 g, 0.036 mol) and DIAD (7.2 g. 0.036 mol) in THF (100 mL) at 0° C. was added a solution of (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol (4.55 g, 0.021 mol) and 5-bromo-3-hydroxy-2-nitropyridine (3.35 g, 0.023 mol) in THF (200 mL). The resulting bright orange solution was stirred under a nitrogen atmosphere at ambient temperature for 4 hours at which point all starting materials had been consumed. The solvent was removed, and the crude material was dry loaded onto silica gel, and eluted with ethyl acetate-hexanes (20:80) to yield the title compound as a white solid (8.6 g, 85%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:23](=[O:24])[N:5]2[C:6]([C:20]([O-:22])=[O:21])=[C:7]([CH2:10][N+:11]3[N:12]([CH2:17][CH2:18][OH:19])[C:13]([NH2:16])=[CH:14][CH:15]=3)[CH2:8][S:9][C@H:4]12.C(=O)(O)[O-].[Na+].Cl.[NH2:31][C:32]1[S:36][N:35]=[C:34](/[C:37](=[N:41]/[O:42][CH2:43][CH3:44])/[C:38](Cl)=[O:39])[N:33]=1>C(#N)C.O>[NH2:31][C:32]1[S:36][N:35]=[C:34]([C:37](=[N:41][O:42][CH2:43][CH3:44])[C:38]([NH:2][C@@H:3]2[C:23](=[O:24])[N:5]3[C:6]([C:20]([O-:22])=[O:21])=[C:7]([CH2:10][N+:11]4[N:12]([CH2:17][CH2:18][OH:19])[C:13]([NH2:16])=[CH:14][CH:15]=4)[CH2:8][S:9][C@H:4]23)=[O:39])[N:33]=1
Reactant: CCO/N=C(\C(=O)Cl)c1nsc(N)n1
Reactant: Nc1cc[n+](CC2=C(C(=O)[O-])N3C(=O)[C@@H](N)[C@H]3SC2)n1CCO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccc(N)n3CCO)CS[C@H]12)c1nsc(N)n1
Temperature: 5 °C
Yield: 71.6 %

Procedure:
A solution of 7β-amino-3-[3-amino-2-(2-hydroxyethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate hydrochloride (50 g) in a mixture of acetonitrile (500 ml) and water (500 ml) was adjusted to pH 6.0 with aqueous sodium bicarbonate solution. To the resulting solution was added (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetyl chloride hydrochloride (40 g) under stirring at 5° C. and the mixture was stirred at the same temperature for 1.5 hours, keeping pH 5.0-6.5 with aqueous sodium bicarbonate solution. The reaction mixture was evaporated to remove the containing organic solvent. The water solution was subjected to column chromatography on Sepabeads SP-205 (Trademark: Mitsubishi Kasei Corporation) (1.3 l). The column was washed with water (5 l) and the object compound was eluted with 15% isopropyl alcohol, and the eluate was lyophilized to give 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido]-3-[3-amino-2-(2-hydroxyethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate (syn isomer) (51.2 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[NH2:9][C@H:10]([C:13]([OH:15])=[O:14])[CH2:11][SH:12].C>C(O)C>[N:1]1[CH:2]=[CH:3][C:4]([CH:7]2[NH:9][CH:10]([C:13]([OH:15])=[O:14])[CH2:11][S:12]2)=[CH:5][CH:6]=1
Reactant: N[C@@H](CS)C(=O)O
Reactant: O=Cc1ccncc1
Solvent: CCO
Product: O=C(O)C1CSC(c2ccncc2)N1
Yield: 57.1 %

Procedure:
Pyridine-4-carbaldehyde (1.07 g) and 1.21 g of L-cysteine were heated in 60% ethanol at a refluxing temperature for 4 hours. Activated charcoal (100 mg) was added to the reaction mixture while it was warm. The mixture was filtered. After cooling, the resultant crystalline precipitate was collected by filtration and washed with ethanol to give 1.2 g of 2-(4-pyridyl)-thiazolidine-4-carboxylic acid. Melting point 171°-173° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:16][CH2:15][C@H:14]([NH:17][CH3:18])[CH2:13][CH2:12]2)=[C:7]([CH2:19][NH:20][CH3:21])[CH:6]=1.[C:22]([OH:28])(=O)[CH2:23][CH2:24][C:25]#[CH:26]>>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:16][CH2:15][C@H:14]([N:17]([CH3:18])[C:22](=[O:28])[CH2:23][CH2:24][C:25]#[CH:26])[CH2:13][CH2:12]2)=[C:7]([CH2:19][NH:20][CH3:21])[CH:6]=1
Reactant: CNCc1cc(CCCO)ccc1[C@H]1CC[C@H](NC)CC1
Reactant: C#CCCC(=O)O
Product: C#CCCC(=O)N(C)[C@H]1CC[C@H](c2ccc(CCCO)cc2CNC)CC1

Procedure:
from trans-4-[4-(3-hydroxypropyl)methylaminomethyl-phenyl)-N-methylcyclohexylamine, N,N'-carbonyldiimidazole and 4-pentynoic acid. Oil. Rf value: 0.66 (alumina/ethyl acetate/methanol=100:1, v:v).
Reaction SMILES: [C:1]([C:4]1[C:13]([N:14]2[CH2:18][CH2:17][C@H:16]([NH:19][C:20](=[O:23])[CH2:21][CH3:22])[CH2:15]2)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[C:6]([Cl:24])[CH:5]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:31].[Na+].O1CCCC1>CO.C(#N)C>[NH2:31][CH:1]([C:4]1[C:13]([N:14]2[CH2:18][CH2:17][C@H:16]([NH:19][C:20](=[O:23])[CH2:21][CH3:22])[CH2:15]2)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[C:6]([Cl:24])[CH:5]=1)[CH3:2]
Reactant: CCC(=O)N[C@H]1CCN(c2c(C(C)=O)cc(Cl)c3cccnc23)C1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CO
Product: CCC(=O)N[C@H]1CCN(c2c(C(C)N)cc(Cl)c3cccnc23)C1
Temperature: 65 °C

Procedure:
A mixture of N-[(3S)-1-(7-acetyl-5-chloroquinolin-8-yl)pyrrolidin-3-yl]propanamide (0.011 g, 0.032 mmol) and ammonium acetate (0.0245 g, 0.318 mmol) in methanol (0.15 mL) and acetonitrile (0.15 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.080 mL, 0.080 mmol). The reaction was heated at 65° C. overnight, then cooled to room temperature, quenched with sat. NaHCO3 solution and extracted with dichloromethane. The combined organic phase were dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C18H24ClN4O (M+H)+: m/z=347.2; Found: 347.1.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1.[CH3:10][O:11][C:12]1[CH:22]=[CH:21][C:15]([C:16](C(Cl)=O)=[O:17])=[CH:14][CH:13]=1>>[F:9][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([F:8])[CH:5]=1)[C:16]([C:15]1[CH:21]=[CH:22][C:12]([O:11][CH3:10])=[CH:13][CH:14]=1)=[O:17]
Reactant: COc1ccc(C(=O)C(=O)Cl)cc1
Reactant: Fc1cc(F)cc(Br)c1
Product: COc1ccc(C(=O)c2cc(F)cc(F)c2)cc1

Procedure:
The procedure from Step 1 of Example 1 was followed except that: 1-bromo-3,5-difluorobenzene was used instead of tribromobenzene and 4-methoxybenzoyl carbonyl chloride was used in place of benzoyl chloride to provide a product with mass spectrum corresponding the structure of 3,5-difluoro-4′-methoxybenzophenone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[N:13]([CH2:14][CH2:15][CH2:16][N:17]([C:25](=[NH:32])[N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)C(=O)OC(C)(C)C)[C:12]([C:33]3[CH:38]=[CH:37][C:36]([N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)=[CH:35][CH:34]=3)=[CH:11][S:10]2)=[CH:4][CH:3]=1.Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[N:13]([CH2:14][CH2:15][CH2:16][NH:17][C:25]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)=[NH:32])[C:12]([C:33]3[CH:38]=[CH:37][C:36]([N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)=[CH:35][CH:34]=3)=[CH:11][S:10]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(CCCn1c(-c2ccc(N3CCOCC3)cc2)csc1=Nc1ccc(F)cc1)C(=N)N1CCOCC1
Agent: Cl
Product: N=C(NCCCn1c(-c2ccc(N3CCOCC3)cc2)csc1=Nc1ccc(F)cc1)N1CCOCC1

Procedure:
The compound (535 mg) obtained in the above (1) was treated in a similar manner to in Example 9 (2) to give the title compound (467 mg) as hydrochloride.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1C(C1C=C(C)C=CC=1C1C=NN(C)C=1)=O.[CH3:25][C:26]1[N:31]=[C:30]([C:32]([OH:34])=O)[C:29]([N:35]2[N:39]=[CH:38][CH:37]=[N:36]2)=[CH:28][CH:27]=1>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:32]([C:30]1[C:29]([N:35]2[N:39]=[CH:38][CH:37]=[N:36]2)=[CH:28][CH:27]=[C:26]([CH3:25])[N:31]=1)=[O:34]
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)n1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1, using 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid. ESI-MS (m/z): 315 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])=[O:9])[CH:7]=1.[N:27]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:28]=[O:29]>N1C=CC=CC=1>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][NH:27][C:28]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8](=[O:9])[C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])[CH:7]=1)=[O:29])[CH3:35]
Reactant: CCOC(=O)CN=C=O
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Solvent: c1ccncc1
Product: CCOC(=O)CNC(=O)Nc1ccc(C)c(C(=O)c2ccc(Nc3ccc(F)cc3F)cc2Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound 494 (0.047 g, 0.13 mmol) was dissolved in pyridine (0.3 mL) and ethyl isocyanatoacetate (0.022 mL, 0.19 mmol) was added. The solution was stirred at room temperature for 2 h. Work up as described in the preparation of compound 259. The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 1:1 as the eluent. This afforded the title compound as a slightly coloured solid. 13C NMR (DMSO-d6) δ 195.2, 170.7, 158.7 (dd), 155.7 (dd), 155.0, 149.0, 139.0, 137.8, 133.3, 131.4, 129.1, 127.0, 126.3 (dd), 124.3 (dd), 120.0, 118.1, 114.8, 111.9 (dd), 111.8, 105.0 (dd), 60.2, 41.3, 19.0, 14.0
Reaction SMILES: [S:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1.F[P-](F)(F)(F)(F)F.FC(N(C)C)=[N+](C)C.O>CN(C)C=O.C(N(CC)C(C)C)(C)C>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:6]2[CH2:7][CH2:8][C:9]3[S:1][C:2]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:3][C:4]=3[CH2:5]2)=[O:21])=[CH:18][CH:17]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)c1cc2c(s1)CCNC2
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2c(s1)CCN(C(=O)c1ccc(Cl)cc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
To ethyl 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate (0.237 g, 1.12 mmol), 4-chlorobenzoic acid (0.228 g, 1.46 mmol) in N,N-dimethylformamide (6 mL) was added a solution of fluoro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (0.444 g, 1.68 mmol) in N,N-diisopropylethylamine (0.6 mL). The reaction solution was then stirred overnight at room temperature. Water was then added and the mixture was extracted into ethyl acetate. The organic layer was washed with brine and evaporated. Purification of the residue obtained on silica gel (0-10% ethyl acetate/DCM) afforded a sticky white solid (208 mg, 53%). LCMS (FA) ES+ 350.
Reaction SMILES: C[Si](I)(C)C.[Cl:6][C:7]1[CH:50]=[CH:49][C:10]([CH2:11][CH:12]2[N:17]3[C:18](=[O:44])[CH:19]([NH:33]C(=O)OCC4C=CC=CC=4)[CH2:20][N:21]([S:22]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=4[Cl:32])(=[O:24])=[O:23])[CH:16]3[CH2:15][N:14]([CH:45]([CH3:47])[CH3:46])[C:13]2=[O:48])=[CH:9][CH:8]=1.CO>CC#N>[NH2:33][CH:19]1[C:18](=[O:44])[N:17]2[CH:12]([CH2:11][C:10]3[CH:49]=[CH:50][C:7]([Cl:6])=[CH:8][CH:9]=3)[C:13](=[O:48])[N:14]([CH:45]([CH3:46])[CH3:47])[CH2:15][CH:16]2[N:21]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])(=[O:24])=[O:23])[CH2:20]1
Reactant: CC(C)N1CC2N(C(=O)C(NC(=O)OCc3ccccc3)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Agent: C[Si](C)(C)I
Solvent: CO
Solvent: CC#N
Product: CC(C)N1CC2N(C(=O)C(N)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Reaction time: 2 h
Yield: 91.8 %

Procedure:
206 ml (1.44 mmol) of trimethylsilyl iodide (TMSI) are added to a solution of 250 mg (0.36 mmol) of benzyl [6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7-dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate in 10 ml of CH3CN at 0° C. The reaction solution is allowed to reach room temperature and is stirred at this temperature for 2 h. 5 ml of MeOH are added to the reaction solution, and then the solution is concentrated in vacuo. The residue is purified on a 5 g SCX cartridge (eluted with MeOH followed by 3N NH3/MeOH). 185 mg of the desired compound are obtained as a white powder. LC/MS 558.07 (calculated, monoisotopic); measured value (M+H)+: 559.10
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]Cl)[CH:5]=[CH:6][CH:7]=1.[NH:10]1[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11]1>>[F:1][C:2]1[CH:3]=[C:4]([S:8][C:14]2[NH:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc[nH]c1
Reactant: Fc1cccc(SCl)c1
Product: COC(=O)c1c[nH]c(Sc2cccc(F)c2)c1

Procedure:
By the same procedure, m-fluorobenzenesulfenyl chloride is reacted with methyl pyrrole-3-carboxylate to form methyl 5-(3-fluorophenylthio)pyrrole-3-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:6](=[C:7]([C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=3)[N:8]([CH:11]([CH3:13])[CH3:12])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.C1CCCCC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]([CH:11]([CH3:13])[CH3:12])[CH:7]2[C:14]1[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=1
Reactant: COc1ccc(-c2c3cccc(Cl)c3nn2C(C)C)cc1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: CC(C)N1Nc2c(Cl)cccc2C1c1ccc(O)cc1
Yield: 41.6 %

Procedure:
Prepared according to Method D step C from 7-chloro-2-isopropyl-3-(4-methoxyphenyl)-2H-indazole (0.016 g, 0.05 mmol), boron tribromide (0.050 mL, 0.5 mmol) and 0.2 mL of cyclohexene to give the product (0.006 g).
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]3[O:16][CH2:15][O:14][C:11]=3[CH:12]=2)[CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:6][C:5]1=[O:23])([CH3:3])[CH3:2].O1CCOCC1.[Mn]([O-])(=O)(=O)=O.[K+].C=O>O>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]3[O:16][CH2:15][O:14][C:11]=3[CH:12]=2)[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:6][C:5]1=[O:23])([CH3:3])[CH3:2]
Reactant: CC(C)N1C(=O)NC(c2ccccc2)c2cc3c(cc21)OCO3
Agent: O=[Mn](=O)(=O)[O-]
Agent: C=O
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)n1c(=O)nc(-c2ccccc2)c2cc3c(cc21)OCO3

Procedure:
To a solution of 8.5 gm. of 1-isopropyl-4-phenyl-6,7-methylenedioxy-3,4-dihydro-2(1H)-quinazolinone in 225 ml. of p-dioxane, cooled to 10°-13°C., is added dropwise a solution of 4.3 gm. of potassium permanganate in 185 ml. of water. When the addition is complete, 2 ml. of formalin solution are added. Precipitated solids are removed by filtration and the solvents stripped from the filtrate at reduced pressure. The residue is decolorized with activated charcoal in ethyl acetate and recrystallized from ethyl acetate to obtain 1-isopropyl-4-phenyl-6,7-methylenedioxy-2(1H)-quinazolinone, m.p. 187°-191°C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([CH2:17][CH:18](OC(=O)C(F)(F)F)[C:19]2[C:20]([O:26][CH3:27])=[N:21][CH:22]=[CH:23][C:24]=2[I:25])=[C:11]([N+:35]([O-:37])=[O:36])[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:10]=[C:11]([N+:35]([O-:37])=[O:36])[C:12](/[CH:17]=[CH:18]/[C:19]2[C:20]([O:26][CH3:27])=[N:21][CH:22]=[CH:23][C:24]=2[I:25])=[CH:13][C:14]=1[O:15][CH3:16])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1cc(CC(OC(=O)C(F)(F)F)c2c(I)ccnc2OC)c([N+](=O)[O-])cc1NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(/C=C/c2c(I)ccnc2OC)c([N+](=O)[O-])cc1NC(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
A solution of crude trifluoro-acetic acid 2-(4-tert-butoxycarbonylamino-5-methoxy-2-nitro-phenyl)-1-(4-iodo-2-methoxy-pyridin-3-yl)-ethyl ester (crude 1.35 g, 2.12 mmol) in THF (10 mL) was added 8-diazabicyclo[5.4.0]undec-7-ene (1.48 g, 9.75 mmol) at 25° C. The reaction was allowed to stir at 70° C. for 3 h, cooled to 25° C. and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown solid. Flash chromatography (80/20 hexanes/ethyl acetate) afforded {4-[(E)-2-(4-iodo-2-methoxy-pyridin-3-yl)-vinyl]-2-methoxy-5-nitro-phenyl}-carbamic acid tert-butyl ester (560 mg, 55%) as an oil. MH+ 527.8.