Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5]O)(C)([CH3:3])[CH3:2].[CH3:7][C:8]([CH3:28])([CH3:27])[C:9]([O:11][CH2:12][C:13]1[NH:22][C:21](=[O:23])[C:20]2[C:15](=[CH:16][C:17]3CCC[C:18]=3[CH:19]=2)[N:14]=1)=[O:10]>C(Cl)Cl>[CH3:7][C:8]([CH3:28])([CH3:27])[C:9]([O:11][CH2:12][C:13]1[NH:22][C:21](=[O:23])[C:20]2[C:15](=[CH:16][C:17]3[CH2:18][CH2:3][C:1](=[O:5])[C:2]=3[CH:19]=2)[N:14]=1)=[O:10]
Reactant: CC(C)(C)OO
Reactant: CC(C)(C)C(=O)OCc1nc2cc3c(cc2c(=O)[nH]1)CCC3
Solvent: ClCCl
Product: CC(C)(C)C(=O)OCc1nc2cc3c(cc2c(=O)[nH]1)C(=O)CC3
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of (Ph3SiO)2CrO2 (L. M. Baker and W. L. Carrick, J. Org. Chem. 1970, 35, 774) (10.6 mg, 0.017 mmol) in CH2Cl2 (5 ml) was added sequentially aqueous 70% tert-butyl hydroperoxide (0.18 ml, 1.3 mmol) and 2-(2,2-dimethylpropionyloxymethyl)-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-4-one (0.1 g, 0.33 mmol). The mixture was stirred at room temperature with protection from the light for 24 h. The solvents were removed in vacuo and the residue purified by column chromatography (20 g of silica gel) eluting with a gradient of 10-30% EtOAC in CHCl3 to yield 2-(2,2-dimethylpropionyloxymethyl)-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-4,6-dione as a while solid (47 mg, 45%); m.p. 185-190° C.; 1H-NMR (DMSO-d6) δ 1.23 (s, 9H, CMe3), 2.72 (m, 2H, 7-H), 3.25 (m, 2H, 8-H), 5.00 (s, 2H, 2-CH2), 7.70 (s, 1H, 9-H), 8.29 (s, 1H, 5-H), 12 20 (br, 1H, NH); MS (FAB, m/z): Found 315 [(M+H)+, 100%], 337 [(M+Na)+, 75%]; HRMS: measured 315.1360; calculated for C17H19N2O4 (M+H)+: 315.1345. Found C, 64.18; H, 5.72; N, 8.81, C17H18N2O4.0.2H2O requires C, 64.23; H, 5.79; N, 8.82%.
Reaction SMILES: [CH3:1][O:2]C1C=CC([N+]([O-])=O)=C(C=1)N.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[C:23]2[CH:24]=[CH:25][C:26](C(F)(F)F)=[CH:27][C:22]=2[N:21]=[C:20]1/[CH:32]=[CH:33]/[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[C:40]([OH:45])(=[O:44])[C:41]([OH:43])=[O:42]>C(OCC)(=O)C>[C:40]([OH:45])(=[O:44])[C:41]([OH:43])=[O:42].[CH3:1][O:2][C:25]1[CH:26]=[CH:27][C:22]2[N:21]=[C:20](/[CH:32]=[CH:33]/[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=3)[C:23]=2[CH:24]=1
Reactant: FC(F)(F)c1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1
Reactant: COc1ccc([N+](=O)[O-])c(N)c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc2nc(/C=C/c3ccccc3)n(-c3ccccn3)c2c1

Procedure:
Free base of the titled compound was prepared from 5-methoxy-2-nitroaniline according to the preparation of (E)-1-(2-pyridyl)-2-styryl-5-trifluoromethyl-1H-benzimidazole (Example 57). The free base and oxalic acid were dissolved into ethyl acetate. Concentration and recrystallization from ethyl acetate/n-hexane yielded the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[C@@H:6]3[C@@H:11]([CH2:12][CH2:13][C:4]=2[CH:3]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]3.[CH3:17]I>C1COCC1>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[C@@H:6]3[C@@H:11]([CH2:12][CH2:13][C:4]=2[CH:3]=1)[N:10]([CH3:17])[C:9](=[O:14])[CH2:8][CH2:7]3
Reactant: CI
Reactant: O=C1CC[C@@H]2c3ccc(Cl)cc3CC[C@H]2N1
Solvent: C1CCOC1
Product: CN1C(=O)CC[C@@H]2c3ccc(Cl)cc3CC[C@H]21
Reaction time: 13 h
Yield: 104.7 %

Procedure:
Two hundred L of THF was added to a reactor, and 24.6 kg of (4aR)-(10bR)-8-chloro-1,2,3,4,4a,5,6,10b-octahydrobenzo[f] quinolin-3-one was added. Then 35 kg of methyl iodide was added, rinsed in with 10 L of THF. A 79.6 kg portion of 50% aqueous sodium hydroxide was added in 13 minutes at 15°-25°, rinsed in with 40 L of THF. The mixture was stirred at 36°-39° for 13 hours, and was then cooled to 15°-25°. The layers were allowed to separate, and the water/THF phase was neutralized to pH 7 with hydrochloric acid and heated to reflux. Distillate was removed until the temperature reached 77°. A total of 154 kg of water was added from time to time. The solution was cooled over 3 hours to 3°-10°, and was then stirred vigorously at that temperature until solids began to form. Then the slurry was stirred gently at constant temperature for 3 hours. The slurry was filtered, and the vessel and filter cake were washed with cold water. The cake was air dried at 25°-35° for 75 hours to obtain 27.3 kg of the desired product, potency 85.1% by liquid chromatographic analysis.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].[C:10]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]>>[C:13]([O:12][C:10]([N:17]1[CH2:22][CH2:21][CH:20]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=2)[CH2:19][CH2:18]1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NCc1cccc(F)c1
Product: CC(C)(C)OC(=O)N1CCC(NCc2cccc(F)c2)CC1
Yield: 91.4 %

Procedure:
Using general procedure A, 3-fluorobenzylamine (0.25 mL, 2.2 mmol) and 1-Boc-4-piperidone (482 mg, 2.4 mmol) afforded 4-(3-fluoro-benzylamino)-piperidine-1-carboxylic acid tert-butyl ester as a colourless oil (620 mg, 91%).
Reaction SMILES: [NH2:1][C@@H:2]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[NH:28]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C@H:29]([C:41](O)=[O:42])[CH2:30][C:31](=[O:40])[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[NH:28]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C@H:29]([C:41]([NH:1][C@@H:2]([C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:9]=1)=[O:42])[CH2:30][C:31](=[O:40])[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: N[C@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)N[C@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)OCc1ccccc1
Temperature: 4 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
14 g of H-D-Tyr(Bzl)-OBzl (38.7 mmoles) and 12.53 g of Boc-Asp(OBzl)-OH (38.7 mmoles) are dissolved in 145 ml of CH2Cl2. In the ice-cooled solution 8.78 g of DCC (42.5 mmoles) dissolved in 35 ml of CH2Cl2 are dropped. The mixture is left under stirring for 1 h at room temperature and for one night at 4° C. The resulting precipitate (dicyclohexylurea) is filtered off and the filtrate is evaporated to dryness under vacuum. The semi-solid residue is taken up with 170 ml of 70/30 ethanol/H2O, the mixture is refluxed while two immiscible phases are formed, and left to cool under vigorous stirring. The resulting white solid is filtered and treated again with 70/30 ethanol/H2O to reflux. Thus 20 g of Boc-Asp(OBzl)-D-Tyr(Bzl)-OBzl are obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:16]=[CH:17][C:18]([C:21](O)=[O:22])=[N:19][CH:20]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[Li+].[OH-]>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:21](=[O:22])[C:18]3[CH:17]=[CH:16][C:15]([C:14]([F:24])([F:13])[F:25])=[CH:20][N:19]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: O=C(O)c1ccc(C(F)(F)F)cn1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.6 %

Procedure:
TEA (0.61 mL, 4.35 mmol) was added to 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.87 mmol, Example 1, Step H), 5-(trifluoromethyl)picolinic acid (200 mg, 1.04 mmol) and BOP—Cl (330 mg, 1.30 mmol) in DCM (5 mL). The reaction was stirred at room temperature for 1 hour, and then a LiOH solution (3 mL, 2N) was added. The mixture was stirred for 30 minutes, and water (10 mL) was added. The solid formed was collected by filtration, washed with DCM (10 mL) and dried to give N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)picolinamide (195 mg, 55% yield) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:36]=[CH:35][C:5]([C:6]([NH:8][C@@:9]([C:21]2[CH:26]=[C:25]([O:27][C:28]([F:33])([F:32])[CH:29]([F:31])[F:30])[CH:24]=[C:23]([F:34])[CH:22]=2)([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:10][C:11]([OH:13])=[O:12])=[O:7])=[CH:4][C:3]=1[C:37]([F:40])([F:39])[F:38].[CH:41]1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.CO.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:36]=[CH:35][C:5]([C:6]([NH:8][C@@:9]([C:21]2[CH:26]=[C:25]([O:27][C:28]([F:32])([F:33])[CH:29]([F:31])[F:30])[CH:24]=[C:23]([F:34])[CH:22]=2)([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[CH2:10][C:11]([O:13][CH3:41])=[O:12])=[O:7])=[CH:4][C:3]=1[C:37]([F:40])([F:39])[F:38]
Reactant: O=C(O)C[C@@](NC(=O)c1ccc(F)c(C(F)(F)F)c1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C[C@@](NC(=O)c1ccc(F)c(C(F)(F)F)c1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Temperature: 100 °C
Yield: 15.2 %

Procedure:
To a solution of (R)-3-(4-fluoro-3-(trifluoromethyl)benzamido)-3-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-3-(4-fluorophenyl)propanoic acid (32 mg, 0.055 mmol) in toluene (0.5 mL) was added DPPA (18 mg, 0.066 mmol) and TEA (7 mg, 0.066 mmol). The reaction mixture was heated at 100° C. for 1 h followed by the addition of MeOH and TEA. The reaction was heated at 65° C. overnight. Excess K2CO3 was added and the reaction was heated to reflux for 3 h. The reaction mixture was concentrated and the resulting residue was purified by preparative HPLC (phenominex 30×100 mm column, 30-100% MeOH (90% in water, 0.1% TFA) gradient over 12 min with flow rate 40 mL/min and UV detection at 220 nm) to yield (R)-methyl 3-(4-fluoro-3-(trifluoromethyl)benzamido)-3-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-3-(4-fluorophenyl)propanoate (Example 318) as a white solid (5 mg, 15% yield). LCMS: RT=3.92 min [M+H] 613.3 (4 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm). 1H NMR (400 MHz, CDCl3) ppm 3.74 (s, 3H), 3.87-4.11 (m, 2H), 4.89 (m, 1H), 5.86 (t, 1H), 6.95 (d, 1 H), 6.99-7.13 (m, 5H), 7.28-7.40 (m, 3H), 8.09-8.16 (m, 1H), 8.26 (d, 1H), 8.94 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7](=[O:12])[C:8]([Cl:11])([Cl:10])[Cl:9])[NH:5][CH:6]=1.Cl[C:14](Cl)(Cl)C(C1N(C)C=CC=1)=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:7](=[O:12])[C:8]([Cl:9])([Cl:10])[Cl:11])[N:5]([CH3:14])[CH:6]=1
Reactant: Cn1cccc1C(=O)C(Cl)(Cl)Cl
Reactant: O=C(c1cc(Br)c[nH]1)C(Cl)(Cl)Cl
Product: Cn1cc(Br)cc1C(=O)C(Cl)(Cl)Cl
Yield: 81 %

Procedure:
Using the same general procedure as used for the synthesis of 1-(4-bromo-1H-pyrrol-2-yl)-2,2,2-trichloro-ethanone 7, 5.00 g of 2-trichloroacetyl-1-methylpyrrole afforded 5.46 g (81%) of the title compound 13 as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 7.66 (d, 1H, J=1.2 Hz), 7.42 (d, 1H, J=1.8 Hz), 3.91 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 171.48, 134.40, 123.62, 121.19, 95.36, 95.12; HRMS (FAB) calcd for C7H6BrCl3NO (MH+) 303.8698. Found 303.8678.
Reaction SMILES: C([Li])(CC)C.[F:6][C:7]([F:22])([F:21])[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:20])[O:17][CH2:18][CH3:19].[I:23]I>C1CCCCC1.C1COCC1>[I:23][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][C:7]([F:21])([F:22])[F:6])[C:10]=1[NH:15][C:16](=[O:20])[O:17][CH2:18][CH3:19]
Reactant: CCOC(=O)Nc1ccccc1OC(F)(F)F
Reactant: II
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CCOC(=O)Nc1c(I)cccc1OC(F)(F)F
Reaction time: 1 h
Yield: 73 %

Procedure:
A 1.4 M solution of sec-butyllithium in cyclohexane (3.0 mL) was added drop-wise to a solution of ethyl N-[2-(trifluoromethoxy)phenyl]carbamate (0.5000 g, 0.002006 mol) in THF (9 mL) at −70° C. After stirring for 1 hour a solution of iodine (0.51 g, 0.002 mol) in THF (1.0 mL) was added drop-wise at −70° C. Stirring was continued for another 1 hour then the mixture was quenched with saturated ammonium chloride solution. Water (50 mL) was added and the mixture extracted with diethyl ether (3×40 mL). The combined organic phases was washed with 40% sodium meta-bisulfite solution, water and brine, then dried over Na2SO4 and the solvent removed in vacuo to give the desired product in a 73% yield. 1H NMR (400 MHz, CDCl3): δ 1.29-1.36 (m, 3H), 4.21-4.28 (m, 2H), 6.21 (br, 1H), 7.05 (t, J=8.0 Hz, 1H), 7.30 (m, 1H) and 7.80 (dd, J=6.8, 1.2 Hz, 1H). MS (ES+): m/z 375.78 [MH+].
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:15][C:16](Cl)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2:19][C:20]1[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=1>C(Cl)(Cl)Cl>[CH3:25][C:23]1[CH:24]=[C:20]([NH:19][C:16](=[O:17])[O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:21][N:22]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cc(NC(=O)OCc2ccccc2)[nH]n1
Reaction time: 18 h
Yield: 71.4 %

Procedure:
Triethylamine (2.02 g) and benzyloxycarbonyl chloride (1.71 g) were added dropwise to a solution of 3-amino-5-methylpyrazole (971 mg) in chloroform (20 ml) at 0° C., and the mixture was stirred for 18 hours. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluting solvent; n-hexane:ethyl acetate 2:1) to give benzyl 5-methyl-2H-pyrazol-3-ylcarbamate (1.65 g, Y.:67%).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1>>[OH:28][CH2:27][C@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:33]3[CH:34]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Reactant: OB(O)c1cncnc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(-c2cncnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 75 using (S)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 78.1) and pyrimidin-5-ylboronic acid to afford a white solid. UPLC-MS (condition 1) tR=2.12 min, m/z=460.1-461.1 [M+H]+, m/z=458.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.53-1.64 (m, 1H) 1.81-1.90 (m, 1H) 2.20-2.28 (m, 1H) 2.97 (dd, J=10.76, 6.85 Hz, 1H) 3.15-3.40 (m, 5H) 4.61 (t, J=5.14 Hz, 1H) 7.35 (d, J=8.80 Hz, 2H) 7.85 (d, J=9.05 Hz, 2H) 8.09 (d, J=2.20 Hz, 1H) 8.79 (d, J=2.20 Hz, 1H) 8.89 (s, 2H) 9.19 (s, 1H) 10.16 (s, 1H).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([N:16]=[C:17]([NH2:19])[NH2:18])[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1.[N-:20]=[C:21]=[O:22].[K+]>O>[NH:3]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([N:16]=[C:17]([NH2:19])[NH2:18])[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)[C:21]([NH2:20])=[O:22]
Reactant: [N-]=C=O
Reactant: NCc1cccc(-c2csc(N=C(N)N)n2)c1
Agent: Cl
Agent: [K+]
Solvent: O
Product: NC(=O)NCc1cccc(-c2csc(N=C(N)N)n2)c1
Yield: 44.1 %

Procedure:
A solution of 4-(3-aminomethylphenyl)-2-(diaminomethyleneamino)thiazole dihydrochloride (1.5 g) and potassium isocyanate (0.76 g) in water (30 ml) was stirred at room temperature for 8.5 hours. The resulting precipitate was collected by filtration and then suspended in water (50 ml). The mixture was alkalilied with an aqueous potassium carbonate solution. The resulting precipitate was collected by filtration. Recrystallization from a mixture of methanol and diisopropyl ether afforded 4-(3-ureidomethylphenyl)-2-(diaminomethyleneamino)thiazole (0.6 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][Br:8].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH2:17][CH2:18][OH:19]>>[Br:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:19][CH2:18][CH2:17][CH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[F:9]
Reactant: OCCCc1ccccc1F
Reactant: BrCCCCCCBr
Product: Fc1ccccc1CCCOCCCCCCBr

Procedure:
(4.71 g), T.l.c. (ER- CX 1:79) Rf 0.22, from 1,6-dibromohexane (14.28 g) and 3-(2-fluorophenyl)-1-propanol (3.0 g).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].CON(C)[C:20](=[O:32])[CH:21]([O:30][CH3:31])[C:22]1[CH:23]=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1>>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][C:12]([C:20](=[O:32])[CH:21]([O:30][CH3:31])[C:22]3[CH:23]=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COc1ccc(C(OC)C(=O)N(C)OC)cn1
Reactant: COc1cc(-c2ccco2)cc(OC)c1Br
Product: COc1ccc(C(OC)C(=O)c2ccc(-c3cc(OC)c(Br)c(OC)c3)o2)cn1

Procedure:
1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(6-methoxypyridin-3-yl)ethanone was prepared from 2-(4-bromo-3,5-dimethoxyphenyl)furan and N,2-dimethoxy-2-(6-methoxypyridin-3-yl)-N-methylacetamide according to the procedure used in Example 30. Purification by chromatography (50% EtOAc/hexanes) gave the product as a pale yellow solid (0.092 g, 28% yield). MS: m/z 462.2 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([S:4](Cl)(=[O:6])=[O:5])[CH3:3].C(N(CC)CC)C.Cl.[C@@H:16]12[CH2:23][NH:22][CH2:21][C@@H:20]1[CH2:19][N:18]([C:24]1[NH:25][C:26]3[CH:32]=[C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH:30]=[CH:29][C:27]=3[N:28]=1)[CH2:17]2>C1COCC1>[CH:2]([S:4]([N:22]1[CH2:21][C@@H:20]2[C@@H:16]([CH2:17][N:18]([C:24]3[NH:25][C:26]4[CH:32]=[C:31]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[CH:30]=[CH:29][C:27]=4[N:28]=3)[CH2:19]2)[CH2:23]1)(=[O:6])=[O:5])([CH3:3])[CH3:1]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: c1ccc(-c2ccc3nc(N4C[C@H]5CNC[C@H]5C4)[nH]c3c2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)N1C[C@H]2CN(c3nc4ccc(-c5ccccc5)cc4[nH]3)C[C@H]2C1
Reaction time: 0.25 h

Procedure:
2-Propanesulfonyl chloride and triethylamine were added to the THF suspension (5 mL) containing 2-(cis-3,7-diazabicyclo[3.3.0]oct-3-yl)-5-phenylbenzimidazole hydrochloride (26 mg) at room temperature, followed by stirring for 15 min. The reaction mixture was concentrated under reduced pressure, and the residue was separated and purified on a collective thin-layer chromatograph (chloroform:methanol=10:1) to give the title compound (12 mg).
Reaction SMILES: [N:1]([O-])=O.[Na+].[Cl:5][C:6]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2[S:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][C:17]=3[N:22]=2)[C:9]([NH2:23])=[CH:8][CH:7]=1.[OH-].[Na+]>O.CC(O)=O>[Cl:5][C:6]1[N:11]=[C:10]2[N:12]([CH2:13][C:14]3[S:15][C:16]4[CH:21]=[CH:20][N:19]=[CH:18][C:17]=4[N:22]=3)[N:1]=[N:23][C:9]2=[CH:8][CH:7]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(Cl)nc1NCc1nc2cnccc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Clc1ccc2nnn(Cc3nc4cnccc4s3)c2n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of NaNO2 (42.5 mg, 0.62 mmol) in H2O (0.5 mL) was added dropwise to a solution of 6-chloro-N2-(thiazolo[4,5-c]pyridin-2-ylmethyl)pyridine-2,3-diamine (90 mg, 0.31 mmol) in AcOH (1 mL) and H2O (1 mL) at 0° C. The reaction solution was stirred at 0° C. for 1 h, then basified with 30% aqueous NaOH to pH ˜9. The resulting precipitate was collected by filtration to afford the title compound. MS (m/z): 303 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19](=[O:24])[NH:20][CH2:21][CH2:22]Cl)[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:16]([O:18][C:19](=[O:24])[NH:20][CH2:21][CH2:22][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1)[CH3:17]
Reactant: CCOC(=O)NCCCl
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)NCCOc1ccc(C(=O)c2ccccc2)cc1
Temperature: 100 °C
Yield: 79.1 %

Procedure:
10 g of p-hydroxybenzophenone are dissolved in 100 ml of dimethylformamide. 8.3 g of 2-chloroethylcarbamic acid ethyl ester and 13.8 g of potassium carbonate are added to the solution and the mixture is warmed to 100° C. and maintained there for 3 hours with stirring. The mixture is poured onto an ice/water bath. The resulting crystals are filtered and washed with water. The crystalline substance is dried at 40° C. in a vacuum drying oven. Recrystallization once from ether yields 12.5 g (80%) of 2-(p-benzoylphenoxy)ethylcarbamic acid ethyl ester, m.p.--84°-86° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[CH:2]1.CN(C)C=O.C(Cl)(=O)C([Cl:21])=O>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([Cl:21])=[O:12])=[CH:2]1
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1c[nH]c2ccccc12
Temperature: 23 °C
Reaction time: 0.33 h

Procedure:
Next, a solution of indole-3-carbonyl chloride was prepared. A well-stirred suspension of indole-3-carboxylic acid (67.7 mg, 0.42 mmol) in dry DCM (2 ml) containing a small amount of dimethylformamide (DMF) (20 μL) was treated with oxalyl chloride (0.84 mmol, 107 mg, 72 μL) at 0° C. Following addition to the oxalyl chloride, the mixture was stirred for 20 minutes at 23° C., producing a clear, slightly yellow solution. This solution was evaporated to dryness in vacuo at 0.1 Torr to ensure removal of excess oxalyl chloride, and was subsequently re-dissolved in 2 ml of dry DCM.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[C:17]([CH2:22][S:23]([C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:36]([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.Cl.O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]2[CH:16]=[C:17]3[C:18](=[CH:19][CH:20]=2)[NH:21][N:36]=[C:22]3[S:23]([C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(OC2CCCN(Cc3ccccc3)C2)cc1CS(=O)(=O)c1cccc2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2ccc(OC3CCCN(Cc4ccccc4)C3)cc12

Procedure:
A mixture of 4-(1-benzylpiperidin-3-yloxy)-2-(1-naphthylsulfonylmethyl)phenylamine (1.0 g, 2 mmoles) in THF and 4M HCl (10 mL), under nitrogen, at 3° C. was treated dropwise with a solution of sodium nitrite (0.16 g, 2.4 mmoles) in H2O, poured into a cold solution of saturated sodium bicarbonate and extracted with EtOAc. The extracts were combined, dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (0.7 g, 1.4 mmoles).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[NH3:10]>C1COCC1>[CH3:1][S:2][CH2:3][CH2:4][CH2:5][S:6]([NH2:10])(=[O:8])=[O:7]
Reactant: CSCCCS(=O)(=O)Cl
Reactant: N
Solvent: C1CCOC1
Product: CSCCCS(N)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
To a stirred suspension of sodium 3-(methylthio)propane-1-sulfonate (20 g) in dry DCM (200 mL), is added dropwise oxalyl chloride (80 mL) at 0° C. After stirring at room temperature for 3 h, the reaction mixture is concentrated under reduced pressure and ice (100 g) is added. The product is extracted with DCM (2×200 mL) and the organic phase is washed with brine then dried over Na2SO4. The solvent is removed under reduced pressure to afford 12 g of 3-(Methylthio)propane-1-sulfonyl chloride as colorless liquid. A solution of 3-(methylthio)propane-1-sulfonyl chloride (12 g) in dry THF (100 mL) is added dropwise to a solution of ammonia in dry THF (250 mL) at −78° C. After stirring at room temperature for 3 h, the reaction mixture is concentrated under reduced pressure. The residue is purified by chromatography using silica gel (60-120 mesh) and CHCl3/MeOH as eluent to afford 9 g (84%) of the title compound as pale a yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ 6.80 (br s, 2H), 3.02-3.06 (m, 2H), 2.55-2.59 (m, 2H), 2.03 (s, 3H), 1.89-1.92 (m, 2H).