Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].ClCCl.[CH3:10][S:11]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([C:23]1[CH:28]=[C:27]([O:29][CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[N:26]=[CH:25][N:24]=1)[CH2:18][CH2:17]2)(=[O:13])=[O:12]>O>[CH:1]([NH:4][C:5]([N:33]1[CH2:32][CH2:31][CH:30]([O:29][C:27]2[CH:28]=[C:23]([N:19]3[C:20]4[C:16](=[CH:15][C:14]([S:11]([CH3:10])(=[O:13])=[O:12])=[CH:22][CH:21]=4)[CH2:17][CH2:18]3)[N:24]=[CH:25][N:26]=2)[CH2:35][CH2:34]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)N=C=O
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCNCC2)ncn1
Solvent: ClCCl
Solvent: O
Product: CC(C)NC(=O)N1CCC(Oc2cc(N3CCc4cc(S(C)(=O)=O)ccc43)ncn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
Isopropyl isocyanate (31 μL, 0.315 mmol) was added to a dichloromethane (5 mL) solution of the 5-(methylsulfonyl)-1-[6-(piperidin-4-yloxy)pyrimidin-4-yl]indoline (78.1 mg, 0.209 mmol) produced in Reference Example 28, and the mixture was stirred at room temperature for 30 minutes. To the reaction solution, water was added, followed by extraction with ethyl acetate three times. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound as white powder (87.3 mg, yield: 91%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][NH2:9])[CH:5]=[CH:6][CH:7]=1.Cl.[C:11]1(NN)[CH:16]=CC=[CH:13][CH:12]=1>>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:16]=[CH:11][C:12]([CH3:13])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NNc1cccc(Br)c1
Reactant: NNc1ccccc1
Agent: Cl
Product: Cc1ccn(-c2cccc(Br)c2)n1

Procedure:
This compound was prepared by the same methodology described for EXAMPLE 1 with 3-bromophenyl hydrazine.HCl substituted for phenyl hydrazine. There was obtained 1-(3-bromophenyl)-3-methyl-1H-pyrazole-5-[(2′-aminosulfonyl-[1,1′]-biphen-4-yl)carboxyamide; HRMS(M+H)+ calc. 511.043949; found: 511.043295.
Reaction SMILES: [C:1]([C:6]1[CH:17]=[CH:16][C:9]2[N:10]([CH3:15])[C:11]([CH2:13][OH:14])=[N:12][C:8]=2[CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[Mn]([O-])(=O)(=O)=[O:19].[K+]>>[C:1]([C:6]1[CH:17]=[CH:16][C:9]2[N:10]([CH3:15])[C:11]([C:13]([OH:19])=[O:14])=[N:12][C:8]=2[CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1ccc2c(c1)nc(CO)n2C
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: CCCC(=O)c1ccc2c(c1)nc(C(=O)O)n2C

Procedure:
In a manner analogous to that described in Example 12, 18.5 g of 5-butyryl-1-methyl-benzimidazole-2-methanol can be oxidised with 18.5 g of potassium permanganate to give 5-butyryl-1-methyl-benzimidazole-2-carboxylic acid with a melting point above 90° (decomposition).
Reaction SMILES: [CH:1]([S:4][CH:5]([NH:10][C:11](=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][C:19](=[O:21])[CH3:20])[C:6]([Cl:9])([Cl:8])[Cl:7])([CH3:3])[CH3:2].C(O)(=[O:25])C.OO.O>C(OCC)(=O)C>[CH:1]([S:4]([CH:5]([NH:10][C:11](=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][C:19](=[O:21])[CH3:20])[C:6]([Cl:7])([Cl:9])[Cl:8])=[O:25])([CH3:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(=O)Oc1ccccc1C(=O)NC(SC(C)C)C(Cl)(Cl)Cl
Agent: OO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)Oc1ccccc1C(=O)NC(S(=O)C(C)C)C(Cl)(Cl)Cl
Reaction time: 3 h

Procedure:
To 15.0 g of N-(1-iso-propylthio-2,2,2-trichloroethyl)-2-acetoxybenzamide was added 80 ml of acetic acid and 3.8 g of 35% hydrogen peroxide solution was added dropwise thereto under stirring. Then the reaction was effected at 40°-50° C. for three hours and the reaction mixture was poured into water. 100 ml of ethyl acetate was added thereto and the solution was separated, dried, concentrated, washed and dried again to obtain 12.3 g of N-(1-iso-propylsulfinyl-2,2,2-trichloroethyl)-2-acetoxybenzamide.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH:31]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[CH:32]([F:34])[F:33])=[C:13]([CH:30]=1)[CH2:14][NH:15][C:16](=[O:29])[C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1C(OC(C)(C)C)=O>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH:31]([NH:35][C:36]2[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=2)[CH:32]([F:34])[F:33])=[C:13]([CH:30]=1)[CH2:14][NH:15][C:16](=[O:29])[C@@H:17]1[CH2:21][CH2:20][CH2:19][NH:18]1
Reactant: COc1ccc(NC(c2ccc(Cl)cc2CNC(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)C(F)F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(NC(c2ccc(Cl)cc2CNC(=O)[C@@H]2CCCN2)C(F)F)cc1
Yield: 99.7 %

Procedure:
TFA (2.50 mL) was added to a stirred solution of N-(5-chloro-2-{2,2-difluoro-1[(4-methoxyphenyl)amino]ethyl}benzyl)-1-(tert-butoxycarbonyl)-L-prolinamide (0.256 g, 0.49 mmol) in CH2Cl2 (5.0 mL). After 1 h the solvent was evaporated in vacuo and the residue was partitioned between EtOAc and saturated aqueous Na2CO3. The organic layer was dried (Na2SO4) and evaporated in vacuo to give the N-(5-Chloro-2-{2,2-difluoro-1-[(4-methoxyphenyl)amino]ethyl}benzyl)-L-prolinamide (0.207 g) as a gum.
Reaction SMILES: Br[C:2]1[C:3]([F:27])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]4[NH:22][N:21]=[C:20]([CH:23]5[CH2:25][CH2:24]5)[N:19]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:26]=1.[CH3:28][C:29]([OH:34])([C:32]#[CH:33])[CH2:30][OH:31].C(NC(C)C)(C)C>CN(C=O)C>[CH:23]1([C:20]2[N:19]=[C:18]([C:12]3[N:8]4[CH2:9][CH2:10][O:11][C:5]5[CH:4]=[C:3]([F:27])[C:2]([C:33]#[C:32][C:29]([OH:34])([CH3:28])[CH2:30][OH:31])=[CH:26][C:6]=5[C:7]4=[N:14][C:13]=3[C:15]([NH2:17])=[O:16])[NH:22][N:21]=2)[CH2:25][CH2:24]1
Reactant: C#CC(C)(O)CO
Reactant: NC(=O)c1nc2n(c1-c1nc(C3CC3)n[nH]1)CCOc1cc(F)c(Br)cc1-2
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1-c1nc(C2CC2)n[nH]1)CO
Yield: 47.1 %

Procedure:
3-(3-cyclopropyl-1H-1,2,4-triazol-5-yl)-10-(3,4-dihydroxy-3-methyl-but-1-ynyl)-9-fluoro-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide was prepared similarly according to General Procedure E with slight modification. 10-bromo-3-(3-cyclopropyl-1H-1,2,4-triazol-5-yl)-9-fluoro-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide was reacted with 2-methylbut-3-yne-1,2-diol in a solution of DMF (1.3 mL/mmol) and diisopropylamine (2.6 mL/mmol) to afford 30 mg of the titled compound (47.1% yield). M+1=453.0.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([O:17][C:18]([NH:20][CH2:21][C:22]([NH:24][C@H:25]1[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C@H:27]([C:37](O)=[O:38])[CH2:26]1)=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].[C:40]1([CH2:46][CH2:47][CH2:48][C:49]([N:51]2[CH2:56][CH2:55][N:54](C([O-])=O)[CH2:53][CH2:52]2)=[O:50])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.ON1C2C=CC=CC=2N=N1>ClCCl.C(N(CC)CC)C>[C:13]([O:17][C:18]([NH:20][CH2:21][C:22]([NH:24][C@H:25]1[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:34])[CH3:35])=[O:31])[C@H:27]([C:37]([N:54]2[CH2:55][CH2:56][N:51]([C:49](=[O:50])[CH2:48][CH2:47][CH2:46][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:52][CH2:53]2)=[O:38])[CH2:26]1)=[O:23])=[O:19])([CH3:15])([CH3:16])[CH3:14]
Reactant: O=C([O-])N1CCN(C(=O)CCCc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](C(=O)N2CCN(C(=O)CCCc3ccccc3)CC2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 100.7 %

Procedure:
Triethylamine (72 μL) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (98.9 mg) were added to a solution of trans-4-(N-tert-butoxycarbonylglycylamino)-N-tert-butoxycarbonyl-L-proline (Compound D103 (B), 144.9 mg), 4-(4-phenylbutanoyl)l-piperazinecarboxylate (B, 100 mg), and 1-hydroxybenzotriazole (65 mg) in dichloromethane at room temperature. After stirring at room temperature for 20 hr, the reaction mixture was partitioned between ethyl acetate and 1 N hydrochloric acid. The organic layer was washed with saturated sodium hydrogen carbonate and brine. After drying over anhydrous sodium sulfate, the organic layer was evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform:methanol=50:1 to 20:1) to give the titled compound (220 mg) as a white powder: 1H-NMR(400 MHz, CDCl3) δ 1.46 (s, 18H), 1.99 (t, 2H), 2.33 (m, 2H), 2.69 (t, 2H), 3.39-3.85 (m, 13H), 7.18-7.31(m, 5H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH3:16][O:17][C:18]1[CH:19]=[C:20](O)[CH:21]=[C:22]([CH3:24])[CH:23]=1.O>N1C=CC=CC=1>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:20]1[CH:21]=[C:22]([CH3:24])[CH:23]=[C:18]([O:17][CH3:16])[CH:19]=1)(=[O:5])=[O:4]
Reactant: COc1cc(C)cc(O)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: O
Product: COc1cc(C)cc(OS(=O)(=O)C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 97.1 %

Procedure:
Trifluoromethanesulphonic anhydride (2.02 ml, 12.0 mmol) was added dropwise to a stirred solution of 3-methoxy-5-methylphenol (1.50 g, 10.9 mmol) in pyridine (20 ml) at −20° C. under nitrogen. The reaction was warmed to 0° C., stirred for 90 minutes and re-cooled to −20° C. More trifluoromethanesulphonic anhydride (1.01 ml, 6.00 mmol) was added dropwise. The reaction was allowed to warm to room temperature, stirred for 14 hours and cautiously poured into water (100 ml). The aqueous phase was extracted with ether (150 ml) and the organic phases were washed with water (3×75 ml), 0.2M hydrochloric acid (3×75 ml), 1.0M aqueous sodium carbonate solution (2×75 ml), water (75 ml) and brine (75 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure to provide the title compound (2.86 g) as a pale brown oil.
Reaction SMILES: C(OC([N:11]1[C:50]2[C:45](=[CH:46][C:47]([F:51])=[CH:48][CH:49]=2)[C:13]2([CH2:18][CH2:17][N:16]([C:19]([C@H:21]([NH:31][C:32](=[O:44])[C:33]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])([CH3:35])[CH3:34])[CH2:22][O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:20])[CH2:15][CH2:14]2)[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>C(O)C.C(N(CC)CC)C>[F:51][C:47]1[CH:46]=[C:45]2[C:13]3([CH2:14][CH2:15][N:16]([C:19]([C@H:21]([NH:31][C:32](=[O:44])[C:33]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])([CH3:35])[CH3:34])[CH2:22][O:23][CH2:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[O:20])[CH2:17][CH2:18]3)[CH2:12][NH:11][C:50]2=[CH:49][CH:48]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](COCc1ccccc1)C(=O)N1CCC2(CC1)CN(C(=O)OCc1ccccc1)c1ccc(F)cc12
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](COCc1ccccc1)C(=O)N1CCC2(CC1)CNc1ccc(F)cc12
Yield: 100.7 %

Procedure:
To a solution of 0.330 g of the intermediate obtained from Step A in 5 mL of ethanol at was added 1 drop of triethylamine and hydrogenated with hydrogen balloon for 3 h. The catalyst was filtered off through a pad of celite and washed with ethyl acetate. The filtrate was concentrated to give 0.269 g of the product as a colorless foam.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1OS(C(F)(F)F)(=O)=O)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4].[CH:36]([C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1)=[O:37]>>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([S:32]([CH3:35])(=[O:33])=[O:34])=[CH:30][CH:31]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:41]1[CH:42]=[CH:43][C:38]([CH:36]=[O:37])=[CH:39][CH:40]=1)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1
Product: COC(=O)c1c(-c2ccc(C=O)cc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1

Procedure:
The present compound was synthesized by a method similar to that in Example 272 and using 6-chloro-2-(4-methanesulfonylbenzyl)-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester and 4-formylphenylboronic acid.
Reaction SMILES: CI.[CH2:3](OCC)C.[Mg].[CH3:9][C:10]1([CH3:20])[CH2:16][CH2:15][CH2:14][CH2:13][C:12]([CH3:18])([CH3:17])[C:11]1=[O:19]>>[CH3:3][C:11]1([OH:19])[C:12]([CH3:18])([CH3:17])[CH2:13][CH2:14][CH2:15][CH2:16][C:10]1([CH3:20])[CH3:9]
Reactant: CCOCC
Reactant: CC1(C)CCCCC(C)(C)C1=O
Agent: [Mg]
Solvent: CI
Product: CC1(C)CCCCC(C)(C)C1(C)O
Yield: 55.3 %

Procedure:
A mixed solution of methyl iodide (23.90 g, 0.16 moles)/dried diethyl ether (10 ml) was dropped into a mixture of magnesium (2.90 g, 0.12 moles)/dried diethyl ether (20 ml) in 1 hour while stirring under water-cooling conditions. The mixture was stirred for 48 hours at room temperature and subjected to separation by filtration. Into the resulting filtrate was dropped a mixed solution of 2,2,7,7-tetramethylcycloheptanone (16.80 g, 0.10 mole)/dried diethyl ether (30 ml) in 30 minutes while stirring at room temperature. The mixture was stirred at room temperature for 48 hours. The resulting reaction mixture was treated in the same manner as in Example 1 to obtain 10.20 g (yield 55.3%) of the captioned compound. This compound was a white solid having a woody, earthy camphoraceous and patchuli oil-like odor.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5](=[N:14]S(C2C=CC(C)=CC=2)(=O)=O)[N:6]([CH:8]([C:10](=O)[CH2:11][CH3:12])[CH3:9])[CH:7]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1COCC1>[CH2:11]([C:10]1[N:14]=[C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:7][N:6]2[C:8]=1[CH3:9])[CH3:12]
Reactant: CCC(=O)C(C)n1cc(I)ccc1=NS(=O)(=O)c1ccc(C)cc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: CCc1nc2ccc(I)cn2c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.1 %

Procedure:
To a stirred solution of N-(5-iodo-1-(3-oxopentan-2-yl)pyridin-2(1H)-ylidene)-4-methylbenzenesulfonamide (4 g) in THF (50 ml) was added trifluoroacetic anhydride (10 ml) at 0° C., and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo, poured into saturated aqueous NaHCO3 solution and extracted with DCM. The extract was washed with brine, dried over Na2SO4, concentrated in vacuo, and purified by silica gel column chromatography (hexane/EtOAc) to afford the title compound (1.3 g) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH:40](C)[CH3:41])=[CH:35][CH:34]=3)=[CH:29][C:28]=2[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:23]([F:26])([F:25])[F:24])[N:3]=1.[CH:49](OC1C=CC(B(O)O)=CC=1)(C)C>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][CH3:49])=[CH:35][CH:34]=3)=[CH:29][C:28]=2[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:23]([F:24])([F:26])[F:25])[N:3]=1
Reactant: CC(C)Oc1ccc(-c2ccc([C@@H](Oc3cc(N4CCC5(CC4)CN[C@H](C(=O)O)C5)nc(N)n3)C(F)(F)F)c(-c3ccccc3)c2)cc1
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Product: CCCOc1ccc(-c2ccc([C@@H](Oc3cc(N4CCC5(CC4)CN[C@H](C(=O)O)C5)nc(N)n3)C(F)(F)F)c(-c3ccccc3)c2)cc1

Procedure:
The title compound was prepared as described above for (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-isopropoxy-[1,1′:3′,1″-terphenyl]-4′-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 54b) by substituting 4-propoxyphenyl boronic acid for 4-isopropoxyphenyl boronic acid in Step 2.
Reaction SMILES: [N:1]([CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)=[C:2]=[S:3].O[CH:15]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H:16]1[NH2:17]>C(O)(=O)C>[CH2:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:12][CH2:13][CH:4]1[N:1]1[CH:15]=[CH:16][NH:17][C:2]1=[S:3]
Reactant: S=C=NC1CCc2ccccc2C1
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Solvent: CC(=O)O
Product: S=c1[nH]ccn1C1CCc2ccccc2C1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
A mixture of 2-isothiocyano-1,2,3,4-tetrahydronaphthalene (1.89 g, 10 mmol), prepared as in Example 10, and D-(+)-glucosamine (1.78 g, 10 mmol) was stirred at 90° C. until homogenous and then 0.8 mL of acetic acid was added. The mixture was stirred at 90° C. for 30 minutes and then cooled. The solvents were removed by rotary evaporation and the residue was co-evaporated with toluene (2×25 mL). The residue was dissolved in acetic acid and heated at 90° to 100° C. for 30 minutes. The mixture was cooled and triturated with acetone giving a crystalline material. The material was isolated by filtration and the filter residue washed with acetone. Drying gave 4-(1R,2R,3S,4)-tetrahydroxybut-1-yl)-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione (1.48 g, 4.23 mmol).
Reaction SMILES: [OH-:1].[Na+:2].[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[O:15][C:13](=[O:14])[CH2:12][CH2:11]1>CO>[Na+:2].[OH:15][CH:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH3:3])[CH2:11][CH2:12][C:13]([O-:14])=[O:1]
Reactant: CCCCCCCC1CCC(=O)O1
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCC(O)CCC(=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
To a solution of 43.6 g sodium hydroxide in 150 ml of methanol heated to reflux, 200 g gamma-undecalactone were added. After stirring for 2 hours at reflux, the mixture was cooled to room temperature and evaporated to dryness. The resulting crystals were washed with hexane to yield 240 g of colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH3:16].Cl>>[NH2:16][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1Cl
Reactant: N
Agent: Cl
Product: CS(=O)(=O)c1cc(C(=O)O)c(N)cc1Cl

Procedure:
50 g of 2,4-dichloro-5-methylsulphonylbenzoic acid [obtainable in accordance with Ex. 2] are heated in an autoclave, at 180° and under a pressure of 30 bar for 12 h, together with 500 ml of a 32% aqueous solution of ammonia. The reaction mixture is then poured onto ice, acidified with conc. HCl and extracted by boiling with methanol. 2-Amino-4-chloro-5-methylsulphonylbenzoic acid is obtained, m.p. 284°-286°.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[C:5]([C:15]#[N:16])=[C:6]([C:13]#[N:14])[C:7]([Cl:12])=[C:8](Cl)[C:9]=1[Cl:10].[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O.CC(C)=O>[Cl:12][C:7]1[C:6]([C:13]#[N:14])=[C:5]([C:15]#[N:16])[C:4]([Cl:3])=[C:9]([Cl:10])[C:8]=1[O:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Oc1ccccc1
Reactant: N#Cc1c(Cl)c(Cl)c(Cl)c(Cl)c1C#N
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: N#Cc1c(Cl)c(Cl)c(Oc2ccccc2)c(Cl)c1C#N
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of potassium hydroxide (11.2 parts) in water (22 parts) was added dropwise to a stirred solution of 3,4,5,6-tetra-chloro-1,2-dicyanobenzene (26.6 parts) and phenol (9.4 parts) in acetone (100 arts) at 0° C. The solution was stirred at 60° C. for 2 hours before pouring into water (500 parts). The aqueous mixture was extracted with dichloromethane (3×500 parts). The dichloromethane extracts were washed with water (3×200 parts), dried over anhydrous Na2SO4, filtered and the dichloromethane was removed under reduced pressure to leave a brown solid. The solid was recrystallised from butan-1-ol. 3,5,6-Trichloro-1,2-dicyano-4-phenoxybenzene (17 parts) was obtained as a brown solid, m.p. 147°-150° C.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:15]=[CH:16][N:17]([C:19]3[N:24]=[C:23]([CH3:25])[CH:22]=[C:21]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)[N:20]=3)[CH:18]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:25][C:23]1[CH:22]=[C:21]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][CH:27]=2)[N:20]=[C:19]([N:17]2[CH:18]=[C:14]([C:11]3[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=3)[N:15]=[CH:16]2)[N:24]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(-c3ccc(S(N)(=O)=O)s3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 19.6 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-5-{1-[4-methyl-6-(4-trifluoromethylphenyl)-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonamide (0.08 g) in dichloromethane (3 mL) was added TFA (3 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (3 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried. Further purification by flash-chromatography on silica gel (ethyl acetate/hexane) and crystallization (diethyl ether) yielded the title compound as a white solid (0.014 g, 3%). MS (ISP) 466.1 [(M+H)+]; mp 277° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[S:12][C:11]([N:13]2[CH2:20][C:19]3[CH2:18][NH:17][CH2:16][C:15]=3[CH2:14]2)=[N:10][CH:9]=1)=[O:7].FC(F)(F)C([O-])=O.C(N(CC)CC)C.[F:36][C:37]([F:48])([F:47])[C:38]1[CH:46]=[CH:45][CH:44]=[CH:43][C:39]=1[C:40](Cl)=[O:41]>CN(C=O)C>[CH3:1][CH:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[S:12][C:11]([N:13]2[CH2:14][C:15]3[CH2:16][N:17]([C:40](=[O:41])[C:39]4[CH:43]=[CH:44][CH:45]=[CH:46][C:38]=4[C:37]([F:36])([F:47])[F:48])[CH2:18][C:19]=3[CH2:20]2)=[N:10][CH:9]=1)=[O:7]
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CC(C)CCNC(=O)c1cnc(N2CC3=C(CNC3)C2)s1
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)CCNC(=O)c1cnc(N2CC3=C(CN(C(=O)c4ccccc4C(F)(F)F)C3)C2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(3-Methylbutyl)-2-(3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl)thiazole-5-carboxamide, trifluoroacetate (220 mg, 0.52 mmol) and triethylamine (0.22 ml, 1.57 mmol) were dissolved in 10 ml of DMF and admixed in an ice bath with 2-trifluoromethylbenzoyl chloride (218 mg, 1.04 mmol). The mixture was stirred further for 1 h and allowed to warm to room temperature, and concentrated, water and ethyl acetate were added and the organic phase was removed, concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 25 mg (10%), M+H+: 479.06.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:7](O)=[O:8])[CH3:2].C(Cl)[Cl:16].C(Cl)(=O)C(Cl)=O>CN(C=O)C.C1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:7]([Cl:16])=[O:8])[CH3:2]
Reactant: ClCCl
Reactant: CCOc1cc(C(=O)O)ccc1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCOc1cc(C(=O)Cl)ccc1OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3-ethoxy-4-methoxybenzoic acid (5 g, 25.5 mmol) was added to a solution of CH2Cl2 (40 mL) and benzene (20 mL) in a flame-dried 150 mL round bottom flask. Anhydrous DMF (9 drops) was added and the solution was cooled on ice. Oxalyl chloride (11 mL, 128 mmol) was added dropwise, and the reaction was then allowed to warm to RT. The reaction was stirred at RT for 90 minutes, then concentrated in vacuo yield an off-white solid. The solid was placed on a high-vacuum line for 2 hours, and then taken onto the next step without further characterization.