Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[Br:12]Br>C(Cl)(Cl)(Cl)Cl>[Br:12][C:9]1[CH:10]=[CH:11][C:2]([OH:1])=[C:3]2[C:8]=1[CH:7]=[N:6][CH:5]=[CH:4]2
Reactant: BrBr
Reactant: Oc1cccc2cnccc12
Solvent: ClC(Cl)(Cl)Cl
Product: Oc1ccc(Br)c2cnccc12

Procedure:
For example, 5-hydroxyisoquinoline 66.7 is reacted with bromine in carbon tetrachloride to afford 8-bromo-5-hydroxyisoquinoline 66.8. The product is reacted with acetic anhydride in pyridine to give 5-acetoxy-8-bromoisoquinoline 66.9. The latter compound is coupled with a dialkyl propenyl phosphonate 66.10 (Aldrich) in the presence of ca. 3 mol % of bis(triphenylphosphine)palladium(II) chloride and triethylamine, in dimethylformamide at ca. 60°, to produce the coupled product 66.11. The acetyl protecting group is then removed by reaction with dilute aqueous methanolic ammonia, as described in J. Chem. Soc., 2137, 1964, to afford the phenol 66.12. The product is optionally reduced to yield the saturated analog 66.13. The reduction reaction is effected chemically, for example by the use of diimide or diborane, as described in Comprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p. 5, or catalytically.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH:28]([F:30])[F:29])=[CH:22][C:21]=4[O:31][CH2:32][CH:33]4[CH2:35][CH2:34]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH:28]([F:30])[F:29])=[CH:22][C:21]=4[O:31][CH2:32][CH:33]4[CH2:34][CH2:35]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3cc(F)c(OC(F)F)cc3OCC3CC3)ncnc12
Agent: Cl
Product: CC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4cc(F)c(OC(F)F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-cyclopropylmethoxy-4-(1,1-difluoro-methoxy)-5-fluoro-phenyl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A189) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [OH-].[Na+].C([NH:11][C:12]([NH:14][C:15]1[CH:20]=[C:19]([Br:21])[CH:18]=[C:17]([Br:22])[CH:16]=1)=[S:13])(=O)C1C=CC=CC=1>O.C1COCC1>[Br:21][C:19]1[CH:20]=[C:15]([NH:14][C:12]([NH2:11])=[S:13])[CH:16]=[C:17]([Br:22])[CH:18]=1
Reactant: O=C(NC(=S)Nc1cc(Br)cc(Br)c1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=S)Nc1cc(Br)cc(Br)c1
Temperature: 70 °C
Reaction time: 12 h
Yield: 95.4 %

Procedure:
A solution of NaOH (46.30 g, 1.16 mol) dissolved in 480 mL of H2O was added to a solution of 1-benzoyl-3-(3,5-dibromo-phenyl)-thiourea (96.0 g, 0.23 mol) in 1.20 L of THF. The resulting reaction mixture was stirred at 70° C. for 12 hours. THF was distilled off and extracted with ethyl acetate (×3). The combined organic layer was dried over Na2SO4, filtered and distilled off to get the crude residue that was washed with hexane to obtain the desired compound as a grey solid (68 g, 95%).
Reaction SMILES: Br[CH:2]([CH2:11][CH2:12][CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=[O:8].[CH3:14][C:15]([C:17]1[CH:18]=[CH:19][C:20]([OH:24])=[CH:21][C:22]=1[OH:23])=[O:16]>C(C(C)=O)C>[C:15]([C:17]1[CH:18]=[CH:19][C:20]([O:24][CH:2]([CH2:11][CH2:12][CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[CH:21][C:22]=1[OH:23])(=[O:16])[CH3:14]
Reactant: CCCC(Br)CCCCC(=O)OC
Reactant: CC(=O)c1ccc(O)cc1O
Solvent: CCC(C)=O
Product: CCCC(CCCCC(=O)O)Oc1ccc(C(C)=O)c(O)c1

Procedure:
Following the procedure of Example 48, 1.13 g. of methyl 6-bromo-nonanoate and 1.31 g. of 2,4-dihydroxyacetophenone were reacted in 50 ml. of methyl ethyl ketone. Hydrolysis of the resulting methyl ester intermediate gave 0.3 g. of the title product, M+ =308; NMR, IR.
Reaction SMILES: Cl[C:2]1[CH:26]=[CH:25][C:5]2[C:6](=[O:24])[C:7]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18]4)=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1.[C:27]1([NH2:34])[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH2:33].P.O(C(C)(C)C)[Na]>C1(C)C=CC=CC=1.C(O)(C)(C)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[NH:34][C:2]1[CH:26]=[CH:25][C:5]2[C:6](=[O:24])[C:7]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18]4)=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: CC1(C)OC[C@H](COc2ccc3c(c2)CCc2cc(Cl)ccc2C3=O)O1
Reactant: Nc1ccccc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[Na]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: CC1(C)OC[C@H](COc2ccc3c(c2)CCc2cc(Nc4ccccc4N)ccc2C3=O)O1

Procedure:
For the synthesis of the title compound, 0.91 g (0.0024 mol) of (S)-2-chloro-8-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one, 1.00 g (0.0092 mol) of phenylenediamine, 2 spatula tips of Pd(OAc)2, 0.18 g of phosphine ligand and 1.60 g (0.0166 mol) of NaOtert-Bu in 10 ml of toluene and 2 ml of tert-BuOH are reacted by method O.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[C:28]([Cu])#[N:29]>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:28]#[N:29])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2cc(Oc3ccc(F)cc3)ccc2c1O
Reactant: N#C[Cu]
Product: CCCCOC(=O)c1nc(C#N)c2cc(Oc3ccc(F)cc3)ccc2c1O

Procedure:
This compound was synthesized from 1-bromo-7-(4-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (prepared as shown in Scheme 2, according to US 2004/0254215 A1, 1H NMR (CDCl3) δ=11.89 (s, 1H), 8.36 (d, 1H), 7.57 (d, 1H), 7.44 to 7.50 (m, 1H), 7.08 to 7.16 (m, 4H), 4.47 (t, 2H), 1.78 to 1.93 (m, 2H), 1.38 to 1.58 (m, 2H), 0.99 (t, 3H)) and CuCN in analogy to Example 3(a)); MS-(−)-ion: M−1=379.2.
Reaction SMILES: B(F)(F)[F:2].CCOCC.[CH:10]1(N)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1.N(OC(C)(C)C)=O>C(COC)OC>[F:2][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[CH2:10][CH2:11][CH2:12][CH2:13]2
Reactant: FB(F)F
Reactant: NC1CCCc2ccccc21
Agent: CC(C)(C)ON=O
Solvent: COCCOC
Solvent: CCOCC
Product: Fc1cccc2c1CCCC2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A modified procedure of Mirsadehgi et al. was used (J. Org. Chem. 1989, 54, 3091). Boron trifluoride etherate (30.0 g, 26.8 mL, 0.21 mol) was dissolved and stirred in dimethoxyethane (50 mL) and cooled to 0° C. A solution of tetrahydro-1-naphthylamine (25 g, 0.17 mol) in dimethoxyethane (75 mL) was added dropwise and the solution was allowed to warm slowly to room temperature over the period of 1 hour. The reaction was cooled to 0° C. and a solution of t-butyl nitrite (18.0 g, 20.7 mL, 0.17 mol) in dimethoxyethane (75 mL) was added dropwise. The reaction was stirred for 2 hours at 0° C. upon which a large quantity of material crystallized. The solvent was removed in vacuo and chlorobenzene (200 mL) was charged to the reaction flask. The flask was stirred vigorously and heated to 135° C. (Caution: N2 evolution) for 1 hour until gas evolution ceased. The flask was cooled to room temperature and the solvent removed in vacuo. Kughelrohr distillation of the residue (1 mm Hg) afforded a yellow liquid. Wt: 14.4 g (56%). 1H NMR (300 MHz, CDCl3) δ 7.04 (dd, 1H), 6.83 (m, 2H), 2.75 (m, 4H), 1.80 (m, 4H)
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:8])[CH2:4][CH2:5][CH2:6]Cl.C1(C)C=CC=CC=1.[C:16]1([CH2:34][OH:35])[S:17][CH:18]=[C:19]2[C:25]=1[C:24]1[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=1[O:22][C:21]1[CH:30]=[CH:31][CH:32]=[CH:33][C:20]2=1>[OH-].[Na+].[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[CH3:2][N:3]([CH3:8])[CH2:4][CH2:5][CH2:6][O:35][CH2:34][C:16]1[S:17][CH:18]=[C:19]2[C:25]=1[C:24]1[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=1[O:22][C:21]1[CH:30]=[CH:31][CH:32]=[CH:33][C:20]2=1
Reactant: CN(C)CCCCl
Reactant: OCc1scc2c1-c1ccccc1Oc1ccccc1-2
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C)CCCOCc1scc2c1-c1ccccc1Oc1ccccc1-2
Temperature: 25 °C

Procedure:
To a 3-dimethylaminopropylchloride-hydrochloride solution (2.5 mmoles) in 50% sodium hydroxide (3 ml), benzyltriethylammonium chloride (0.3 mmole) and a toluene solution of the alcohol 12 (0.25 mmole) were added. The reaction mixture was heated under vigorous stirring and refluxing for 4 hours. Then it was cooled to room temperature, diluted with water and extracted with dichloromethane. After purification by column chromatography an oily product was isolated.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[C:18]([CH3:27])[CH:17]=3)[CH2:13][CH:12]([C:28](OC)=[O:29])[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:33]=[C:34]([NH2:38])[CH:35]([CH3:37])[CH3:36]>>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:11][CH:12]([C:28]3[O:29][N:38]=[C:34]([CH:35]([CH3:37])[CH3:36])[N:33]=3)[CH2:13][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:25])([F:24])[F:26])=[C:18]([CH3:27])[CH:17]=3)[CH2:15]2)=[O:9])[CH2:4][CH2:3]1
Reactant: COC(=O)C1CC(c2ccc(OC(F)(F)F)c(C)c2)CN(C(=O)N2CCC(O)CC2)C1
Reactant: CC(C)C(N)=NO
Product: Cc1cc(C2CC(c3nc(C(C)C)no3)CN(C(=O)N3CCC(O)CC3)C2)ccc1OC(F)(F)F

Procedure:
500 mg (1.12 mmol) of the compound from Example 169A and 125 mg (1.23 mmol) of N′-hydroxy-2-methylpropanimidamide were reacted according to the General Method 1. Yield: 373 mg (67% of theory).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=3[CH3:24])[C:15]([NH:17][CH:18]3[CH2:20][CH2:19]3)=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[NH:25]1[C:29]2[CH2:30][NH:31][CH2:32][CH2:33][C:28]=2[C:27]([OH:34])=[N:26]1.C(N(CC)C(C)C)(C)C>CN1C(=O)CCC1.O>[CH:18]1([NH:17][C:15](=[O:16])[C:14]2[CH:21]=[CH:22][C:23]([CH3:24])=[C:12]([C:8]3[CH:7]=[C:6]4[C:11](=[CH:10][CH:9]=3)[C:2]([N:31]3[CH2:32][CH2:33][C:28]5[C:27]([OH:34])=[N:26][NH:25][C:29]=5[CH2:30]3)=[N:3][N:4]=[CH:5]4)[CH:13]=2)[CH2:20][CH2:19]1
Reactant: Oc1n[nH]c2c1CCNC2
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(Cl)nncc2c1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(N3CCc4c(O)n[nH]c4C3)nncc2c1
Temperature: 160 °C

Procedure:
A mixture of 3-(1-chlorophthalazin-6-yl)-N-cyclopropyl-4-methylbenzamide (300 mg, 888 μmol), 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-ol (247 mg, 1776 μmol) and N,N-diisopropylethylamine (310 μl, 1776 μmol) in NMP (3 mL) was heated to 160° C. for 18 h. After cooling to RT, the mixture was diluted with H2O and extracted with 25% i-PrOH/CHCl3 (3×). The combined organics were dried over Na2SO4, filtered and concentrated. The residue was purified with reverse-phase chromatography (Phenomenex Synergi 4m Max RP 80 A column, 150×21 mM, 20 mL/min, 10-95% CH3CN/H2O, 0.1% TFA, 10.5 min gradient) to obtain the title compound. MS (ESI, pos. ion) m/z: 441 (M+1).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:15]=[CH:14]C2N[C:11](=O)[NH:12][C:8]=2[CH:7]=1)([O-:5])=[O:4].[CH3:16][N:17]([CH:19]=[O:20])[CH3:18]>>[CH3:16][N:17]1[C:18]2[CH:14]=[CH:15][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][C:8]=2[N:12]([CH3:11])[C:19]1=[O:20]
Reactant: CN(C)C=O
Reactant: O=c1[nH]c2ccc([N+](=O)[O-])cc2[nH]1
Agent: [H-]
Agent: [Na+]
Product: Cn1c(=O)n(C)c2cc([N+](=O)[O-])ccc21
Reaction time: 0.42 h
Yield: 93 %

Procedure:
DMF (10 ml) was added to 0.6 g of 60% NaH (15.12 mM) in a 100 mL round bottom flask under N2. Added to the flask was 1.29 g of 5-nitro-2-benzimidazolinone (7.20 mM) in 10 mL DMF and rinsed with 10 mL more DMF. The solution was stirred 25 minutes and 10.22 g MeI (72 mM) was added and then stirred a further 3 hours. HCl (200 mL, 1 M) was added to the solution and then was extracted with EtOAc, washed with brine, and dried over MgSO4 and then concentrated in vacuo and flashed 0 to 100% EtOAc in hexanes to give 1.4 g of 1,3-dimethyl-5-nitro-1H-benzo[d]imidazol-2(3H)-one (93% yield).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:25][CH:24]=3)[C@H:8]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]4[CH2:33][CH2:34][CH2:35][CH2:36]4)=[CH:25][CH:24]=3)[C@H:8]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)OC[C@@H](c1ccc(C(F)(F)F)cc1)[C@H]2c1ccc(OCCN2CCCC2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1ccc2c(c1)OC[C@@H](c1ccc(C(F)(F)F)cc1)[C@H]2c1ccc(OCCN2CCCC2)cc1

Procedure:
In an manner analogous to that described in step 5 for Example 10, (±)-cis-7-methoxy-4-(4-(2-pyrrolidinoethoxy)phenyl)-3-(4-(trifluoromethyl)phenyl)chromane (0.30 g, 0.60 mmol) was de-methylated by heating with pyridine hydrochloride to give the title compound as a colourless powder.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH2:9])[S:8][C:4]=2[CH:3]=1.[CH3:12][C:13](=O)[CH2:14][CH2:15][C:16](=O)[CH3:17].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.O>C1C=CC=CC=1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([N:9]3[C:16]([CH3:17])=[CH:15][CH:14]=[C:13]3[CH3:12])[S:8][C:4]=2[CH:3]=1
Reactant: CC(=O)CCC(C)=O
Reactant: Nc1nc2ccc(Br)cc2s1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: c1ccccc1
Product: Cc1ccc(C)n1-c1nc2ccc(Br)cc2s1
Yield: 83.8 %

Procedure:
A solution 6-bromobenzo[d]thiazol-2-amine (5.75 g, 25.1 mmol), hexane-2,5-dione (2.95 mL, 25.1 mmol), and PPTS (0.95 g, 3.76 mmol) in benzene (100 ml) was refluxed for 16 h while water was removed with a Dean-Stark trap. The cooled mixture was poured into EtOAc (100 mL) and extracted with saturated aq. NaHCO3 (2×100 mL) and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 9:1 EtOAc:hexanes as the eluent to give the title compound as an orange oil (6.46 g, 84%).
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[C:6](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1.[CH3:17]S(C)=O>>[I:3][C:4]1[CH:5]=[C:6]([C@@H:10]2[CH2:17][C@H:11]2[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)/C=C/c1cccc(I)c1
Reactant: CS(C)=O
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)[C@@H]1C[C@H]1c1cccc(I)c1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
Me3SOI (379 mg, 1.72 mmol) was suspended in 3 mL of DMSO. NaH (60% suspension in mineral oil, 70 mg, 1.72 mmol) was added. Stirred at room temperature before the 3-iodoethyl cinnamate (400 mg, 1.32 mmol) from Example 1A was added. The resulting mixture was heated at 65° C. for 20 minutes before it was stirred at room temperature for 2 hours. The resulting mixture was then worked up by partitioning between diethyl ether and water. The organic layer was washed with water and brine, dried over MgSO4, filtered, evaporated to provide the titled compound (127 mg, 31.8 mmol) as a light brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH2:12])=[S:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:14][C:15](=O)[C:16]([OH:18])=[O:17]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[S:11][CH:14]=[C:15]([C:16]([OH:18])=[O:17])[N:12]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)C(=O)CBr
Reactant: NC(=S)Nc1ccc(Cl)c(Cl)c1
Solvent: CO
Product: O=C(O)c1csc(Nc2ccc(Cl)c(Cl)c2)n1
Yield: 95.6 %

Procedure:
2-(3,4-Dichloro-phenylamino)-thiazole-4-carboxylic acid (275 mg) was prepared according to General Procedure B using (3,4-dichloro-phenyl)-thiourea (220 mg) and 3-bromo-2-oxo-propionic acid (200 mg) in methanol (2 mL). The crude product was used in a subsequent step without further purification.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]([NH2:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.[C:14]1(=[O:20])[O:19][C:17](=[O:18])[CH2:16][CH2:15]1.CC(=O)OCC.CO>CCOCC>[O:20]=[C:14]([NH:11][CH:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=1)[CH3:10])[CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=C1CCC(=O)O1
Reactant: CC(N)c1cccc(C(F)(F)F)c1
Solvent: CCOCC
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(NC(=O)CCC(=O)O)c1cccc(C(F)(F)F)c1
Reaction time: 72 h
Yield: 54.5 %

Procedure:
A solution of 5.0 g (26.5 mmol) of 1-(3-(trifluoromethyl)phenyl)ethylamine in ether (6 ml) was added dropwise in the course of 30 min to a suspension of 2.33 g (23.3 mmol) of succinic anhydride in ether (28 ml). Stirring was then carried out for 72 h at RT. The resulting precipitate was filtered off with suction and dried for 1 h in vacuo at 40° C. CC (EA/MeOH 1:4) of the residue yielded 3.68 g (12.7 mmol, 55%) of 4-oxo-4-(1-(3-(trifluoromethyl)phenyl)ethylamino)-butanoic acid (S2).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4](OS(C)(=O)=O)[C:5]1[S:6][C:7]([CH3:10])=[CH:8][CH:9]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(C(C)C)C(C)C)C>CC#N>[CH3:1][O:2][C:3](=[O:16])[CH:4]([C:5]1[S:6][C:7]([CH3:10])=[CH:8][CH:9]=1)[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)C(OS(C)(=O)=O)c1ccc(C)s1
Reactant: Nc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)C(Nc1ccccc1)c1ccc(C)s1
Yield: 24.1 %

Procedure:
A solution of methanesulfonyloxy-(5-methyl-thiophen-2-yl)-acetic acid methyl ester (I266) (2.10 g, 7.94 mmol), aniline (1.09 mL, 11.9 mmol) and N-ethyl-N-isopropylpropan-2-amine (2.04 mL, 11.9 mmol) in MeCN (10 mL) is heated under microwave irradiation at 100° C. for 1 hour. The solvent is removed, DCM is added and the organic phase is washed with water and brine, dried over Na2SO4 and evaporated. The resulting brown oil is purified by silica gel flash chromatography (Hexane/EtOAc=9575 to 90/10) to obtain intermediate I269 as a yellow oil (500 mg, 24% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][CH2:8][C:9]1[C:10]([Br:38])=[N:11][C:12]([N:15]2[CH2:19][CH2:18][C:17]([C:24]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=3)([C:20]([F:23])([F:22])[F:21])[CH2:16]2)=[CH:13][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].C(#N)C.[N+]([O-])([O-])=[O:44].[NH4+].[Ce]>C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:39])[NH:7][CH2:8][C:9]1[C:10]([Br:38])=[N:11][C:12]([N:15]2[CH2:19][CH2:18][C:17]([C:24]3[CH:29]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:27]=[C:26]([C:34]([F:37])([F:35])[F:36])[CH:25]=3)([C:20]([F:22])([F:23])[F:21])[CH:16]2[OH:44])=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(C)(C)OC(=O)NCc1ccc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)nc1Br
Agent: [Ce]
Agent: [NH4+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1ccc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2O)nc1Br
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a mixture of t-butyl[(6-{3-[3,5-bis(trifluoromethyl)phenyl]-3-(trifluoromethyl)-pyrrolidin-1-yl}-2-bromopyridin-3-yl)methyl]carbamate (0.5 g) and acetonitrile (30 ml), which had been stirred in ice water bath, a 1 M aqueous solution of cerium ammonium nitrate (IV) (1.6 ml) was added, stirred approximately for 10 minutes and the reaction mixture was diluted with ethyl acetate. After that, the mixture was washed with an aqueous solution of sodium thiosulfate and then an aqueous saturated brine solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel chromatography to obtain t-butyl[(6-{3-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl}-2-bromopyridin-3-yl)methyl]carbamate (0.35 g).
Reaction SMILES: ClC(Cl)(OC(=O)[O:6][C:7]([Cl:10])(Cl)Cl)Cl.[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]2[CH2:25][NH:24][CH2:23][CH:22]2[CH:26]([O:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=2)[CH3:27])[CH:17]=[CH:18][C:19]=1[Cl:20].N1C=CC=CC=1.CCOC(C)=O>C(Cl)Cl>[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]2[CH:22]([CH:26]([O:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:31][N:30]=3)[CH3:27])[CH2:23][N:24]([C:7]([Cl:10])=[O:6])[CH2:25]2)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(Oc1ccc(C(F)(F)F)cn1)C1CNCC1c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(Oc1ccc(C(F)(F)F)cn1)C1CN(C(=O)Cl)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 104 %

Procedure:
To a stirred solution of carbonic acid ditrichloromethyl ester (triphosgene) (22 mg 0.074 mmol) in CH2Cl2 (3 mL) at −78° C., was added a solution of 2-{(SR)-1-[(3RS,4SR)-4-(3,4-dichloro-phenyl)pyrrolidin-3-yl]-ethoxy}-5-trifluoromethyl-pyridine (intermediate XV-B-3) (76 mg, 0.19 mmol) and pyridine (0.03 mL, 0.42 mmol) in CH2Cl2 (1 mL) over 30 minutes. The temperature was raised to RT, and stirring was continued over night. The organic phase was washed with H2O, dried over Na2SO4. Concentration under vacuo yielded and column chromatography (SiO2, EtOAc/H, 1:4) yielded 36 mg (41%) of the title compound as a viscous colorless oil.
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][Si:10]([O:13][CH3:14])(Cl)Cl.[Cl-].[NH4+]>C1COCC1>[CH:1]1([CH:9]([SiH2:10][O:13][CH3:14])[CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CO[Si](C)(Cl)Cl
Reactant: Cl[Mg]C1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CO[SiH2]C(C1CCCCC1)C1CCCCC1
Yield: 80 %

Procedure:
The THF solution of cyclohexyl magnesium chloride as prepared above was added dropwise to the methylmethoxydichlorosilane solution obtained in Example 7, in the same manner as in Example 3(c), to effect the Grignard reaction. The post-treatment of the resulting Grignard reaction solution was carried out in the same manner as in Example 3 (c), except that the saturated aqueous ammonium chloride solution used in Example 3 (c), was used in a reduced amount of 80 ml instead of 120 ml. The organic layer was separated and was fractionally distilled under a reduced pressure, thereby to afford 39 g of dicyclohexylmethylmethoxysilane as a fraction boiling at 128° C.-129° C./7 mm Hg (yield; 80%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:11][CH2:12][O:13][CH3:14])[CH3:10])=[CH:5][C:4]=1[NH:15][C:16]([NH2:18])=[S:17].Br.CC(O)=O.CS(C)=O>CC(O)=O>[CH3:1][O:2][C:3]1[C:4]2[N:15]=[C:16]([NH2:18])[S:17][C:5]=2[C:6]([N:9]([CH2:11][CH2:12][O:13][CH3:14])[CH3:10])=[CH:7][CH:8]=1
Reactant: COCCN(C)c1ccc(OC)c(NC(N)=S)c1
Agent: Br
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: COCCN(C)c1ccc(OC)c2nc(N)sc12

Procedure:
From {2-methoxy-5-[(2-methoxy-ethyl)-methyl-amino]-phenyl}-thiourea with HBr—AcOH (2 equiv.) and DMSO (1.1 equiv.) in AcOH. ES-MS m/e (%): 268 (M+H+, 100).
Reaction SMILES: [C:1]1([CH2:7][C@H:8]([OH:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.Cl>N1C=CC=CC=1>[C:1]1([CH2:7][C@H:8]([O:10][S:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=2)(=[O:19])=[O:18])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](O)Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O[C@H](C)Cc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
(2R)-1-Phenyl-2-propanol (0.5 ml, 3.65 mmol) was added dropwise to a solution of p-toluenesulfonyl chloride (0.73 g, 3.83 mmol) in pyridine) (3 ml) at 0° C. The mixture was stirred at 0° C. under nitrogen for 30 minutes then at room temperature overnight. The reaction mixture was poured into 2M hydrochloric acid (75 ml) and extracted with diethyl ether (2×50 ml). The extracts were washed with 2M hydrochloric acid (50 ml), saturated sodium hydrogen carbonate (50 ml) and brine (50 ml), combined, dried (MgSO4) and concentrated in vacuo to give the title compound as a white solid (0.95 g, 90%); δH (250MHz, CDCl3) 1.30 (3H, d, J 6.2Hz, CHCH3), 2.42 (3H, s, ArCH3), 2.77 (1H, dd, J 13.8, 6.6Hz, CH(OTs)CHAHBPh), 2.92 (1H, dd, J 13.8, 6.6Hz, CH(OTs)CHAHBPh), 4.74 (1H, m, CHOTs), 7.03 (2H, m, ArH), 7.20 (5H, m, ArH), 7.62 (1H, m. ArH).