Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]2[CH:16]=[C:15]([CH2:17][CH:18]=[CH2:19])[CH:14]=[CH:13][C:12]=2[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br)[CH:5]=1)[CH:2]=[CH2:3].[C:28]([OH:31])(=[O:30])[CH3:29]>C([O-])(=O)C.[Ag+]>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]2[CH:16]=[C:15]([CH2:17][CH:18]=[CH2:19])[CH:14]=[CH:13][C:12]=2[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:31][C:28](=[O:30])[CH3:29])[CH:5]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1ccc(O)c(-c2cc(CC=C)ccc2OCCCCCCBr)c1
Reactant: CC(=O)O
Agent: [Ag+]
Agent: CC(=O)[O-]
Product: C=CCc1ccc(O)c(-c2cc(CC=C)ccc2OCCCCCCOC(C)=O)c1

Procedure:
A mixture was prepared by adding 0.2 g of 4-allyl-2-[5-allyl- 2-(6-bromohexyloxy)phenyl]phenol and 0.1 g of silver acetate to 3 ml of acetic acid. The mixture was refluxed by heating for 2 hours and concentrated. The concentrate was extracted with diethylether. The extract was washed with solution sodium hydrogencarbonate and an aqueous solution saturated with NaCl, dried with sodium sulfate and concentrated. The concentrate was purified by a silica gel column-chromatography (n-hexane:ethyl acetate=15:1) to yield 0.12 g of 4-allyl-2-[5allyl-2-(6-acetoxyhexyloxy)phenyl]phenol.
Reaction SMILES: [ClH:1].Cl.[CH3:3][C@H:4]1[N:9]([CH3:10])[CH2:8][CH2:7][N:6]([CH2:11][C@@H:12](C2(O)CCCCC2)[C:13]2[CH:18]=[CH:17][CH:16]=[C:15](OC(F)(F)F)[CH:14]=2)[CH2:5]1.Cl.Cl.C[C@H]1NCCN(C[C@@H](C2(O)CCCCC2)[C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([O:48][C:49]([F:52])([F:51])[F:50])[CH:43]=2)C1.C[OH:61]>>[ClH:1].[ClH:1].[CH3:3][C@H:4]1[N:9]([CH3:10])[CH2:8][CH2:7][N:6]([CH2:11][CH:12]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@@H:14]2[OH:61])[C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([O:48][C:49]([F:51])([F:52])[F:50])[CH:43]=2)[CH2:5]1
Reactant: C[C@@H]1CN(C[C@H](c2cccc(OC(F)(F)F)c2)C2(O)CCCCC2)CCN1C
Reactant: CO
Reactant: C[C@@H]1CN(C[C@H](c2cccc(OC(F)(F)F)c2)C2(O)CCCCC2)CCN1
Agent: Cl
Product: C[C@@H]1CN(CC(c2cccc(OC(F)(F)F)c2)C2CCCC[C@@H]2O)CCN1C

Procedure:
In an analogous manner to Example 24, 1-{(1S)-2-[(3R)-3,4-dimethylpiperazin-1-yl]-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol dihydrochloride was prepared from 1-{(1S)-2-[(3R)-3-methylpiperazin-1-yl]-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol (See Example 369). MS (ESI) m/z 401; HRMS: calcd for C21H31F3N2O2+H+, 401.24104; found (ESI, [M+H]+), 401.241. [α]D25=−13° (c=0.0085 g/mL, MeOH); CD=+@281 nm.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([OH:18])=[CH:13][C:12]=2[CH3:19])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CO[C:22]([C:24]1[S:25][C:26]([CH:29]([CH2:32]O)[CH2:30][CH3:31])=[CH:27][CH:28]=1)=[O:23].Cl.[CH3:35][O:36][C:37](=[O:41])[CH2:38][CH2:39][NH2:40]>>[CH3:35][O:36][C:37](=[O:41])[CH2:38][CH2:39][NH:40][C:22]([C:24]1[S:25][C:26]([CH:29]([CH2:32][O:18][C:14]2[CH:13]=[C:12]([CH3:19])[C:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][CH:9]=3)=[C:16]([CH3:17])[CH:15]=2)[CH2:30][CH3:31])=[CH:27][CH:28]=1)=[O:23]
Reactant: Cc1cc(O)cc(C)c1-c1ccc(C(C)(C)C)cc1
Reactant: COC(=O)CCN
Reactant: CCC(CO)c1ccc(C(=O)OC)s1
Agent: Cl
Product: CCC(COc1cc(C)c(-c2ccc(C(C)(C)C)cc2)c(C)c1)c1ccc(C(=O)NCCC(=O)OC)s1

Procedure:
This compound is made by the general method as exemplified in Preparation 94 using 4′-tert-butyl-2,6-dimethyl-biphenyl-4-ol and 5-(1-hydroxymethyl-propyl)-thiophene-2-carboxylic acid methyl ester in Step A and 3-amino-propionic acid methyl ester hydrochloride salt in Step C as the starting materials to provide (±)-3-({5-[1-(4′-tert-butyl-2,6-dimethyl-biphenyl-4-yloxymethyl)-propyl]-thiophene-2-carbonyl}-amino)-propionic acid methyl ester (0.213 g) as a white solid. MS (ES): 520.3 [M−H]−. The racemic material is separated by chiral HPLC (column: Chiralpak AD-H 4.6×150 mm; eluent: 20:80 IPA/supercritical CO2; flow rate: 5 mL/min; UV absorbance wavelength: 270 nm) to provide Isomer 1 (0.074 g, >99% ee) and Isomer 2 (0.078 g, >99% ee).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3=[N:14][NH:15][C:16](=[O:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:11]([C:12]=43)[NH:10][CH:9]2[C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.C(Cl)Cl.[CH2:33]([NH:35][CH2:36][CH3:37])[CH3:34].[BH4-].[Na+]>C(O)(=O)C>[CH2:33]([N:35]([CH2:26][C:25]1[CH:24]=[CH:23][C:22]([CH:9]2[NH:10][C:11]3[C:12]4[C:13](=[N:14][NH:15][C:16](=[O:21])[C:17]=4[CH:18]=[CH:19][CH:20]=3)[CH:8]2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:29][CH:28]=1)[CH2:36][CH3:37])[CH3:34]
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(F)cc2)cc1
Reactant: CCNCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCN(CC)Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.1 %

Procedure:
To a stirred solution of 4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (260 mg, 0.68 mmol) in dryness DCM (15 mL) was added acetic acid (0.2 mL) followed by diethylamine (148 mg, 2.03 mmol). After the addition, the mixture was stirred at room temperature overnight. Then sodium borohydride (212 mg, 1.01 mmol) was added to the mixture at 0° C. The mixture was stirred at this temperature for 12 hr. DCM was removed under reduced pressure. The residue was washed with ethyl acetate/methanol (10/1) and filtered. The filtrate was concentrated to give the crude product, which was purified by flash chromatography to give the title compound as white solid (27.3 mg, yield 9%). LC-MS (ESI) m/z: 442 (M+1)+. 1H-NMR (400 MHz, CD3OD) δ (ppm): 3.12-3.17 (m, 4H), 4.27 (s, 2H), 4.34 (d, 1H), 4.78 (d, 1H), 6.91 (t, 2H), 7.09-7.12 (m, 1H), 7.38-7.45 (m, 4H), 7.56-7.58 (m, 1H), 7.64 (t, 1H).
Reaction SMILES: [Fe:1].[C:2]1([C:16]([OH:17])=[C:12]([N+:13]([O-:15])=[O:14])[CH:11]=[C:7]([N+:8]([O-:10])=[O:9])[CH:6]=1)[N+:3]([O-:5])=[O:4]>>[C:12]1([C:16]([O-:17])=[C:2]([N+:3]([O-:5])=[O:4])[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[CH:11]=1)[N+:13]([O-:15])=[O:14].[Fe+2:1].[C:12]1([C:16]([O-:17])=[C:2]([N+:3]([O-:5])=[O:4])[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[CH:11]=1)[N+:13]([O-:15])=[O:14]
Reactant: [Fe]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c([O-])c([N+](=O)[O-])c1
Product: [Fe+2]

Procedure:
adding a +2 iron source to said picric acid solution of step (ii) with stirring to obtain a green iron (II) picrate solution; and
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[IH:10].OO>O>[Cl:1][C:2]1[C:3]([I:10])=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5]
Reactant: I
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: OO
Solvent: O
Product: Nc1ccc(Cl)c(Cl)c1I
Reaction time: 8 h

Procedure:
To a stirred suspension of 3,4-dichloroaniline (20 g, 123 mmol), HI (48%, 15.7 g, 123 mmol), H2O2 (30%, 8.3 g, 246 mmol) in H2O (62 mL) at r.t. The reaction mixture was stirred in dark at r.t for overnight. The supernatant was discarded, diluted with ethyl acetate:hexanes (1:10), quenched with saturates NaHSO3, stirred for 1 h at ambient temperature, filtered the solids. The filtrate was washed with water, saturated aqueous NaHCO3, dried (Na2SO4), filtered and concentrated to get 1:4 regioisomeric mixture of iodo derivative (minor isomer is required). It was recrystallized from cyclohexane to afford 1:1 mixture of regioisomers enriched in the filtrate. This mixture was further purified by flash column chromatography on silica gel, eluting with ethyl acetate:hexanes (0-2%) to get the required compound as a cream color solid (5.2 g, ˜15% yield). 1H NMR (400 MHz, CDCl3) δ 7.22 (d, J=8.6 Hz, 1H), 6.60 (d, J=8.6 Hz, 1H), 4.32 (br, 2H).
Reaction SMILES: CO.CCN(CC)CC.[NH2:10][C:11]1[C:16]([N+:17]([O-])=O)=[CH:15][C:14]([C:20]2[CH:21]=[N:22][C:23]([C:26]([OH:29])([CH3:28])[CH3:27])=[N:24][CH:25]=2)=[C:13]([F:30])[C:12]=1[CH:31]1[CH2:35][CH2:34][CH2:33][O:32]1>[Pd].C1COCC1>[NH2:10][C:11]1[C:16]([NH2:17])=[CH:15][C:14]([C:20]2[CH:21]=[N:22][C:23]([C:26]([OH:29])([CH3:27])[CH3:28])=[N:24][CH:25]=2)=[C:13]([F:30])[C:12]=1[CH:31]1[CH2:35][CH2:34][CH2:33][O:32]1
Reactant: CC(C)(O)c1ncc(-c2cc([N+](=O)[O-])c(N)c(C3CCCO3)c2F)cn1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(O)c1ncc(-c2cc(N)c(N)c(C3CCCO3)c2F)cn1
Yield: 402.8 %

Procedure:
5% Palladium on carbon (14.21 g, 50% wet, 3.339 mmol, Aldrich 330116) was placed in a Parr bottle under nitrogen, followed by MeOH (242 mL, JT-Baker 909333) and NEt3 (46.54 mL, 333.9 mmol, Sigma-Aldrich 471283). 2-[5-(4-Amino-2-fluoro-5-nitro-3-tetrahydrofuran-2-yl-phenyl)pyrimidin-2-yl]propan-2-ol (20) (121.0 g, 333.9 mmol) was dissolved in hot THF (360 mL), allowed to cool, added to the reaction mixture, and rinsed the residual amount of 20 with another portion of THF (124 mL). The bottle was placed on a Parr shaker and saturated with H2. After adding 45 psi H2, the bottle was shaken until consumption of 20 was complete (HPLC and LCMS showed complete reaction). The reaction mixture was purged with nitrogen, filtered through Celite™ and rinsed with EtOAc. It was re-filtered through paper (glass microfiber) and the filtrate concentrated in vacuo. The reaction was repeated three more times on the same scale and the batches were combined giving 21 as a brown solid (447 g, 99% yield; 93% HPLC purity). LCMS (C18 column eluting with 10-90% CH3CN/water gradient over 5 minutes with formic acid modifier) M+1: 333.46 (1.79 min). 1H NMR (300 MHz, CDCl3) δ 8.81 (d, J=1.4 Hz, 2H), 6.69 (d, J=7.3 Hz, 1H), 5.27-5.20 (m, 1H), 4.73 (s, 1H), 4.70 (s, 2H), 4.23-4.14 (m, 1H), 3.94-3.86 (m, 1H), 3.22 (s, 2H), 2.32-2.22 (m, 1H), 2.18-1.99 (m, 3H), 1.63 (s, 6H) ppm.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([C:10]([OH:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[C:14]1[S:18][C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][OH:27])[N:21]=2)=[C:16]([C:28]([NH2:30])=[O:29])[CH:15]=1.I[CH2:32][CH3:33]>CN(C=O)C>[CH2:32]([O:27][CH2:26][C:22]1[N:21]=[C:20]([NH:19][C:17]2[S:18][C:14]([C:5]3[CH:6]=[CH:7][C:8]([C:10]([OH:13])([CH3:11])[CH3:12])=[CH:9][C:4]=3[F:3])=[CH:15][C:16]=2[C:28]([NH2:30])=[O:29])[CH:25]=[CH:24][CH:23]=1)[CH3:33]
Reactant: CCI
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(CO)n3)s2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCc1cccc(Nc2sc(-c3ccc(C(C)(C)O)cc3F)cc2C(N)=O)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a suspension of NaH (10 mg, 0.25 mmol) in DMF (1.25 mL) at 0° C. under argon was added 5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-{[6-(hydroxymethyl)pyridin-2-yl]amino}thiophene-3-carboxamide (Example 48) (50 mg, 0.125 mmol) and the mixture was allowed to stir for 20 minutes. Iodoethane (29 mg, 0.19 mmol) was then added and the reaction was allowed to warm to room temperature and subsequently heated to 60° C. overnight. The reaction was cooled to ambient temperature, quenched by the addition of water, extracted with ethyl acetate and concentrated in vacuo. The crude residue was reverse phase HPLC (acteonitrile/water with formic acid as a modifier) to afford the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[C:12]([CH3:20])[CH:11]=1.Cl.Cl.[CH:24]1([CH2:28][N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH2:27][CH2:26][CH2:25]1.CCN(C(C)C)C(C)C>ClCCl.CN(C=O)C>[CH3:7][O:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([N:32]2[CH2:33][CH2:34][N:29]([CH2:28][CH:24]3[CH2:25][CH2:26][CH2:27]3)[CH2:30][CH2:31]2)=[O:19])=[C:12]([CH3:20])[CH:11]=1
Reactant: COC(=O)c1ccc(CC(=O)O)c(C)c1
Reactant: C1CC(CN2CCNCC2)C1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(CC(=O)N2CCN(CC3CCC3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46 %

Procedure:
Oxalyl chloride (0.36 ml, 3.3 mmol) was added to a solution of 4-carboxymethyl-3-methyl-benzoic acid methyl ester from Example E32 (687 mg, 3.3 mmol) in dichloromethane (20 ml) and few drops of DMF. The mixture was stirred for 3 h at room temperature, concentrated in vacuo and azeotroped with toluene. The residue was dissolved in dichloromethane (10 ml) and added to a solution of 1-cyclobutylmethyl-piperazine dihydrochloride (750 mg, 3.3 mmol) in dichloromethane (10 ml) and DIEA (1.73 ml, 9.9 mmol) at 0° C. The mixture was stirred for 20 h at room temperature and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 3% methanol:97% dichloromethane) to yield the title compound (528 mg, 46%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[CH2:13][CH2:12]1)=[O:10])(C)(C)C>Cl>[NH2:7][C@H:8]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[CH2:15][CH2:16]1)=[O:10]
Reactant: COc1ccccc1N1CCN(C(=O)[C@@H](CC2CCCCC2)NC(=O)OC(C)(C)C)CC1
Agent: Cl
Product: COc1ccccc1N1CCN(C(=O)[C@H](N)CC2CCCCC2)CC1
Yield: 98 %

Procedure:
2.75 g (6.20 mmol) of the above-described (R)-{1-Cyclohexylmethyl-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester was stirred overnight in a mixture of 30 mL of peroxide-free dioxane and 30 mL of 6N aq. HCl. The resulting yellow mixture was concentrated to dryness on a rotary evaporator and the residue was partitioned between dichloromethane and saturated aq. sodium bicarbonate solution. The aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to yield the desired (R)-2-amino-3-cyclohexyl-1-[4-(2-methoxyphenyl)-piperazin-1-yl]-propan-1-one (2.10 g, 98% yield), which was characterized as its dihydrochloride salt by conversion with ethereal HCl to yield the white solid; mp=165-168° C.; MS (+) ESI m/z=346 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:17])([C:6]1([OH:16])[CH2:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:8]([CH3:15])([CH3:14])[CH2:7]1)[C:3]([OH:5])=O.CCN(CC)CC.ClC(OCC)=O.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:48]=[CH:49][C:50]=1[O:51][CH3:52])[O:36][CH2:37][C:38]1[O:42][C:41]([C@@H:43]2[CH2:47][CH2:46][CH2:45][NH:44]2)=[N:40][CH:39]=1>C1COCC1.O>[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:48]=[CH:49][C:50]=1[O:51][CH3:52])[O:36][CH2:37][C:38]1[O:42][C:41]([C@@H:43]2[CH2:47][CH2:46][CH2:45][N:44]2[C:3](=[O:5])[C:2]([F:1])([F:17])[C:6]2([OH:16])[CH2:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:8]([CH3:15])([CH3:14])[CH2:7]2)=[N:40][CH:39]=1
Reactant: CC1(C)CC(C)(C)CC(O)(C(F)(F)C(=O)O)C1
Reactant: COc1ccc(OCc2cnc([C@@H]3CCCN3)o2)cc1OC
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(OCc2cnc([C@@H]3CCCN3C(=O)C(F)(F)C3(O)CC(C)(C)CC(C)(C)C3)o2)cc1OC
Yield: 78.6 %

Procedure:
To a solution of 2,2-difluoro-2-(1-hydroxy-3,3,5,5-tetramethylcyclohexyl)acetic acid (0.075 g) and Et3N (0.038 ml) in THF (1 ml), ethyl chloroformate (0.028 g) was added over an ice bath, followed by stirring at the same temperature for an hour. To the reaction mixture, a solution of (S)-5-((3,4-dimethoxyphenoxy)methyl)-2-(pyrrolidin-2-yl)oxazole (0.075 g) in THF (1 ml) was added over an ice bath, followed by stirring at room temperature for 15 hours. After adding water and performing extraction with AcOEt, the organic layer was washed with saturated aqueous sodium chloride, dried (MgSO4), filtered and concentrated to give a crude product, which was further purified by silica gel chromatography (AcOEt/hexane) to give the titled compound (0.104 g, colorless amorphous.)
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[O:9]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[O:12][CH:11]=[C:10]1[C:19]([O:21][CH2:22][CH3:23])=[O:20].Cl>C(=S)=S>[C:5]([C:17]1[CH:16]=[CH:15][C:14]2[O:9][C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:11][O:12][C:13]=2[CH:18]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C1=COc2ccccc2O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCOC(=O)C1=COc2cc(C(C)=O)ccc2O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
Slowly add 8.1 g (60.7 mmol) of aluminium chloride to a solution of 2.85 g (36.3 mmol) of acetyl chloride and 5 g (24.7 mmol) of ethyl 1,4-benzodioxin-2-carboxylate in 120 cm3 of carbon disulfide at 0° C. Stir for 4 hours at room temperature and then, after acid hydrolysis with 20 cm3 of 2N hydrochloric acid, extract the reaction mixture with methylene chloride. After drying the methylene chloride phase over magnesium sulfate, concentrating to dryness and washing with ethanol, ethyl 6-acetyl-1,4-benzodioxin-2-carboxylate is obtained in a yield of 95%. Melting point: 122° C. ##STR30##
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[NH:9][C:8]=2[CH:14]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20]Cl.O>C1COCC1.C1(C)C=CC=CC=1>[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20][N:9]1[C:8]2[CH:14]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[O:12][CH2:11][C:10]1=[O:13]
Reactant: CN(C)CCCl
Reactant: O=C1COc2ccc([N+](=O)[O-])cc2N1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CCN1C(=O)COc2ccc([N+](=O)[O-])cc21
Yield: 71.4 %

Procedure:
To a suspension of 6-nitro-2H-1,4-benzoxazin-3(4H)-one (J. Med. Chem. 1989, 32, 1627-1630) (1 g, 5.7 mmol) in dry THF (20 ml) at 0° C. under argon, was added NaH (0.16 g, 5.7 mmol, 80% dispersion in mineral oil). A solution of 2-dimethylaminoethyl chloride (2.3 g, 20.8 mmol) in dry toluene (15 ml) was added and the reaction mixture heated under reflux for 19 hr. After cooling, water was added dropwise until effervescence had ceased, then the mixture was separated and the aqueous further extracted with EtOAc. The organic layers were combined, dried (Na2SO4) and evaporated under reduced pressure to give a pale brown solid (1.08 g, 79%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[N:3]=1.F[B-](F)(F)F.[C:37]([C:39]1[CH:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[CH:41][C:40]=1[CH2:49][C:50]([O:52][CH3:53])=[O:51])#[CH:38].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CCN(CC)CC>[CH3:53][O:52][C:50](=[O:51])[CH2:49][C:40]1[CH:41]=[CH:42][C:43]([C:45]([F:47])([F:46])[F:48])=[CH:44][C:39]=1[C:37]#[C:38][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Reactant: C#Cc1cc(C(F)(F)F)ccc1CC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(C(F)(F)F)cc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 120 °C

Procedure:
A stirred suspension of tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (K5) (0.200 g, 0.438 mmol), PdCl2(PPh3)2 (0.031 g, 0.044 mmol), t-Bu3PH.BF4 (0.013 mg, 0.044 mmol), CuI (0.008 g, 0.044 mmol) and methyl 2-(2-ethynyl-4-(trifluoromethyl)phenyl)acetate (A59) (0.212 g, 0.875 mmol) in anhydrous, degassed DMF (6 mL) and Et3N (6 mL) was heated at 120° C. for 20 minutes under nitrogen. The volatiles were evaporated under reduced pressure then the residue adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A60 as a brown solid (0.176 g, 61%); 1H NMR (400 MHz, CDCl3) δ 8.64 (s, 1H), 7.93 (d, J=0.8 Hz, 1H), 7.67 (dd, J=8.2, 1.3 Hz, 1H), 7.56 (d, J=8.5 Hz, 2H), 7.51-7.49 (m, 2H), 7.23 (d, J=8.5 Hz, 2H), 4.36-4.18 (m, 2H), 4.01 (s, 2H), 3.72 (s, 3H), 2.91-2.74 (m, 2H), 2.72-2.58 (m, 1H), 1.83 (d, J=12.6 Hz, 2H), 1.64-1.56 (m, 2H), 1.50 (s, 9H). LCMS-A: rt 7.227 min; m/z 661 [M−H]−.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([C:8](=O)[CH2:9][CH3:10])[C:6](=[O:12])[CH2:5][CH:4]([C:13]#[N:14])[CH2:3]1.[CH:15]([NH2:18])([CH3:17])[CH3:16]>O1CCCC1>[O:1]=[C:2]1[CH:7]([C:8](=[N:18][CH:15]([CH3:17])[CH3:16])[CH2:9][CH3:10])[C:6](=[O:12])[CH2:5][CH:4]([C:13]#[N:14])[CH2:3]1
Reactant: CCC(=O)C1C(=O)CC(C#N)CC1=O
Reactant: CC(C)N
Solvent: C1CCOC1
Product: CCC(=NC(C)C)C1C(=O)CC(C#N)CC1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.2 g (0.006 mol) of 3,5-dioxo-4-propionylcyclohexanenitrile were dissolved in 40 ml of dry tetrahydrofuran, and 0.4 g (0.006 mol) of isopropylamine was added. The mixture was stirred for 16 hours at room temperature, the solvent was stripped off under reduced pressure and the residue was filtered under suction over a little silica gel using methylene chloride/methanol. The solvent was stripped off to give 1.3 g 92% of theory) of 3,5-dioxo-4-(1-isopropyliminopropyl)-cyclohexanenitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:41].CC1C=CC(CN2C=CC(N)=N2)=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:36]3[CH:37]=[CH:38][C:39]([CH3:40])=[CH:41][CH:35]=3)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: Cc1cccc(C)n1
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: Cc1ccc(Cn2ccc(N)n2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1ccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.3 %

Procedure:
To a solution containing 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 100 mg, 0.30 mmol) in methylene chloride (20 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (181 μL, 0.36 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (70 μL, 0.61 mmol) was added to the solution at 0° C. After 1 h, crude 1-(4-methyl-benzyl)-1H-pyrazol-3-ylamine (0.42 mmol based on theory) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(4-methyl-benzyl)-1H-pyrazol-3-yl]-propionamide (86 mg, 57%) as a white solid: ESI-LRMS m/e calcd for C26H30ClN3O3S [M+] 499.2, found 500.3 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.05-1.19 (m, 2H, CH2), 1.41-1.95 (m, 8H, 4×CH2), 2.10-2.27 (m, 1H, CH), 2.32 (s, 3H, ArCH3), 3.24 (s, 3H, SO2CH3), 3.55 (t, J=7.6 Hz, 1H, CH), 5.07 (s, 2H, NCH2), 6.67 (d, J=2.3 Hz, 1H, Ar), 7.04 (d, Jo=8.1 Hz, 2H, Ar), 7.11 (d, Jo=8.1 Hz, 2H, Ar), 7.26 (d, J=2.3 Hz, 1H, Ar), 7.43 (dd, Jo=8.2, Jm=1.7 Hz, 1H, Ar), 7.57 (d, Jm=1.7 Hz, 1H, Ar), 8.04 (d, Jo=8.2 Hz, 1H, Ar), 8.31 (s, 1H, NH).