Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1C=[CH:9][C:8]([N:11]([CH3:28])[C:12]([C:14]2[N:18]([CH3:19])[N:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:15]=2[C:24]([F:27])([F:26])[F:25])=[O:13])=[CH:7][C:3]=1C(O)=O.CN(C)C=O.[C:34](Cl)(=O)[C:35]([Cl:37])=[O:36]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:7][C:8]([N:11]([CH3:28])[C:12]([C:14]2[N:18]([CH3:19])[N:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:15]=2[C:24]([F:25])([F:26])[F:27])=[O:13])=[CH:9][C:34]=1[C:35]([Cl:37])=[O:36]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(C(=O)c1c(C(F)(F)F)c(C(F)(F)F)nn1C)c1ccc(Cl)c(C(=O)O)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C(=O)c1c(C(F)(F)F)c(C(F)(F)F)nn1C)c1ccc(Cl)c(C(=O)Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
150.0 mg (0.29 mmol) of 2-chloro-5-(methyl{[1-methyl-3,4-bis(trifluoromethyl)-1H-pyrazol-5-yl]carbonyl}amino)benzoic acid are suspended in 5.0 ml of dichlormethane p.a. 0.02 ml of N,N-dimethylformamide p.a. and 0.075 ml (0.86 mmol) oxalyl chloride are then added successively to the suspension. The reaction mixture is stirred at room temperature for 0.5 h and then heated under reflux for 40 minutes. The solvent is removed under reduced pressure on a rotary evaporator. The 2-chloro-5-(methyl{[1-methyl-3,4-bis(trifluoromethyl)-1H-pyrazol-5-yl]carbonyl}amino)benzoyl chloride formed is used for the subsequent synthesis step without further purification.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][CH2:6][S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:30](=[O:32])[CH3:31])[CH:24]=2)CC2CCCC2)=[O:15])=[N:10][CH:9]=1)C.[CH:34]1(CN(C2C=CC(F)=C(F)C=2)C(=O)NC2SC=C(CC(O)=O)N=2)[CH2:38][CH2:37][CH2:36][CH2:35]1.N[C:62]1C=C(NC(=O)C)C=CC=1.C1(C=O)CCCC1.C(OC(=O)CCSC1SC(N)=NC=1)C>>[C:30]([NH:29][C:25]1[CH:24]=[C:23]([N:16]([CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[C:14](=[O:15])[N:13]([CH3:62])[C:11]2[S:12][C:8]([S:7][CH2:6][CH2:5][C:4]([OH:3])=[O:33])=[CH:9][N:10]=2)[CH:28]=[CH:27][CH:26]=1)(=[O:32])[CH3:31]
Reactant: O=C(O)Cc1csc(NC(=O)N(CC2CCCC2)c2ccc(F)c(F)c2)n1
Reactant: CCOC(=O)CCSc1cnc(NC(=O)N(CC2CCCC2)c2cccc(NC(C)=O)c2)s1
Reactant: CC(=O)Nc1cccc(N)c1
Agent: CCOC(=O)CCSc1cnc(N)s1
Agent: O=CC1CCCC1
Product: CC(=O)Nc1cccc(N(C(=O)N(C)c2ncc(SCCC(=O)O)s2)C2CCCC2)c1

Procedure:
The title compound was prepared via 3-{2-[3-(3-acetylamino-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-propionic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using N-(3-amino-phenyl)-acetamide, cyclopentanecarbaldehyde and 3-(2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([C:18]2[CH:31]=[CH:30][C:21]3[O:22][C:23]([CH3:29])([CH3:28])[C@@:24]4([CH3:27])[O:26][C@H:25]4[C:20]=3[CH:19]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[CH3:32][N:33]1[C:38](=[O:39])[CH:37]=[CH:36][C:35]([OH:40])=[N:34]1.N1C=CC=CC=1>O1CCOCC1>[CH3:32][N:33]1[C:38](=[O:39])[CH:37]=[CH:36][C:35]([O:40][C@H:25]2[C@@:24]([OH:26])([CH3:27])[C:23]([CH3:28])([CH3:29])[O:22][C:21]3[CH:30]=[CH:31][C:18]([S:15]([C:12]4[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=4)(=[O:16])=[O:17])=[CH:19][C:20]2=3)=[N:34]1
Reactant: Cn1nc(O)ccc1=O
Reactant: CC1(C)Oc2ccc(S(=O)(=O)c3ccc(O[Si](C)(C)C(C)(C)C)cc3)cc2[C@@H]2O[C@@]21C
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: Cn1nc(O[C@@H]2c3cc(S(=O)(=O)c4ccc(O)cc4)ccc3OC(C)(C)[C@@]2(C)O)ccc1=O
Yield: 21.2 %

Procedure:
(3S,4S)-6-(4-tert-Butyldimethylsilyloxyphenyl)sulphonyl-3,4-dihydro-3,4-epoxy-2,2,3-trimethyl-2H-benzo[b]pyran (1.618 g) (see Preparation 14) and 2,3-dihydro-2-methyl-3-oxo-6-hydroxypyridazin (1.33 g) (see J.Org.Chem, 1971, 36, 3372) were suspended in dry 1,4-dioxane (15 ml), pyridine (0.275 ml) was added and the mixture was heated under reflux (a calcium chloride drying tube was attached to the flask) for 3 days. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic phase was separated and dried (anhydrous sodium sulphate), the solvent was removed under reduced pressure and the crude product was chromatographed on silica using 1:99 methanol:ethyl acetate as the eluent to yield (3S,4R)-3,4-dihydro-4-(2,3-dihydro-2-methyl-3-oxopyridazin-6-yl)oxy-3-hydroxy-6-(4-hydroxyphenyl)sulphonyl-2,2,3-trimethyl-2H-benzo[b]pyran (0.352 g) as a white solid. Found: C,58.13; H,5.00; N,5.70. C23H24N2O7S requires C,58.46; H,5.12; N,5.93%.
Reaction SMILES: [CH3:1][NH-:2].[Cl:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]([C:10](Cl)=[O:11])[CH:5]=1.C(=O)([O-])O.[Na+]>O1CCCC1.[OH-].[Na+].ClCCl>[CH3:1][NH:2][C:10]([C:6]1[CH:5]=[C:4]([Cl:3])[N:9]=[CH:8][N:7]=1)=[O:11]
Reactant: C[NH-]
Reactant: O=C(Cl)c1cc(Cl)ncn1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)c1cc(Cl)ncn1
Temperature: 25 °C

Procedure:
0.5 ml of a 2 M methylamide solution in tetrahydrofuran and 1 ml 1 N sodium hydroxide solution are added to 177 mg 6-chloro-pyrimidin-4-carboxylic acid chloride in 5 ml dichloromethane under an argon atmosphere and while cooling with a bath of ice/acetone. The reaction mixture is heated overnight with stirring to ambient temperature and then combined with some saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The combined organic phases are washed with 0.1 N hydrochloric acid and saturated sodium chloride solution, dried on magnesium sulphate and evaporated down.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:18]=[C:17]2[C:13]([NH:14][C:15](=[O:25])[N:16]2[CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[C:12]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[N:11]=1.[CH3:32]OC(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[CH:32][N:9]([C:10]3[N:18]=[C:17]4[C:13]([NH:14][C:15](=[O:25])[N:16]4[CH:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[C:12]([C:26]4[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=4)[N:11]=3)[C:3]=2[CH:4]=1
Reactant: Nc1ccc(Cl)cc1Nc1nc(-c2ccncc2)c2[nH]c(=O)n(C3CCOCC3)c2n1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: O=c1[nH]c2c(-c3ccncc3)nc(-n3cnc4ccc(Cl)cc43)nc2n1C1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 18 %

Procedure:
To a vial containing crude 2-(2-amino-5-chlorophenylamino)-6-(pyridin-4-yl)-9-(tetrahydro-2H-pyran-4-yl)-7H-purin-8(9H)-one (0.015 mmol) was added anhydrous methanol (2.5 mL), followed by anhydrous trimethylorthoformate (0.5 mL) and p-toluene sulfonic acid (1 mg) and the reaction mixture was stirred under Ar at room temperature for 4 h (HPLC monitoring). Preparative HPLC purification, after evaporation of solvent and drying, provided the desired product (1.2 mg, 18% yield on two steps), as a yellow solid. TFA salt. 1H NMR (300 MHz, CD3OD) δ, ppm: 9.18 (s, 1H), 8.83 (br m, 2H), 8.71 (s, 1H), 8.07 (br m, 2H), 7.76 (d, J=8.6 Hz, 1H), 7.41 (d, J=8.9 Hz, 1H), 4.76-4.72 (m, 1H), 4.26-4.23 (m, 2H), 3.66 (app t, J=11.5 Hz, 2H), 2.90-2.87 (m, 2H), 1.91 (br d, J=12.8 Hz, 2H); MS (EI) m/z 448.3 (MH)+.
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[C:11]([CH3:17])[NH:12]3)[CH2:4][CH2:3]1.Cl[C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20].C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:24][C:23]([Cl:26])([Cl:25])[CH2:22][O:21][C:19]([N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[C:11]([CH3:17])[NH:12]3)[CH2:4][CH2:3]1)=[O:20]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Cc1cc2c(N3CCN(C)CC3)cccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc2c(N3CCN(C(=O)OCC(Cl)(Cl)Cl)CC3)cccc2[nH]1
Yield: 85 %

Procedure:
A solution of 4-methyl-1-(2-methyl-1H-indol-4-yl)piperazine (0.510 g, 2.22 mmol) and 2,2,2-trichloroethyl chloroformate (5 mL) was heated at 100-110° C. for 48 hours. The reaction solution was cooled, and methylene chloride (200 mL) followed carefully by a saturated solution of sodium hydrogen carbonate (20 mL) were added. The organic layer was removed, dried (potassium carbonate), and evaporated under reduced pressure. The residue was chromatographed using silica gel (approximately 300 g) using elution with 10% ethyl acetate in hexanes to afford 4-(2,2,2-trichloroethoxycarbonyl)-1-(2-methyl-1H-indol-4-yl)piperazine as a white amorphous solid (0.74 g, 1.89 mmol, 85%): FAB LRMS (m/z, relative intensity) 394 (9), 392 (27), 390 ([MH+ with 35Cl], 32), 358 (18), 356 (29), 216 (99), 194 (100). This compound was used directly as outlined below.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:24][C:25](Br)=[O:26].[NH2:28][CH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[CH2:24][C:25]([NH:28][CH:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:31][CH2:30]2)=[O:26])=[CH:21][CH:22]=1
Reactant: O=C(Br)CBr
Reactant: NC1CCc2ccccc21
Reactant: COc1cc2c(cc1OC)C(Cc1ccc(Cl)cc1)NCC2
Product: COc1cc2c(cc1OC)C(Cc1ccc(Cl)cc1)N(CC(=O)NC1CCc3ccccc31)CC2

Procedure:
prepared by reaction of 1-(4-Chloro-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 1-amino-indane
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2B(O)O)[CH:4]=[CH:3][CH:2]=1.Cl[C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1.[IH:22]>>[I:22][C:15]1[CH:20]=[C:19]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[N:1]=[CH:2][CH:3]=[CH:4]3)[N:18]=[CH:17][N:16]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: I
Reactant: OB(O)c1cccc2cccnc12
Product: Ic1cc(-c2cccc3cccnc23)ncn1

Procedure:
The compound was prepared according to Example 1 using quinolin-8-boronic acid and 4,6-dichloropyrimidine. The resultant chloro compound was converted to iodo with hydroiodic acid as described in the general procedure.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]#[N:12])[C:5]=2[CH2:4][CH2:3]1.[BH4-].[Na+]>C(O)C>[OH:1][CH:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]#[N:12])[C:5]=2[CH2:4][CH2:3]1
Reactant: N#Cc1cccc2c1CCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cccc2c1CCC2O
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a stirred suspension of 1-oxo-2,3-dihydro-1H-indene-4-carbonitrile (1.0 equiv, 0.4M) and silica gel (catalytic) in ethanol at 0° C. was added NaBH4 (⅓ equiv). The reaction was allowed to warm up to room temperature and stirred for 2 h. The Solvent was removed under reduced pressure and the product purified by CC in hexane/EtOAc (5:5) to offer 1-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile in 80% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CC(C)=O.C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)CCBr
Reactant: Sc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CC(C)=O
Product: CCOC(=O)CCSc1ccc(Cl)cc1Cl

Procedure:
2,4-Dichlorothiophenol (5.04 g, 28.2 mmol), caesium carbonate (10.1 g, 31 mmol) and ethyl 3-bromopropanoate (4.2 mL, 33 mmol) in acetone (100 mL) were refluxed overnight under N2(g). After filtration and concentration under reduced pressure, the residue was partitioned between dichloromethane and water. After separation, the aqueous phase was extracted once with dichloromethane. Drying and removal of the solvent in vacuo afforded a liquid residue that contained ˜30% (HPLC) of unreacted 2,4-dichlorothiophenol. The mixture was refluxed again with caesium carbonate (4.7 g) and ethyl 3-bromopropanoate (2 mL) in acetonitrile (100 mL) under N2(g) for 2 h. After filtration and concentration under reduced pressure, the residue was dissolved in diethyl ether and washed with 2 M aq. sodium hydroxide and water. Drying and removal of the solvent in vacuo afforded the sub-title compound.
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[N:4]=1.[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:19]=1[C:20](Cl)=[O:21]>O1CCOCC1>[ClH:17].[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:19]=1[C:20]([NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([N:2]([CH3:1])[CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[N:4]=1)=[O:21]
Reactant: O=C(Cl)c1c(F)cccc1Cl
Reactant: CN1CCC(N(C)c2cccc(N)n2)CC1
Solvent: C1COCCO1
Product: CN1CCC(N(C)c2cccc(NC(=O)c3c(F)cccc3Cl)n2)CC1
Product: Cl
Yield: 150.3 %

Procedure:
Prepare according to procedure in Example 66 starting with N-methyl-N-(1-methyl-piperidin-4-yl)-pyridine-2,6-diamine (Preparation 34) (200 mg, 0.907 mmol), 2-chloro-6-fluorobenzoyl chloride (179 mg, 0.998 mmol), and 1,4-dioxane (10 mL) to yield 310 mg (83%) of the title compound: mass spectrum (ion spray): m/z=377.2 (M+1); Analysis calc'd for C19H23N4OCl2.0.5H2O: C, 54.03; H, 5.73; N, 13.27. Found: C, 53.71; H, 5.71; N, 13.45. mp 283-6° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([O:10][CH3:11])[CH:3]=1.[Li+].C[Si]([N-:17][Si](C)(C)C)(C)C>C1COCC1>[ClH:1].[Cl:1][C:2]1[C:7]([C:8]([NH2:17])=[NH:9])=[CH:6][N:5]=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(Cl)c(C#N)cn1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(Cl)c(C(=N)N)cn1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-chloro-6-methoxy-nicotinonitrile (10.1 g, 59.7 mmol) in THF (300 mL) at −78° C. was added LiHMDS (65.7 mL) dropwise and the reaction mixture stirred for 30 min before allowing to warm to RT and stirring for a further 1 h. The reaction was quenched by the addition of 1N HCl (to pH ˜1) and then extracted three times with ethyl acetate. The aqueous layer was concentrated in vacuo to give brown solid which was azeotroped with toluene to give the title compound as a tan solid. Mixture with ammonium chloride, 72% title compound by weight. (15.2 g, 83%). 1H NMR 400 MHz (DMSO-d) δ: 9.68 (4H, d, J=15.79 Hz), 8.46 (1H, s), 7.47 (5H, t, J=50.66 Hz), 7.27 (1H, s), 3.95 (3H, s).
Reaction SMILES: [F:1][C:2]1([F:21])[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C@@H:4]([C:18]([O-])=[O:19])[CH2:3]1.[Li+].Cl.[NH2:24][C@H:25]([C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1)[CH3:26]>>[F:21][C:2]1([F:1])[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:17])[F:15])[CH:9]=2)[C@@H:4]([C:18]([NH:24][C@H:25]([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)[CH3:26])=[O:19])[CH2:3]1
Reactant: O=C([O-])[C@H]1CC(F)(F)CN1Cc1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Agent: [Li+]
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CC(F)(F)CN2Cc2cccc(C(F)(F)F)c2)cc1
Yield: 48.6 %

Procedure:
The title compound (D164) (37 mg) was prepared according to the general procedure for amides preparation (Method A) starting from lithium (R)-4,4-difluoro-1-(3-(trifluoromethyl)benzyl)pyrrolidine-2-carboxylate (D115) (51 mg) and (S)-methyl 4-(1-aminoethyl)benzoate hydrochloride (35 mg). (Reaction time: 48 hrs; RT).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([NH:16][CH:17]=[O:18])[CH:6]=[C:7]([CH2:14]Br)[CH2:8][CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH3:2].[P:20]([O:29]C(C)C)([O:25][CH:26]([CH3:28])[CH3:27])[O:21][CH:22]([CH3:24])[CH3:23]>>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([NH:16][CH:17]=[O:18])[CH:6]=[C:7]([CH2:14][P:20]([O:25][CH:26]([CH3:28])[CH3:27])([O:21][CH:22]([CH3:24])[CH3:23])=[O:29])[CH2:8][CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH3:2]
Reactant: CCOC(=O)C(C=C(CBr)CCOC(C)=O)NC=O
Reactant: CC(C)OP(OC(C)C)OC(C)C
Product: CCOC(=O)C(C=C(CCOC(C)=O)CP(=O)(OC(C)C)OC(C)C)NC=O
Reaction time: 19 h

Procedure:
8.7 g (25 mmol) of 6-acetoxy-4-bromomethyl-2-formylamino-hex-3-enoic acid ethyl ester and 21 ml (75 mmol) of triisopropyl phosphite (90%) are heated to from 80° to 90° C. and stirred for 19 hours under a pressure of approximately 100 mbar. The excess triisopropyl phosphite is distilled off and the evaporation residue is chromatographed on 150 g of silica gel with first ethyl acetate and then ethyl acetate/ethanol (9:1) as eluants. 6-acetoxy-4-diisopropylphosphonomethyl-2-formylamino-hex-3-enoic acid ethyl ester is obtained in the form of a yellowish oil.
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH:4]([NH2:12])[CH2:3][CH2:2]1.[CH3:13][CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH3:24])[CH3:23])[C:17]=1[N:25]=[C:26]=[O:27])[CH3:15]>C(OCC)(=O)C>[CH3:15][CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH3:23])[CH3:24])[C:17]=1[NH:25][C:26]([NH:12][CH:4]1[CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:1][CH2:2][CH2:3]1)=[O:27])[CH3:13]
Reactant: NC1CCOc2ccccc2C1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)NC1CCOc2ccccc2C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 51.7 %

Procedure:
To a solution of 2,3,4,5-tetrahydro-benzoxepin-4-amine (0.95 g, 5.8 mmol) in 50 ml of ethyl acetate was added 1.18 g (5.8 mmol) of 2,6-bis(1-methylethyl)phenyl isocyanate. The resulting mixture was stirred at room temperature for 20 hours. The precipitated solid was collected by filtration, washed with ethyl acetate, and dried to yield 1.1 g of N-[2,6-bis(1-methylethyl)phenyl] -N'-(2,3,4,5-tetrahydrobenzoxepin-4-yl)urea, mp 184°-186° C.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([N:8]=[N:9][N:10]=2)[CH:5]=[CH:6][N:7]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.O=[Si]=O.[OH-].[Na+]>C(Cl)Cl.O>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:2]2[C:3]3[N:4]([N:8]=[N:9][N:10]=3)[CH:5]=[CH:6][N:7]=2)[CH2:14][CH2:13]1
Reactant: Clc1nccn2nnnc12
Reactant: CN1CCNCC1
Agent: O=[Si]=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CN1CCN(c2nccn3nnnc23)CC1
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 81.3 %

Procedure:
8-Chlorotetrazolo[1,5-a]pyrazine (100 g, 0.643 mol, 1 eq.) was suspended in methylene chloride (650 ml) and cooled to 3-7° C. under nitrogen. 1-Methylpiperazine (156 g, 1.56 mol, 2.42 eq) was added at such a rate that the temperature of the reaction mixture was maintained at 3-7° C. The mixture is stirred at approximately 10° C. for 15 minutes after which time conversion to product was ≧99%. Celite 545 (40 g) and water (260 g) were added and the pH of the suspension adjusted to 9.5-9.8 by the addition of 27% sodium hydroxide, with the temperature maintained range at 3-7° C. The suspension was filtered on a pad of Celite 545, and the filter cake washed with methylene chloride. The filtrate was separated into an organic and aqueous phase. The aqueous phase was washed with methylene chloride. The organic phases are washed twice with aqueous sodium hydroxide. The organic phases were combined, and dried over magnesium sulfate prior to addition of activated carbon (pH 8-10). The mixture was filtered on a pad of Celite 545 and the filtered cake washed with methylene chloride. The filtrate was concentrated at reduced pressure and crystallization induced by slow addition of heptane, with further concentration and seeding as necessary. The resulting crystal suspension is cooled to 10-15° C., filtered, washed with n-heptane and dried under vacuum at 27-33° C. to afford the product as a buff coloured solid (114.6 g, 81% yield).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][C:6]([N+:29]([O-:31])=[O:30])([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([C:25]([F:28])([F:27])[F:26])[CH2:21][CH2:20]3)[CH:14]=2)[CH:9]=1)[CH3:7].[OH-].[Li+].O>CO.O1CCCC1>[N+:29]([C:6]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][C@H:19]3[CH2:20][CH2:21][C@H:22]([C:25]([F:26])([F:27])[F:28])[CH2:23][CH2:24]3)[CH:14]=2)[CH:9]=1)([CH3:7])[CH2:5][CH2:4][C:3]([OH:32])=[O:2])([O-:31])=[O:30]
Reactant: COC(=O)CCC(C)(c1ccc2cc(O[C@H]3CC[C@H](C(F)(F)F)CC3)ccc2c1)[N+](=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(CCC(=O)O)(c1ccc2cc(O[C@H]3CC[C@H](C(F)(F)F)CC3)ccc2c1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-nitro-4-[6-(trans-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-pentanoic acid methyl ester (0.098 g, 0.22 mmol) in methanol (1.00 mL, Fisher) and tetrahydrofuran (1.00 mL, Acros) was added 2 M lithium hydroxide in water (1.00 mL, 2.00 mmol). The mixture was stirred at room temperature. After 2 hours, the mixture was concentrated under vacuum. The resulting product was diluted in methylene chloride and washed with 1N HCl. The combined organic phases were dried over Na2SO4, filtered and concentrated to give the product in 99 mg yield (100%).
Reaction SMILES: COC(=O)CC1C(C)=NN([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)C=1C.[C:23]([O:27][C:28](=[O:42])[CH2:29][C:30]1[C:31]([CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[N:32][NH:33][C:34]=1[CH3:35])([CH3:26])([CH3:25])[CH3:24].C(OC(=O)CC1C(CC)=NNC=1CC)(C)(C)C.C1(C(=O)CC(=O)C)CCCCC1.COC(=O)CC1C(C)=NNC=1C>>[C:23]([O:27][C:28](=[O:42])[CH2:29][C:30]1[C:31]([CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[N:32][N:33]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[C:34]=1[CH3:35])([CH3:26])([CH3:24])[CH3:25]
Reactant: COC(=O)Cc1c(C)nn(Cc2ccc([N+](=O)[O-])cc2)c1C
Reactant: Cc1[nH]nc(C2CCCCC2)c1CC(=O)OC(C)(C)C
Agent: CC(=O)CC(=O)C1CCCCC1
Agent: CCc1n[nH]c(CC)c1CC(=O)OC(C)(C)C
Agent: COC(=O)Cc1c(C)n[nH]c1C
Product: Cc1c(CC(=O)OC(C)(C)C)c(C2CCCCC2)nn1Cc1ccc([N+](=O)[O-])cc1

Procedure:
[3-Cyclohexyl-5-methyl-1-(4-nitro-benzyl)-1H-pyrazol-4-yl]-acetic acid tert-butyl ester was prepared according to the preparation of intermediate 1.1.2, using in the alkylation reaction (3-cyclohexyl-5-methyl-1H-pyrazol-4-yl)-acetic acid tert-butyl ester (preparation according to the preparation of (3,5-diethyl-1H-pyrazol-4-yl)-acetic acid tert-butyl ester, WO2007/141267, employing 1-cyclohexyl-butane-1,3-dione instead of heptane-3,5-dione) instead of (3,5-dimethyl-1H-pyrazol-4-yl)-acetic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][NH:11][CH:12]=2)=[CH:4][CH:3]=1.[CH3:13][N:14]=[C:15]=[S:16]>C(O)C>[CH3:13][NH:14][C:15]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][NH:11][CH:12]=2)=[CH:6][CH:7]=1)=[S:16]
Reactant: CN=C=S
Reactant: Nc1ccc(-c2c[nH]cn2)cc1
Solvent: CCO
Product: CNC(=S)Nc1ccc(-c2c[nH]cn2)cc1

Procedure:
A solution of 2.3 gm of 4-(4-aminophenyl)-1-H-imidazole and 1.15 gm of methyl isothiocyanate in 30 ml of ethanol was refluxed for thirty minutes and evaporated to dryness. The oily base so obtained was purified by conversion into the corresponding hydrochloride salt by bubbling gaseous hydrochloric acid in isopropanol. The desired thiourea was obtained as a white solid.
Reaction SMILES: C([O:8][CH2:9][C:10]1[N:11]([CH3:26])[C:12]([CH:23]([CH3:25])[CH3:24])=[C:13]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[N:14]=1)C1C=CC=CC=1.C(=O)([O-])O.[Na+]>Cl>[Cl:22][C:18]1[CH:17]=[C:16]([S:15][C:13]2[N:14]=[C:10]([CH2:9][OH:8])[N:11]([CH3:26])[C:12]=2[CH:23]([CH3:25])[CH3:24])[CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)c1c(Sc2cccc(Cl)c2)nc(COCc2ccccc2)n1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)c1c(Sc2cccc(Cl)c2)nc(CO)n1C
Temperature: 110 °C
Yield: 64.9 %

Procedure:
In 5.8 ml of concented hydrochloric acid was dissolved 580 mg (1.5 mmol) of 2-benzyloxymethyl-4-(3-chlorophenylthio)-5-isopropyl-1-methyl-1H-imidazole (17ab'), and the mixture was refluxed under heating at 110° C. for 6 hours. The reaction mixture was neutlized with a saturated aqueous solution of sodium hydrogen carbonate, and extracted with methylene chloride. The organic layer was washed with water and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The crude product was recrystallized from ethyl acetate-isopropyl ether to give 289 mg of the objective Compound I-38 (yield 65%). mp 105-106° C.