Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13]CC3C=CC(OC)=CC=3)[C@H:9]2[C:23]2[CH:37]=[CH:36][C:26]([O:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.[N+:38]([C:41]1[C:42]([S:47]Cl)=[N:43][CH:44]=[CH:45][CH:46]=1)([O-:40])=[O:39]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][S:47][C:42]3[C:41]([N+:38]([O-:40])=[O:39])=[CH:46][CH:45]=[CH:44][N:43]=3)[C@H:9]2[C:23]2[CH:24]=[CH:25][C:26]([O:27][CH2:28][C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])=[CH:36][CH:37]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cccnc1SCl
Reactant: COc1ccc(CS[C@H]2C(=O)N(c3ccc(Cl)cc3)[C@@H]2c2ccc(OCC(=O)OC(C)(C)C)cc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)COc1ccc([C@@H]2[C@@H](SSc3ncccc3[N+](=O)[O-])C(=O)N2c2ccc(Cl)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl (4-{(2R,3R)-1-(4-chlorophenyl)-3-[(4-methoxybenzyl)thio]-4-oxoazetidin-2-yl}phenoxy)acetate (Method 26) (0.9 g, 1.7 mmol) was dissolved in CH2Cl2 (50 mL) and given 0° C. under inert atmosphere. 3-Nitro-2-pyridinesulfenyl chloride (0.4 g, 2.0 mmol) was added and the mixture was stirred for 30 minutes at 0° C., then 30 minutes at room temperature. Concentration under reduced pressure and purification by flash-chromatography (Heptane:EtOAc 3:1 then 2:1) afforded the title compound.
Reaction SMILES: [Cl-].[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[O:14][N:13]=[C:12]([C:15]2[N:16]=[C:17]([CH:20]3[CH2:25][CH2:24][NH2+:23][CH2:22][CH2:21]3)[S:18][CH:19]=2)[CH2:11]1)=[O:3].[F:26][CH:27]([F:40])[C:28]1[CH:32]=[C:31]([CH:33]([F:35])[F:34])[N:30]([CH2:36][C:37](O)=[O:38])[N:29]=1>>[F:40][CH:27]([F:26])[C:28]1[CH:32]=[C:31]([CH:33]([F:35])[F:34])[N:30]([CH2:36][C:37]([N:23]2[CH2:24][CH2:25][CH:20]([C:17]3[S:18][CH:19]=[C:15]([C:12]4[CH2:11][CH:10]([C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=5[CH:2]=[O:3])[O:14][N:13]=4)[N:16]=3)[CH2:21][CH2:22]2)=[O:38])[N:29]=1
Reactant: O=C(O)Cn1nc(C(F)F)cc1C(F)F
Reactant: O=Cc1ccccc1C1CC(c2csc(C3CC[NH2+]CC3)n2)=NO1
Agent: [Cl-]
Product: O=Cc1ccccc1C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)F)cc4C(F)F)CC3)n2)=NO1

Procedure:
4-{4-[5-(2-Formylphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidinium chloride (433 mg) and [3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetic acid (285 mg) were reacted analogously to I-40 (step 3). This gave 2-{3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-O-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}benzaldehyde (330 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(N(CC)C(C)C)(C)C.[CH:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)=[O:17]>CN(C)C1C=CN=CC=1>[CH:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[O:23])=[CH:20][CH:19]=1)=[O:17]
Reactant: Nc1nccs1
Reactant: O=Cc1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: O=Cc1ccc(C(=O)Nc2nccs2)cc1
Yield: 54.6 %

Procedure:
In the same manner as that described in Example 2(1), a reaction was carried out using commercially available 2-aminothiazole (333 mg, 3.3 mmol), N,N-diisopropylethylamine (1.21 ml, 7.0 mmol), 4-formylbenzoyl chloride (468 mg, 2.8 mmol) and 4-(dimethylamino)pyridine (a catalytic amount) and the reaction mixture was treated according to a similar procedure to that described in Example 2(1) to afford 4-formyl-N-(2-thiazolyl)benzamide (355 mg, yield 55%) as a pale yellow solid which was recrystallized from ethyl acetate-hexane to give pale yellow powdery crystals.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]2[C:22]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])=[C:21]([O:32][CH2:33][C:34]#[C:35][CH2:36][OH:37])[N:20]=[C:19]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[N:18]=2)(=[O:15])=[O:14])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].[Br:44][C:45]1[CH:46]=[N:47][C:48](Cl)=[N:49][CH:50]=1>CN(C=O)C.C1COCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OCC)(=O)C>[C:3]([C:7]1[CH:8]=[CH:9][C:10]([S:13]([NH:16][C:17]2[C:22]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])=[C:21]([O:32][CH2:33][C:34]#[C:35][CH2:36][O:37][C:48]3[N:49]=[CH:50][C:45]([Br:44])=[CH:46][N:47]=3)[N:20]=[C:19]([N:38]3[CH2:39][CH2:40][O:41][CH2:42][CH2:43]3)[N:18]=2)(=[O:15])=[O:14])=[CH:11][CH:12]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: Clc1ncc(Br)cn1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCC#CCO
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCC#CCOc1ncc(Br)cn1
Yield: 94.5 %

Procedure:
To a suspension of 9 mg of NaH 55% dispersion in mineral oil in 4 ml of DMF:THF 1:1 was added 50 mg of 4-tert.-butyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl]-benzene sulfonamide (Example 14). After the evolution of gas had ceased, 42 mg of 5-bromo-2-chloropyrimidine was added and the mixture was stirred for 1 h at 650C before it was diluted with 50 ml of 10% aqueous citric acid and 50 ml of ethyl acetate. The organic layer was separated, washed with 50 ml of water, dried over MgSO4 and evaporated. The crude product was purified by column chromatography on silica gel eluting with hexane:ethyl acetate 3:2 to give 60 mg of 4-tert.-butyl-N-[6-(4-(5-bromo-2-pyrimidinyloxy)-2-butynyloxy)-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl]-benzene sulfonamide as a colourless foam. MS: tR=6.14 min, [M+1]+=739.18, [M−1]+=741.32.
Reaction SMILES: CN(C)CCCN=C=NCC.[ClH:12].[C:13]1([C:19]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:27][CH2:26][C@@H:25]([F:28])[C@@H:24]3[C@H:20]2[CH2:21][NH:22][CH2:23]3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:35][N:36]([CH3:51])[CH2:37][CH2:38][CH2:39][O:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[CH2:47][C:48](O)=[O:49].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>ClCCl>[ClH:12].[CH3:51][N:36]([CH3:35])[CH2:37][CH2:38][CH2:39][O:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[CH2:47][C:48]([N:22]1[CH2:21][C@@H:20]2[C@@H:24]([C@H:25]([F:28])[CH2:26][CH2:27][C:19]2([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:23]1)=[O:49]
Reactant: CN(C)CCCOc1ccccc1CC(=O)O
Reactant: F[C@@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)CCCOc1ccccc1CC(=O)N1C[C@@H]2[C@H](F)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 73.2 %

Procedure:
A solution of 0.5 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in 50 cm3 of dry dichloromethane is added over 10 minutes to a solution, cooled to +4° C., of 0.72 g of (3aR, 7R,7aR)-4,4-diphenyl-7-fluoroperhydroisoindole hydrochloride, 0.5 g of 2-(3-dimethylaminopropoxy)phenylacetic acid, 0.03 g of 1-hydroxybenzotriazole in 75 cm3 of dichloromethane, followed by 0.37 cm3 of diisopropylethylamine. The reaction mixture is stirred for 3 hours at 0° C. and then washed twice with 50 cm3 of water and twice with 50 cm3 of a saturated solution of sodium chloride. The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 21 cm3 of 0.1N hydrochloric acid, 50 cm3 of diethyl ether and 30 cm3 of water. The aqueous phase is separated and freeze-dried to give 0.85 g of (3aR, 7R,7aR)-2-([2-(3-dimethylaminopropoxy)phenyl]acetyl)-4,4-diphenyl-7-fluoroperhydroisoindole hydrochloride in the form of a white freeze-dried product.
Reaction SMILES: [C:1]([C:4]1[NH:8][C:7]([C:9]([O:11]C)=[O:10])=[C:6]([Cl:13])[CH:5]=1)(=[O:3])[CH3:2].CO.[Li+].[OH-]>C1COCC1>[C:1]([C:4]1[NH:8][C:7]([C:9]([OH:11])=[O:10])=[C:6]([Cl:13])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1[nH]c(C(C)=O)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)c(C(=O)O)[nH]1
Temperature: 60 °C
Yield: 94.6 %

Procedure:
Methyl 5-acetyl-3-chloro-1H-pyrrole-2-carboxylate (0.034 g, 0.169 mmol) was dissolved in THF (1 mL), methanol (1 mL) and 1N LiOH (1 mL). The reaction mixture was heated to 60° C. and stirred. The reaction mixture was evaporated and purification was accomplished by reverse-phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.030 g, 76%) as an impure product which was used with no further purification. LCMS: m/z 186.0 (M−1).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][C:5]([CH:6]=[O:7])=[C:4](F)[CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([O:20][CH3:21])[CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:19][C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][C:15]=2[O:20][CH3:21])[CH:3]=1
Reactant: COc1cc(F)ccc1O
Reactant: O=Cc1cc(Cl)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(F)ccc1Oc1cc(Cl)c(Cl)cc1C=O
Temperature: 70 °C
Yield: 51 %

Procedure:
Crude 4,5-dichloro-2-fluoro-benzaldehyde, 4-fluoro-2-methoxy-phenol (2.31 mL, 20.23 mmol) and K2CO3 (5.59 g, 40.46 mmol) were combined in DMF (100 mL) and heated for ˜30 min at 70° C., then at 55° C. overnight. The reaction was cooled, diluted with water (500 mL) and extracted with diethyl ether. The ether layer was dried over Na2SO4, filtered, and concentrated. Silica gel chromatography using a gradient of ethyl acetate/hexane (0-40%) provided 4,5-dichloro-2-(4-fluoro-2-methoxy-phenoxy)benzaldehyde (3.30 g, 51%) as a crystalline white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 7.93 (s, 1H), 7.35 (dd, J=8.8, 5.8 Hz, 1H), 7.19 (dd, J=10.7, 2.9 Hz, 1H), 6.92-6.85 (m, 2H), 3.78 (s, 3H) ppm.
Reaction SMILES: [S:1]1[C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=[C:2]1[C:9]([OH:11])=[O:10].[C:12](=O)([O-])[O-].[Na+].[Na+].CI>CN(C=O)C>[CH3:12][O:7][C:6]([C:5]1[S:1][C:2]([C:9]([OH:11])=[O:10])=[CH:3][CH:4]=1)=[O:8]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(C(=O)O)s1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(C(=O)O)s1
Yield: 26.3 %

Procedure:
1.72 g (10 mmol) of thiophene-2,5-dicarboxylic acid and 3.18 g (30 mmol) of sodium carbonate suspended in 25 mL of DMF were stirred with 623 μL of methyl iodide at room temperature overnight. The sodium salt of the desired product was extracted with water, and 12M of hydrochloric acid was added to the combined aqueous layer. The desired product was extracted with ethyl acetate, and the combined organic layer was washed with saturated aqueous ammonium chloride and dried over anhydrous magnesium sulfate. The desired product was purified by silica gel column chromatography to give 0.49 g of a colorless solid (yield 28%).
Reaction SMILES: [H-].[Na+].I[CH2:4][CH2:5][CH2:6][C:7]([CH3:12])([N+:9]([O-:11])=[O:10])[CH3:8].[F:13][C:14]1[CH:24]=[CH:23][C:17]2[N:18]([CH3:22])[C:19](=[O:21])[NH:20][C:16]=2[CH:15]=1>CN(C=O)C>[F:13][C:14]1[CH:24]=[CH:23][C:17]2[N:18]([CH3:22])[C:19](=[O:21])[N:20]([CH2:4][CH2:5][CH2:6][C:7]([CH3:12])([N+:9]([O-:11])=[O:10])[CH3:8])[C:16]=2[CH:15]=1
Reactant: Cn1c(=O)[nH]c2cc(F)ccc21
Reactant: CC(C)(CCCI)[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CCCC(C)(C)[N+](=O)[O-])c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
First of all 0.624 g (13.9 mmol) 60% sodium hydride and then, with cooling, 4.6 g (17.8 mmol) 1-iodo-4-methyl-4-nitro-pentane in 10 mL DMF are added to a solution of 2.1 g (12.6 mmol) 5-fluoro-1-methyl-1,3-dihydro-benzimidazol-2-one in DMF. The reaction mixture is stirred overnight at ambient temperature, then poured onto water and extracted with diethyl ether. The organic phases are evaporated down and the residue is recrystallised from isopropylether. Yield: 1.8 g (48%); mass spectroscopy [M+H]+=296.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14](Cl)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1)=[O:5])[CH3:2].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([O:24][C:21]2[CH:22]=[CH:23][C:18]([Br:17])=[CH:19][CH:20]=2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(Cl)c2ccccc2n1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(Oc2ccc(Br)cc2)c2ccccc2n1
Temperature: 60 °C
Yield: 42.3 %

Procedure:
To a solution of 4-chloro-quinoline-2-carboxylic acid ethyl ester (910 mg, 3.87 mmol) in DMF (15 ml) was added 4-bromophenol (737 mg, 4.26 mmol), followed by Cs2CO3 (1.89 g, 5.81 mmol). The reaction mixture was then heated to 60° C. for 16 hrs. On the second day the mixture was cooled to r.t. and concentrated down. The residue was partitioned between EtOAc (10 ml) and water (20 ml). The EtOAc layer was separated, dried over MgSO4, filtrated, concentrated, and purified by Biotage with EtOAc/Hexane (15%, 4 CV) to afford 4-(4-bromo-phenoxy)-quinoline-2-carboxylic acid ethyl ester (609 mg, 42.3%). 1H NMR (300 MHz, DMSO-d6): δ 8.36 (m, 1H), 8.18 (m, 1H), 7.93 (m, 1H), 7.80 (m, 1H). 7.75 (m, 2H), 7.34 (m, 2H), 7.14 (s, 1H), 4.34 (m, 2H), 1.30 (m, 3H). LC-MS m/z=373 [C18H14BrNO3+H]+.
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12][CH2:13][CH:14]([NH2:18])[CH:15]([CH3:17])[CH3:16])=[CH:11][C:6]=2[O:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][CH:20]([CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:21](O)=[O:22].Cl.C(N=C=NCCCN(C)C)C.O>CN(C1C=CN=CC=1)C.ClCCl>[CH3:19][CH:20]([CH2:24][NH:25][C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[C:21]([NH:18][CH:14]([CH:15]([CH3:16])[CH3:17])[CH2:13][CH2:12][C:10]1[CH:9]=[CH:8][C:7]2[O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]=2[CH:11]=1)=[O:22]
Reactant: CC(C)C(N)CCc1ccc2c(c1)OCCCO2
Reactant: CC(CNC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC(CNC(=O)OC(C)(C)C)C(=O)NC(CCc1ccc2c(c1)OCCCO2)C(C)C
Reaction time: 8 h

Procedure:
50 mg of (±)-1-(3,4-dihydro-2H-1,5-benzodioxepine-7-yl)-4-methylpentan-3-ylamine was mixed with of (±)-2-Methyl-3-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid (25 mg), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (53 mg), and DMAP (33 mg) in dichloromethane (5 ml) and stirred overnight. Water (5 ml) was added, and the reaction mixture was extracted with ethyl acetate (5 ml three times). The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by flash chromatography on silica (20% ethyl acetate in hexane) yielded a resin: MS (m+1)=435.6.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16]C)=[O:15])=[CH:12][N:11]=[CH:10][C:9]=2[F:18])=[C:4]([F:19])[CH:3]=1.[Li+].[OH-]>O1CCCC1.CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][N:11]=[CH:10][C:9]=2[F:18])=[C:4]([F:19])[CH:3]=1
Reactant: COC(=O)c1cncc(F)c1-c1ccc(Cl)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cncc(F)c1-c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 93 %

Procedure:
To the solution of methyl 4-(4-chloro-2-fluorophenyl)-5-fluoronicotinate (600 mg, 2.115 mmol) in tetrahydrofuran (2.5 mL), MeOH (2.5 mL) and water (2.5 mL) was added LiOH (50.7 mg, 2.115 mmol) and the mixture was stirred at rt for 12 h. The volatiles were removed and the residue was diluted with water. The pH was adjusted to 4 with 1.5N HCl. The product was extracted with ethyl acetate (2×5 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford 4-(4-chloro-2-fluorophenyl)-5-fluoronicotinic acid (530 mg, 1.966 mmol, 93% crude yield) the pale brown solid. The material was carried on without further purification. LC/MS (ESI) m/e 269.9 [(M+H)+, calcd for C12H7ClF2NO2 270.0]; LC/MS retention time (method D): tR=0.88 min.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1.[BH4-].[Li+].Cl>O1CCCC1>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][OH:2])=[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=2)[CH:6]=1
Reactant: COC(=O)c1ccc(Cl)cc1Oc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(Cl)cc1Oc1cccc(C(F)(F)F)c1
Temperature: 0 °C

Procedure:
A solution of 103 g. of 4-chloro-2-(3-trifluoromethyl-phenoxy)-benzoic acid methyl ester in 400 ml. of tetrahydrofuran is added dropwise at reflux over a period of 30 minutes to a solution of 16.2 g. of lithium borohydride in 280 ml. of absolute tetrahydrofuran. The mixture is then cooled to 0° C. and slowly added dropwise to 400 ml. of 3-N aqueous hydrochloric acid. After the addition of 500 ml. of water, the mixture is extracted twice with ether. After evaporation of the ether, there is obtained 4-chloro-2-(3-trifluoromethyl-phenoxy)-benzyl alcohol in the form of an oil.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH:4]([O:26][CH:27]([CH3:29])[CH3:28])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:17][CH:16]=2)=[CH:8][CH:7]=1.[OH-].[Li+]>O1CCCC1.O>[CH:27]([O:26][CH:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:19][CH:20]=2)=[CH:8][CH:7]=1)[C:3]([OH:30])=[O:2])([CH3:28])[CH3:29]
Reactant: COC(=O)C(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)OC(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)OC(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
2-Isopropoxy-3-[4-(2-{4-methylsulfonyloxyphenyl}ethoxy)phenyl]propanoic acid methyl ester (0.1 g; 0.229 mmole) was dissolved in tetrahydrofuran(2 ml). Lithium hydroxide (0.006 g; 0.25 mmole) in water (2 ml) was added. The reaction mixture was stirred at room temperature for 8 hours. Tetrahydrofuran was evaporated. The remaining water solution was extracted with diethyl ether. The water solution was then acidified with hydorchloric acid (1%) to pH˜2 and extracted twice with ethyl acetate. The organic phases were combined and dried with magnesium sulfate. The solvent was evaporated and 0.085 g (88% yield) of 2-isopropoxy-3-[4-(2-{4-methylsulfonyloxyphenyl}ethoxy)phenyl]propanoic acid was obtained.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@H:13]([O:23]CC2C=CC=CC=2)[C@@H:12]([CH2:31][O:32]CC2C=CC=CC=2)[O:11][C@:10]21[C:43]1[CH:44]=[C:45]([CH2:49][C:50]3[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=3)[C:46]([Cl:48])=[CH:47][C:42]=1[O:41][C:40]2=[O:58])C1C=CC=CC=1.ClC1C=CC=CC=1Cl.[H][H]>CO.C1COCC1.[OH-].[OH-].[Pd+2]>[Cl:48][C:46]1[C:45]([CH2:49][C:50]2[CH:51]=[CH:52][C:53]([CH2:56][CH3:57])=[CH:54][CH:55]=2)=[CH:44][C:43]2[C@@:10]3([C:40](=[O:58])[O:41][C:42]=2[CH:47]=1)[C@H:9]([OH:8])[C@@H:14]([OH:15])[C@H:13]([OH:23])[C@@H:12]([CH2:31][OH:32])[O:11]3
Reactant: [H][H]
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)OC(=O)[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: Clc1ccccc1Cl
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc3c(cc2Cl)OC(=O)[C@]32O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Yield: 80.3 %

Procedure:
To a solution of 48 (5 mg, 6.3 μmol) in a mixture of MeOH (1.5 mL) and THF (0.5 mL) were added Pd(OH)2/C (10 mg) and 1,2-dichlorobenzene (12 μL). A balloon of hydrogen gas was attached for 0.5 h with vigorous stirring. LCMS indicated that de-protection was complete. The reaction mixture was filtered through Celite, concentrated to a residue, and purified by passing through silica gel in a pipette (5% MeOH in DCM) to give 49 (2.2 mg, 80%). 1H NMR (300 MHz, CD3OD) δ 7.35 (s, 1H), 7.20 (s, 1H), 7.09 (s, 4H), 4.24-4.29 (m, 1H), 4.07 (t, J=10.5 Hz, 1H), 4.06 (s, 2H), 3.81 (dd, J=2.1, 12.0 Hz, 1H), 3.61-3.71 (m, 2H), 3.43 (t, J=9.9 Hz, 1H), 2.59 (q, J=7.5 Hz, 2H), 1.20 (t, J=7.5 Hz, 3H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[OH:11][C@H:12]1[CH2:33][CH2:32][C@@:31]2([CH3:34])[CH:14]([CH2:15][CH2:16][C:17]3[C:18]4[C@:27]([CH3:35])([CH2:28][CH2:29][C:30]=32)[C@@H:21]([C@@H:22]([CH3:26])[CH2:23][C:24]#N)[CH2:20][CH:19]=4)[C:13]1([CH3:37])[CH3:36].S(=O)(=O)(O)[OH:39]>C1(C)C=CC=CC=1>[OH:11][C@H:12]1[CH2:33][CH2:32][C@@:31]2([CH3:34])[CH:14]([CH2:15][CH2:16][C:17]3[C:18]4[C@:27]([CH3:35])([CH2:28][CH2:29][C:30]=32)[C@@H:21]([C@@H:22]([CH3:26])[CH2:23][CH:24]=[O:39])[CH2:20][CH:19]=4)[C:13]1([CH3:37])[CH3:36]
Reactant: O=S(=O)(O)O
Reactant: C[C@@H](CC#N)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)C1CC3
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: C[C@@H](CC=O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)C1CC3
Reaction time: 2 h

Procedure:
16 ml diisobutylaluminiumhydride (20% in toluene) were added dropwise to a solution of 920 mg (20S)-3β-hydroxy-4,4,20-trimethyl-pregna-8,14-dien-21-carbonitril in 60 ml toluene at a temperature of −72° C. The mixture was stirred for 2 h at the same temperature, poured into 2N sulfuric acid, extracted with ethyl acetate, washed with 2N sulfuric acid and then washed with a half saturated solution of sodium chloride. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 750 mg (20S)-3β-hydroxy-4,4,20-trimethyl-pregna-8,14-dien-21-carbaldehyde as a white solid, which was used without further purification.
Reaction SMILES: Cl.[F:2][CH:3]([F:12])[C@H:4]1[CH2:9][NH:8][CH2:7][C@@H:6]([OH:10])[C@@H:5]1[OH:11].C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[CH2:20][CH2:21][CH3:22]>CN(C=O)C>[CH2:19]([N:8]1[CH2:9][CH:4]([CH:3]([F:2])[F:12])[CH:5]([OH:11])[CH:6]([OH:10])[CH2:7]1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCBr
Reactant: O[C@H]1[C@H](O)CNC[C@@H]1C(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCN1CC(O)C(O)C(C(F)F)C1
Temperature: 60 °C
Yield: 80 %

Procedure:
A mixture of 6 (0.30 g, 1.4 mmol), K2CO3 (0.48 g, 3.5 mmol) and BuBr (0.20 g, 1.4 mmol) was combined in DMF (10 mL) and heated overnight at 60° C. The solvent was evaporated in vacuo and the residue was dissolved in EtOAc, washed with water and then brine and dried over Na2SO4. After filtration, the filtrate was evaporated in vacuo to give the crude product which was purified by chromatography (CH2Cl2/(9:1) MeOH/NH4OH) to give the title compound (0.25 g, 80%) as a colorless syrup. MH+=224. 1H NMR (DMSO-d6) 6.2 (t, 1H, J=57 Hz), 5.13 (d, 1H, ex), 4.91 (d, 1H, ex), 3.3 (m, 1H), 3.1 (m, 1H), 2.9 (m, 2H), 2.3 (m, 2H), 1.95 (m, 2H), 1.75 (t, 1H), 1.2-1.5 (2m, 4H), 0.9 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([CH2:12][C@@H:13]([NH:38][C:39]([N:41]2[CH2:46][CH2:45][CH:44]([N:47]3[CH2:53][CH2:52][C:51]4[CH:54]=[CH:55][CH:56]=[CH:57][C:50]=4[NH:49][C:48]3=[O:58])[CH2:43][CH2:42]2)=[O:40])[C:14]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:27][CH2:26][N:25](C(OCC4C=CC=CC=4)=O)[CH2:24][CH2:23]3)[CH2:18][CH2:17]2)=[O:15])=[CH:4][C:3]=1[Cl:59]>[Ni].CO>[NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([CH2:12][C@@H:13]([NH:38][C:39]([N:41]2[CH2:46][CH2:45][CH:44]([N:47]3[CH2:53][CH2:52][C:51]4[CH:54]=[CH:55][CH:56]=[CH:57][C:50]=4[NH:49][C:48]3=[O:58])[CH2:43][CH2:42]2)=[O:40])[C:14](=[O:15])[N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]3)[CH2:18][CH2:17]2)=[CH:4][C:3]=1[Cl:59]
Reactant: Nc1c(Cl)cc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(C(=O)OCc4ccccc4)CC3)CC2)cc1C(F)(F)F
Agent: [Ni]
Solvent: CO
Product: Nc1c(Cl)cc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCNCC3)CC2)cc1C(F)(F)F
Reaction time: 12 h

Procedure:
A solution of 600 mg (0.72 mmol) benzyl 4-[1-((R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-carbonyl]-amino}-propionyl)-piperidin-4-yl]-piperazin-1-carboxylate (Example 7.4) and 200 mg Raney nickel in 50 mL MeOH were hydrogenated at RT and 50 psi of H2 for 12 h. The catalyst was filtered off, the solvent evaporated down i.vac. and the residue purified by HPLC.