Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2OCC#N)[C:5]([Cl:19])=[CH:4][N:3]=1.[C:20]([N:23]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][CH2:26][C:25]2[CH:32]=[C:33]([NH2:36])[CH:34]=[CH:35][C:24]1=2)(=[O:22])[CH3:21]>>[C:20]([N:23]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][CH2:26][C:25]2[CH:32]=[C:33]([NH:36][C:2]3[N:7]=[C:6]([NH:8][C:9]4[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=4[CH2:6][CH2:5][C:4]#[N:3])[C:5]([Cl:19])=[CH:4][N:3]=3)[CH:34]=[CH:35][C:24]1=2)(=[O:22])[CH3:21]
Reactant: N#CCOc1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CC(=O)N1CCC(=O)NCc2cc(N)ccc21
Product: CC(=O)N1CCC(=O)NCc2cc(Nc3ncc(Cl)c(Nc4ccccc4CCC#N)n3)ccc21

Procedure:
Title compound was prepared from [2-(2,5-Dichloro-pyrimidin-4-ylamino)-phenoxy]-acetonitrile and Acetyl-8-amino-2,3,5,6-tetrahydro-1H-benzo[b][1,5]diazocin-4-one in an analogous manner to Example 1221d. (120° C., 40 min). Obtained 82 mg (55%) as a white foam. HPLC purity: 96%, LCMS 490.16 (M+H), 1H-NMR (CDCl3, 400 MHz) δ: 8.10 (s, 1H), 7.59 (s, 1H), 7.51-7.45 (m, 5H), 7.08-7.03 (m, 1H), 6.99-6.94 (m, 2H), 6.09 (bt, 1H), 4.81-4.76 (m, 1H), 4.22-4.18 (m, 1H), 3.45 3.41 (m, 1H), 3.01 (t, J=7.1 Hz, 2H), 3.00-2.97 (m, 1H), 2.72-2.63 (m, 3H), 2.58-2.53 (m, 1H), 1.76 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([Br:9])[S:4][C:3]=1[C:10]([O:12]CC)=[O:11].O1CCCC1.CO.[OH-].[Na+].O.Cl>>[Br:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([Br:9])[S:4][C:3]=1[C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)c1sc(Br)c(C#N)c1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1c(Br)sc(C(=O)O)c1Br
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 99.3 %

Procedure:
Ethyl 3,5-dibromo-4-cyanothiophene-2-carboxylate (6.54 g, 0.0193 mol) was dissolved in a mixture of tetrahydrofuran (40.0 mL, 0.493 mol) and methanol (20.0 mL, 0.494 mol), then sodium hydroxide in water (1.0 M, 60.0 mL, 0.0600 mol) was added at 0° C. The resulting solution was warmed to rt and stirred for 20 min. The mixture was neutralized with hydrochloric acid in water (4.0 M, 20 mL, 0.080 mol) and extracted with 80 mL DCM twice. The combined organic layers were washed with 30 mL water, evaporated in vacuo to yield a white solid product (5.96 g, yield 99.4%). LCMS: (FA) ES−, 307, 309, 311.
Reaction SMILES: ClC1C=C(Cl)C=CC=1CC(O)=O.COC1C=CC(C(OC)=O)=CC=1.[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[C:33]1[CH:34]=[C:35]([C:46](O)=[O:47])[S:36][C:37]=1[C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1.[C:49]1([C:55]2([C:61]([NH2:63])=[O:62])[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl.CCN(CC)CC>[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[C:33]1[CH:34]=[C:35]([C:46]([N:58]2[CH2:57][CH2:56][C:55]([C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)([C:61]([NH2:63])=[O:62])[CH2:60][CH2:59]2)=[O:47])[S:36][C:37]=1[C:38]1[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=1
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: COc1ccc(-c2sc(C(=O)O)cc2-c2ccc(Cl)cc2Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: COC(=O)c1ccc(OC)cc1
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2sc(C(=O)N3CCC(C(N)=O)(c4ccccc4)CC3)cc2-c2ccc(Cl)cc2Cl)cc1
Reaction time: 8 h
Yield: 90 %

Procedure:
4-(2,4-dichlorophenyl)-5-(4-methoxyphenyethiophene-2-carboxylic acid is prepared, according to the procedure used in stages 1A)-1E), from (2,4-dichlorophenyl)acetic acid and methyl 4-methoxybenzoate. 3.8 g of 4-(2,4-dichlorophenyl)-5-(4-methoxyphenyl)thiophene-2-carboxylic acid, 2.53 g of 4-phenylpiperidine-4-carboxamide (preparation 2), 0.72 ml of Et3N and 3.53 g of TBTU are added at AT to 100 ml of CH2Cl2. The mixture is stirred overnight. It is evaporated to dryness, water is added and the compound obtained is extracted with ethyl acetate. The organic phase is dried and evaporated to dryness. After crystallizing, washing with ethyl ether, filtering and then drying, 5.1 g of the expected compound are obtained.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH3:16][O:17][C:18](=[O:36])[C@H:19]([CH2:28][C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1)[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].N1C=CC=CC=1>C(Cl)Cl.O>[CH3:16][O:17][C:18](=[O:36])[C@H:19]([CH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[CH:33][CH:34]=1)[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)OC(C)(C)C
Yield: 90.8 %

Procedure:
Trifluoromethanesulphonic anhydride (4 ml, 23 mmol) was added to a mixture of N-Boc tyrosine methyl ester (5.9 g, 20 mmol) and pyridine (8 ml, 100 mmol) in DCM (30 ml) at 0°. After 30 min the reaction mixture was diluted with water (60 ml) and DCM (100 ml) and washed with aqueous NaOH (0.5M, 50 ml), water (60 ml), citric acid (10% solution, 2×75 ml) and water (60 ml), dried (Na2SO4) and evaporated in vacuo. Purification by column chromatography (SiO2; EtOAc/hexane, 2:1) gave the title compound (7.76 g, 91%) as a colourless oil which solidified on standing. δH (CDCl3) 7.25-7.18 (4 H, m, ArH), 5.01 (1 H, brd, CONH), 4.60 (1 H, brq, CHα), 3.71 (3 H, s, CO2Me), 3.17 (1 H, dd, J 13.8, 5.8 Hz, CHAHBAr), 3.03 (1 H, dd, J 13.6, 6.3 Hz, CHAHBAr) and 1.41 (9 H, s, tBu); m/z (ESI, 15 V) 428 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:53]1([C:59]#[CH:60])[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>C(#N)C>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([C:60]#[C:59][C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[CH:3]=3)[N:7]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[N:6]=2)=[CH:18][CH:19]=1
Reactant: Fc1ccc(-c2nn(C3CCCCO3)c3ccc(Br)cc23)cc1
Reactant: C#Cc1ccccc1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Fc1ccc(-c2nn(C3CCCCO3)c3ccc(C#Cc4ccccc4)cc23)cc1
Yield: 32 %

Procedure:
A mixture of 5-bromo-3-(4-fluorophenyl)-1-(tetrahydropyran-2-yl)-1H-indazole (0.375 g, 1.0 mmol), triethylamine (1.5 mL), tri-o-tolylphosphine (0.122 g, 0.4 mmol), tri(dibenzylideneacetone)dipalladium(0) (0.092 g, 0.1 mmol) and phenylacetylene (0.204 g, 2.0 mmol) in dried acetonitrile (10 mL) under nitrogen was heated to reflux overnight. It was quenched with water and extracted with ethyl acetate. The extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was then purified by chromatography (SiO2, 10–15% ethyl acetate/hexane) to provide the title compound (0.127 g, 32% yield). 1H NMR (CDCl3) δ 8.16 (t, 1H), 7.93–7.97 (m, 2H), 7.54–7.64 (m, 4H), 7.34–7.37 (m, 3H), 7.21 (t, 2H) 5.77 (dd, 1H), 4.08 (m, 1H), 3.79 (m, 1H), 2.62 (m, 1H), 2.11–2.21 (m, 2H), 1.57–1.83 (m, 3H); ES-MS (m/z) 397 [M+1]+.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH:9]1[C:15](=[O:20])N(OC)C)=[O:7])([CH3:4])[CH3:3].[Cl:21][C:22]1[CH:23]=[C:24]([Cl:31])[C:25]2[O:29][CH:28]=[CH:27][C:26]=2[CH:30]=1>>[C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH:9]1[C:15]([C:28]1[O:29][C:25]2[C:24]([Cl:31])=[CH:23][C:22]([Cl:21])=[CH:30][C:26]=2[CH:27]=1)=[O:20])=[O:7])([CH3:1])([CH3:3])[CH3:4]
Reactant: Clc1cc(Cl)c2occc2c1
Reactant: CON(C)C(=O)C1CN(C)CCN1C(=O)OC(C)(C)C
Product: CN1CCN(C(=O)OC(C)(C)C)C(C(=O)c2cc3cc(Cl)cc(Cl)c3o2)C1

Procedure:
The title compound (0.94 g) was prepared from (RS)-2-(methoxy-methyl-carbamoyl)-4-methyl-piperazine-1-carboxylic acid dimethyl-ethyl ester, D54 (1.00 g) and 5,7-dichloro-benzofuran (0.65 g, FP1.537.206) using the method of Description 2.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:19]=[C:18]3[C:12]([CH2:13][CH2:14][NH:15][CH2:16][CH2:17]3)=[N:11]2)=[CH:6][CH:5]=1.[CH3:22][CH:23]([CH3:26])[CH:24]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C.CO>[CH3:1][N:2]([CH3:21])[C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:19]=[C:18]3[C:12]([CH2:13][CH2:14][N:15]([CH2:22][CH:23]([CH3:26])[CH3:24])[CH2:16][CH2:17]3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: CN(C)C(=O)c1ccc(-n2cc3c(n2)CCNCC3)cc1
Reactant: CC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)CN1CCc2cn(-c3ccc(C(=O)N(C)C)cc3)nc2CC1
Temperature: 25 °C

Procedure:
A solution of N,N-dimethyl-4-(5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)benzamide (24.0 mg, 0.085 mmol) (may be prepared as described in Description 42) in dichloromethane (2 ml) was treated with 2-methylpropanal (16.0 μl, 0.17 mmol) and acetic acid (1 drop) and stirred at room temperature. Sodium triacetoxyborohydride (36.0 mg, 0.17 mmol) was added and the mixture was stirred at room temperature for approximately 50 hours. The mixture was diluted with methanol and passed down a SCX cartridge eluting with methanol and then a 2M solution of ammonia in methanol. The basic fractions were combined and evaporated to afford the title compound (E1); MS (ES+) m/e 357 [M+NH3]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[CH3:12][CH:13]([OH:16])[CH:14]=[CH2:15].C(=O)(O)[O-].[Na+]>CN1CCCC1=O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[F:1][C:2]1[CH:3]=[C:4]([CH2:15][CH2:14][C:13](=[O:16])[CH3:12])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1
Reactant: Fc1cc(Br)c2occc2c1
Reactant: C=CC(C)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(=O)CCc1cc(F)cc2ccoc12
Temperature: 140 °C
Yield: 76.1 %

Procedure:
Nitrogen was bubbled through a mixture of 1.0 gm (4.65 mMol) 5-fluoro-7-bromobenzofuran, 0.61 mL (6.98 mMol) 3-buten-2-ol, 0.057 gm (0.186 mMol) tri(o-tolyl)phosphine, and 0.47 gm (5.58 mmol) sodium bicarbonate in 35 mL N-methylpyrrolidinone for 10 minutes. To the mixture were then added 0.021 gm (0.093 mMol) palladium(II) acetate and the reaction mixture was heated to 140° C. for 3 hours. The reaction mixture was cooled to room temperature and diluted with 500 mL ethyl acetate. The organic phase was washed sequentially with three 500 mL portions of water and 500 mL saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with a gradient of hexane containing from 0–20% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 0.73 gm (76%) 4-(5-fluorobenzofur-7-yl)-2-butanone as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[NH:7][OH:8])([CH3:4])([CH3:3])[CH3:2].[CH:10]1[CH2:15][CH2:14][CH:13]=[CH:12][CH:11]=1>CO.C(Cl)Cl>[CH:12]12[CH2:13][CH2:14][CH:15]([CH:10]=[CH:11]1)[O:8][N:7]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:9]
Reactant: CC(C)(C)OC(=O)NO
Reactant: C1=CCCC=C1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1OC2C=CC1CC2
Temperature: 37 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
Solid N-hydroxycarbamic acid tert-butyl ester (100.19 g, 752.3 mmol) was added to a slurry of NaIO4 (168.68 g, 788.6 mmol), 1,3-cyclohexadiene (86.0 mL, 902 mmol) and 50% MeOH/CH2Cl2 (3 L) cooled in an ice bath. The ice bath was removed after the addition. After 2 h, a warm (37° C.) water bath was installed for 5 min to raise the temperature from 17° C. to 24° C., at which point the bath was removed. The mixture thickened from a turbid solution to a white slurry, and the temperature climbed over 50 minutes to a peak of 40° C. before dropping slowly. Analysis by TLC (50% EtOAc/hexanes) at the temperature peak indicated the reaction was all but complete, and when it had cooled to room temperature the mixture was filtered and rinsed with EtOAc (3×175 mL). The filtrate was concentrated in vacuo to a cloudy oil which was partitioned between EtOAc (700 mL) and satd NaHSO3 (400 mL). Organic layer was extracted with satd NaHSO3 (200 mL), and the combined aqueous layers were extracted with EtOAc (100 mL). The combined organic layers were washed with H2O (100 mL) and satd NaCl (100 mL), and were then dried (Na2SO4) and concentrated to provide 146.80 g (92%) of amber oil.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=2)[O:5][CH2:4][C@H:3]1[OH:13].C[C@]1(C(O)=O)C(C)(C)[C@@H](C(O)=O)CC1.C(#N)C>O>[NH2:1][C@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=2)[O:5][CH2:4][C@@H:3]1[OH:13]
Reactant: N[C@@H]1c2cc(Br)ccc2OC[C@H]1O
Agent: CC1(C)[C@@H](C(=O)O)CC[C@@]1(C)C(=O)O
Solvent: O
Solvent: CC#N
Product: N[C@H]1c2cc(Br)ccc2OC[C@@H]1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.5 %

Procedure:
Heat a mixture of racemic-trans-4-amino-6-bromochroman-3-ol (21.1 g, 86.4 mmol), D-(+)-camphoric acid (17.3 g, 86.4 mmol), acetonitrile (633 mL) and water (47.6 mL) to 70-75° C. and stir for 10 min. The solution is allowed to cool to ambient temperature over 4 hr. After 24 hr. at ambient temperature, the mixture is filtered. Rinse the solids with 7% H2O in acetonitrile (2×20 mL). Heat the filtrate to 50° C. and add 1N NaOH (216.1 mL). Concentrate the resulting mixture under reduced pressure to remove the acetonitrile. Add H2O (211 mL) and heat the solution to 70° C. Cool to ambient temperature and collect the precipitate by filtration. Wash with water (25 mL) and vacuum dry at 50° C. overnight to obtain the title compound as an off-white solid (9.8 g, 46.4% of 50% theoretical weight, 98.7% ee).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27](O)=[O:28])[CH:5]=[CH:6][CH:7]=1.[CH3:30][C:31]([CH3:36])([CH3:35])[CH2:32][CH2:33][NH2:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:30][C:31]([CH3:36])([CH3:35])[CH2:32][CH2:33][NH:34][C:27]([CH:9]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:24])([CH3:26])[CH3:25])[NH:10]1)=[O:28]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Reactant: CC(C)(C)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CCNC(=O)C1NC(CC(C)(C)C)C(C#N)(c2ccc(Cl)cc2)C1c1cccc(Cl)c1
Yield: 29.5 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.2 mmol) prepared in Example 1d was reacted with 3,3-dimethylbutylamine (30.36 mg, 0.3 mmol), HATU (76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)pyrrolidine-2-carboxylic acid (3,3-dimethyl-butyl)-amide (30.4 mg, 29.5%).
Reaction SMILES: [C:1]1([CH:7](O)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([OH:13])(=[S:12])[CH3:11]>[I-].[Zn+2].[I-].ClCCl>[C:1]1([CH:7]([S:12][C:10](=[O:13])[CH3:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(O)=S
Reactant: CC(O)c1ccccc1
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC(=O)SC(C)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.7 %

Procedure:
In a synthesis carried our according to Gauthier, Bourdon, Young, Tetrahedron Lett., 27(1), 15 (1986), at room temperature, 16.3 g of zinc iodide, 100 mL of dichloromethane and 12.5 g of 1-Phenyl-1-ethylalcohol are added to a 250 ml round-bottom flask. To this suspension 9.52 g of thioacetic acid is added. The mixture is stirred for 16 hours at room temperature. The reaction mixture is extracted with dichloromethane. The organic layer is washed with brine, dried over magnesium sulphate, filtered and concentrated to give 18.2 g of a yellow liquid which is purified by chromatography on silica gel.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH2:5][NH:6][C:7](=[O:30])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:22][C:23]2[CH:28]=[CH:27][C:26](Br)=[CH:25][CH:24]=2)[CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:10][CH:9]=1.[C:32]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33]>>[C:32]([C:36]1[CH:41]=[CH:40][C:39]([C:26]2[CH:25]=[CH:24][C:23]([O:22][CH:14]([C:11]3[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:31])=[O:30])=[CH:13][CH:12]=3)[CH2:15][CH2:16][CH2:17][C:18]([F:19])([F:21])[F:20])=[CH:28][CH:27]=2)=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33]
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCCC(F)(F)F)Oc2ccc(Br)cc2)cc1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: CC(C)(C)c1ccc(-c2ccc(OC(CCCC(F)(F)F)c3ccc(C(=O)NCCC(=O)O)cc3)cc2)cc1

Procedure:
The title compounds are prepared in a manner substantially similar to Example 128 starting from 3-{4-[1-(4-bromo-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-propionic acid methyl ester and 4-tert-butyl phenyl boronic acid. Isomer 1 MS: 540.3 [M−H]−; Isomer 2 MS: 540.3 [M−H]−.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1.[CH3:11][O:12][CH2:13]Cl>O1CCCC1.ClCCl>[CH3:11][O:12][CH2:13][O:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1
Reactant: COC(=O)c1cc(O)no1
Reactant: COCCl
Solvent: ClCCl
Solvent: C1CCOC1
Product: COCOc1cc(C(=O)OC)on1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
A solution of 2.0 g (14.0 mmol) of methyl 3-hydroxy-5-isoxazole carboxylate and 29.2 ml (16.8 mmol) of N,N-diisopropylethylamino in 20 ml of tetrahydrofuran was treated with 1.27 ml of chloromethyl methyl ether. After being stirred at ambient temperature for 2 h, the solution was diluted with dichloromethane, washed with water, dried over MgSO4, and concentrated in vacuo. Silica gel chromatography of the residue using 10% methanol in dichloromethane provided 129.6 mg (78%) of the desired compound as a white solid. 1H NMR (CDCl3) δ3.57 (s, 3H), 3.96 (s, 3H), 5.37 (s, 2H), 6.64 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:19])[CH2:9][C:10]2[NH:14][C:13]3[CH2:15][CH2:16][CH2:17][CH2:18][C:12]=3[N:11]=2)=[CH:4][CH:3]=1.C[O-].[Na+].[C:23](OC)(=[O:26])[C:24]#[CH:25]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:9]2[CH:25]=[CH:24][C:23](=[O:26])[N:14]3[C:13]4[CH2:15][CH2:16][CH2:17][CH2:18][C:12]=4[NH:11][C:10]=23)=[O:19])=[CH:4][CH:3]=1
Reactant: O=C(Cc1nc2c([nH]1)CCCC2)c1ccc(F)cc1
Reactant: C#CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Product: O=C(c1ccc(F)cc1)c1ccc(=O)n2c3c([nH]c12)CCCC3

Procedure:
The compound is prepared as described in example 20 with 450 mg (1.74 mmol) of 1-(4-Fluorophenyl)-2-(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)ethanone (example XXXXIV), 188.2 mg (3.84 mmol) of sodium methylate and 146.5 mg (1.74 mmol) methyl propiolate.
Reaction SMILES: C[Si](C#C[Si](C)(C)C)(C)C.C1(CC(Cl)=O)CCCCC1.[CH:21]1([CH2:27][C:28](=[O:31])[C:29]#[CH:30])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.[C@@H]12CC(C1(C)C)CC(B1C3CCCC1CCC3)C2C>>[CH:21]1([CH2:27][C@H:28]([OH:31])[C:29]#[CH:30])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C#CC(=O)CC1CCCCC1
Agent: CC1C(B2C3CCCC2CCC3)CC2C[C@@H]1C2(C)C
Agent: C[Si](C)(C)C#C[Si](C)(C)C
Agent: O=C(Cl)CC1CCCCC1
Product: C#C[C@@H](O)CC1CCCCC1

Procedure:
As directed by D. R. M. Walton and F. Waugh, J. Organomet. Chem. 37, 45 (1972), bis(trimethylsilyl)acetylene is acylated with cyclohexylacetic acid chloride and hydrolysed with aqueous/methanolic borax solution to 1-cyclohexyl-3-butyn-2-one. Reduction with (S)-B-(3-pinanyl)-9-borabicyclo[3.3.1]nonane ((S)-Alpine-Borane®, Aldrich, 88% ee) as directed by M. M Midland et al., Tetrahedron 40, 1371 (1984) yields 1-cyclohexyl-3-butyn-2(S)-ol.
Reaction SMILES: Br[C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH2:11]([Mg]Cl)[C:12]([CH3:15])([CH3:14])[CH3:13]>C1COCC1.Cl[Ni](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>[CH2:11]([C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: BrC1=Cc2ccccc2C1
Reactant: CC(C)(C)C[Mg]Cl
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)CC1=Cc2ccccc2C1
Reaction time: 8 h

Procedure:
To a mixture of 2-bromoindene (7.5 g, 39 mmol) and 2.5 g of NiCl2(PPh3)2 in 150 mL of THF was added over 1 hour 50 mL of neopentyl magnesium chloride (1.0 M in THF; 50 mmol). The mixture was stirred overnight and then quenched by adding 150 mL of 1.0 M aqueous hydrochloric acid. The product was isolated and purified (hexanes/silica) as for 2-benzyl-indene. Yield: 4.75 g, 66 percent
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]1([CH2:24][O:25][C:26]2[C:31]([F:32])=[CH:30][C:29](Br)=[CH:28][C:27]=2[F:34])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O>CN(C=O)C>[F:32][C:31]1[CH:30]=[C:29]([N:13]2[C:14]3[C:10](=[C:9]([O:8][CH2:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:12]2)[CH:28]=[C:27]([F:34])[C:26]=1[O:25][CH2:24][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Fc1cc(Br)cc(F)c1OCc1ccccc1
Reactant: c1ccc(COc2cccc3[nH]ccc23)cc1
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1cc(-n2ccc3c(OCc4ccccc4)cccc32)cc(F)c1OCc1ccccc1
Temperature: 140 °C

Procedure:
4-[(phenylmethyl)oxy]-1H-indole (500 mg, 2.24 mmoL), 4-bromo-2,6-difluorophenyl phenylmethyl ether (prepared as described in part a), 559 mg, 1.87 mmoL), K3PO4 (990 mg, 4.67 mmoL) and L-Proline (43 mg, 0.373 mmoL) were dissolved in DMF (5 mL) in a microwave vial and degassed by sonication under a flow of argon. To this was added CuI (71 mg, 0.373 mmoL) and the solution was heated to 140° C. in the microwave reactor. After 3 hours the mixture was partitioned between ethyl acetate (100 mL)/water (100 mL), the phases were separated and the aqueous phase re-extracted with ethyl acetate (100 mL). The combined organic phases were washed with sat. NH4Cl (2×100 mL), water (100 mL) and brine (2×100 mL) and finally dried over MgSO4. The crude product was purified by flash chromatography (Biotage SP4, 40+S Cartridge) eluting with a gradient of 0 to 20% Et2O in hexane to give the title compound (D21), (299 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.[N:18]([O-])=O.[Na+]>>[N+:1](=[C:2]1[CH2:15][N:6]([C@@H:7]2[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]2)[C:5](=[O:16])[NH:4][C:3]1=[O:17])=[N-:18]
Reactant: O=N[O-]
Reactant: Nc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: [Na+]
Product: [N-]=[N+]=C1CN([C@H]2C[C@H](O)[C@@H](CO)O2)C(=O)NC1=O

Procedure:
acidifying said 5-amino-deoxyuridine compound and reacting the acidified product with sodium nitrite to produce a 5-diazo-deoxyuridine compound; and