Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[C:13]2[NH2:16])=[N:8]1.F[C:18]1[C:23]([C:24]2[N:29]=[C:28]([CH3:30])[N:27]=[C:26]3[N:31]([CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][O:35]4)[N:32]=[CH:33][C:25]=23)=[CH:22][CH:21]=[CH:20][N:19]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH3:30][C:28]1[N:27]=[C:26]2[N:31]([CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][O:35]3)[N:32]=[CH:33][C:25]2=[C:24]([C:23]2[C:18]([NH:16][C:13]3[C:14]4[C:9]([CH:10]=[CH:11][CH:12]=3)=[N:8][N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[CH:15]=4)=[N:19][CH:20]=[CH:21][CH:22]=2)[N:29]=1
Reactant: Cc1nc(-c2cccnc2F)c2cnn(C3CCCCO3)c2n1
Reactant: Nc1cccc2nn(C3CCCCO3)cc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(-c2cccnc2Nc2cccc3nn(C4CCCCO4)cc23)c2cnn(C3CCCCO3)c2n1
Reaction time: 0.75 h
Yield: 31.2 %

Procedure:
A solution of 2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (80.2 mg, 369 μmol) and 4-(2-fluoropyridin-3-yl)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (112.0 mg, 357 μmol) in THF (1.0 mL) was stirred in an ice bath and treated dropwise with LHMDS (1.0 M in THF, 1.1 mL, 3 equiv.). The mixture was stirred for 45 min and then quenched with water (0.1 mL). The mixture was extracted into EtOAc from saturated aqueous NaHCO3, dried (MgSO4) and concentrated to give a dark residue. The residue was purified by flash chromatography on silica (25-30% EtOAc/hexane) to give N-(3-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pyridin-2-yl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (56.9 mg, 31.2% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 11.97 (br. s, 1H); 8.43-8.53 (m, 1H); 8.30-8.42 (m, 3H); 7.96 (br. s., 1H); 7.38-7.48 (m, 1H); 7.34 (d, J=7.43 Hz, 1H); 6.94-7.03 (m, 1H); 6.16 (d, J=10.17 Hz, 1H); 5.71 (d, J=9.00 Hz, 1H); 4.14 (d, J=9.98 Hz, 2H); 3.73-3.95 (m, 2H); 3.04 (s, 3H); 2.58-2.76 (m, 1H); 2.26-2.39 (m, 1H); 1.94-2.25 (m, 4H); 1.59-1.93 (m, 6H). m/z (ESI, +ve) 511.1 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Br:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:21][C:22]1[N:23]=[C:24]([CH3:30])[NH:25][C:26]=1[C:27](O)=[O:28].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[Br:19][C:17]1[CH:18]=[C:11]([O:10][C:5]2[C:4]([F:20])=[C:3]([CH2:2][NH:1][C:27]([C:26]3[NH:25][C:24]([CH3:30])=[N:23][C:22]=3[Cl:21])=[O:28])[CH:8]=[CH:7][C:6]=2[Cl:9])[CH:12]=[C:13]([C:14]#[N:15])[CH:16]=1
Reactant: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: Cc1nc(Cl)c(C(=O)O)[nH]1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Br)cc(C#N)c3)c2F)[nH]1
Temperature: 25 °C
Reaction time: 6 h
Yield: 44.4 %

Procedure:
To a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-bromobenzonitrile (900 mg, 2.53 mmol) and 4-chloro-2-methyl-1H-imidazole-5-carboxylic acid (813 mg, 2.53 mmol) in DMF (10 ml) was added HOBT (388 mg, 2.53 mmol) and EDC (485 mg, 2.53 mmol) and the reaction mixture was stirred for 6 hours at rt. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give N-({3-[(3-bromo-5-cyanophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-2-methyl-1H-imidazole-5-carboxamide (0.560 g, 1.124 mmol, 44% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.68 (s, 1H), 7.29-7.45 (m, 3H), 7.25 (s, 1H), 4.63 (s, 2H), 2.34 (s, 3H). LC-MS (ES+) m/z 496.87, [M+H].
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:12]1([C:15]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[C:16]=2[C:17](O)=[O:18])[CH2:14][CH2:13]1>>[CH:12]1([C:15]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:29])([F:30])[F:31])[C:16]=2[C:17]([NH:11][C@@H:7]2[CH2:8][CH2:9][CH2:10][C@@H:6]2[N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[O:18])[CH2:14][CH2:13]1
Reactant: O=C(O)c1c(C2CC2)cc(C(F)(F)F)cc1C(F)(F)F
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Product: O=C(N[C@@H]1CCC[C@@H]1N1CCCC1)c1c(C2CC2)cc(C(F)(F)F)cc1C(F)(F)F

Procedure:
The title compound, off-white solid, MS: m/e=435.3 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2-cyclopropyl-4,6-bis-trifluoromethyl-benzoic acid (intermediate AN).
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@@H:18]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:12][C:11]=2[F:31])=[CH:8][CH:7]=[N:6][CH:5]=1.CO.O.[OH-].[Li+]>O1CCCC1>[C:27]([O:26][C:24]([NH:23][C@@H:18]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]2[C:4]([C:3]([OH:32])=[O:2])=[CH:5][N:6]=[CH:7][CH:8]=2)=[C:11]([F:31])[CH:12]=1)=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: COC(=O)c1cnccc1-c1ccc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)C[C@@H](COc1ccc(-c2ccncc2C(=O)O)c(F)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.6 %

Procedure:
(S)-methyl-4-(4-((2-((tert-butoxycarbonyl)amino)-4-methylpentyl)oxy)-2-fluorophenyl)nicotinate (50.0 mg, 0.112 mmol) was taken in a mixture of tetrahydrofuran (1 mL), methanol (1 mL) and water (1 mL). To the solution was added lithium hydroxide (8.05 mg, 0.336 mmol) and the reaction mixture was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water and the pH adjusted to 4 using 1.5N aqueous HCl. The crude product from the aqueous layer was extracted with ethyl acetate (3×5 mL). The combined organic layers were washed with brine (1×5 mL), dried (Na2SO4) and concentrated under reduced pressure to afford (S)-4-(4-((2-((tert-butoxycarbonyl)amino)-4-methylpentyl)oxy)-2-fluorophenyl)nicotinic acid (30 mg, 0.060 mmol, 53% yield) as an off-white solid. LC/MS (ESI) m/e 433.2 [(M+H)+, calcd for C23H30FN2O5 433.2]; LC/MS retention time (method C): tR=1.74 min.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH:36]([CH3:38])[CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:39]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)(=[O:41])[CH3:40]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:45]3[CH2:46][CH2:47][N:42]([C:39](=[O:41])[CH3:40])[CH2:43][CH2:44]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH:36]([CH3:38])[CH3:37])[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)Oc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(C(=O)N2C(c3ccc(C(C)(C)C)cc3OC(C)C)=N[C@@](C)(c3ccc(Cl)cc3)[C@@]2(C)c2ccc(Cl)cc2)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-isopropoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-acetyl-piperazine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C37H55N4O3Cl2 [(M+H)+] 663.2863, observed 663.2857.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10]([O:12][CH3:13])=[O:11])[CH2:7][C:6]=2[CH:14]=1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[C:24]([O:31][CH3:32])=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[C:19]([F:33])=[CH:18][N:17]=1>>[CH3:13][O:12][C:10]([CH:8]1[CH2:7][C:6]2[CH:14]=[C:2]([NH:1][C:16]3[N:21]=[C:20]([NH:22][C:23]4[C:24]([O:31][CH3:32])=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=4)[C:19]([F:33])=[CH:18][N:17]=3)[CH:3]=[CH:4][C:5]=2[O:9]1)=[O:11]
Reactant: COC(=O)C1Cc2cc(N)ccc2O1
Reactant: COc1ccc(Nc2nc(Cl)ncc2F)c(OC)n1
Product: COC(=O)C1Cc2cc(Nc3ncc(F)c(Nc4ccc(OC)nc4OC)n3)ccc2O1

Procedure:
In like manner to the preparation of (±)-N4-(3,4-difluorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine, the reaction of (±)-5-amino-2,3-dihydro-2-methoxycarbonylbenzofuran with 2-chloro-N4-(2,6-dimethoxypyridin-3-yl)-5-fluoro-4-pyrimidineamine gave (±)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-N4-(2,6-dimethoxypyridin-3-yl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 10.03 (bs, 2H), 8.18 (d, 1H, J=4.8 Hz), 7.68 (bd, 1H, J=8.1 Hz), 7.27 (bs, 1H), 6.98 (bd, 1H, J=8.1 Hz), 6.69 (d, 1H, J=8.7 Hz), 6.44 (d, 1H, J=8.1 Hz), 5.33 (dd, 1H, J=5.7 Hz), 3.88 (s, 3H), 3.86 (s, 3H), 3.69 (s, 3H), 3.42 (dd, 1H, J=10.8 and 11.1 Hz), 3.10 (dd, 1H, J=6.3 and 6.6 Hz); LCMS: purity: 99%; MS (m/e): 442 (MH+).
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])[CH2:13][CH2:12]1.C=O.[CH3:27]COCC.C=O.O.[C:35]([BH3-])#[N:36].[Na+]>C(O)(=O)C>[CH3:27][N:36]([CH3:35])[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])[CH2:13][CH2:12]1
Reactant: [BH3-]C#N
Reactant: Nc1cc([N+](=O)[O-])ccc1N1CCN(C(=O)c2ccccc2)CC1
Reactant: CCOCC
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CN(C)c1cc([N+](=O)[O-])ccc1N1CCN(C(=O)c2ccccc2)CC1
Reaction time: 0.17 h
Yield: 69 %

Procedure:
A solution of (4-(2-amino-4-nitrophenyl)piperazin-1-yl)(phenyl)methanone (0.4 g, 1.2 mmol) and 30 ml formaldehyde ether solution extracted from 30 ml 37% water formaldehyde solution in 20 ml acetic acid was stirred for 10 min, followed by the addition of sodium cyanoborohydride (0.13 g, 2.5 mmol). The mixture was stirred for 3 hours under argon atmosphere. The reaction was quenched with water and extracted with ethyl acetate (3×15 ml), followed by drying over anhydrous sodium sulfate. (4-(2-(Dimethylamino)-4-nitrophenyl)piperazin-1-yl)(phenyl)methanone (0.3 g, 69%) was obtained by flash column chromatograph (50% ethyl acetate in hexanes). 1H NMR (500 MHz, CDCl3) δ (ppm) 2.88 (s, 6H), 3.30 (s, br, 4H), 3.68 (s, br, 2H), 4.00 (s, br, 2H), 6.90 (d, J=8.8 Hz, 1H), 7.47-7.50 (m, 5H), 7.82 (d, J=2.6 Hz, 1H), 7.87 (dd, J=8.8, 2.6 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ (ppm) 41.8, 49.2, 114.5, 118.1, 118.6, 127.6, 129.1, 130.4, 136.0, 143.4, 145.6, 149.5, 170.9.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].O1[C:18]2([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[O:17]CC1.CN(C)C=O>O>[N:3]1[CH:4]=[CH:5][N:6]=[CH:7][C:2]=1[N:21]1[CH2:22][CH2:23][C:18](=[O:17])[CH2:19][CH2:20]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: Clc1cnccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCN(c2cnccn2)CC1
Temperature: 100 °C
Reaction time: 72 h
Yield: 27.1 %

Procedure:
A mixture of 20 g (0.1746 mol) of chloropyrazine, 36 g (0.260 mol) of K2CO3, 76 g (0.5308 mol) of 1,4-dioxa-8-azaspiro[4.5]decane, and 80 ml of dimethylformamide is stirred at 100° C. for 3 days. The reaction mixture is cooled, diluted with water, and extracted with ethyl acetate. The combined extracts are washed with water, dried over Na2SO4 and concentrated in vacuo. The residue, 400 ml of 10% sulfuric acid solution and 100 ml of tetrahydrofuran are stirred at ambient temperature for 4 days, diluted with water, basified (NaOH) and extracted with methylene chloride. The extracts are washed with brine, dried over Na2SO4, and concentrated in vacuo. Trituration with ether gives 8.4 g of title compound: IR (KBr) 1720 and 1580 cm-1 ; NMR (CDCl3) δ 8.24-7.88 (m, 3H), 3.98 (t, 4H), and 2.56 (t, 4H).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:18]=[CH:17][N:16]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=4)[N:15]=3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[CH:30]([C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:34]=1[N:40]1[C:44](=[O:45])[CH2:43][S:42]/[C:41]/1=[N:46]\[C:47](=O)[O:48]C1C=CC([N+]([O-])=O)=CC=1)([CH3:32])[CH3:31]>>[CH:1]1([CH2:4][N:5]([CH2:6][CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:18]=[CH:17][N:16]([C:19]4[CH:20]=[CH:21][C:22]([O:25][C:26]([F:27])([F:28])[F:29])=[CH:23][CH:24]=4)[N:15]=3)=[CH:12][CH:13]=2)[C:47](/[N:46]=[C:41]2\[S:42][CH2:43][C:44](=[O:45])[N:40]\2[C:34]2[CH:35]=[C:36]([CH3:39])[CH:37]=[CH:38][C:33]=2[CH:30]([CH3:31])[CH3:32])=[O:48])[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(CCNCC4CC4)cc3)n2)cc1
Product: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)N(CCc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)CC2CC2)c1

Procedure:
The title compound was prepared as described in Example 95 using N-(cyclopropylmethyl)-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)ethanamine (CB27) and (Z)-4-nitrophenyl (3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)carbamate (CA50), purified by flash column chromatography using 0-100% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent and isolated as red-orange oil (0.127 g, 60%).
Reaction SMILES: [CH2:1]=[C:2]1[C:19]2[C@:14]([CH3:21])([CH2:15][CH2:16][C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]3)[CH2:3]1.C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl.CO.CC(OC)(C)C>CN1CCCC1>[CH2:1]=[C:2]1[C:19]2[C@:14]([CH3:21])([CH:15]=[CH:16][C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]3)[CH2:3]1
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)C=C12
Agent: CN1CCCC1
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: CO
Solvent: COC(C)(C)C
Product: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)C=CC(=O)C=C12
Temperature: 77.5 °C
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
6-Methylen-androst-4-ene-3,17-dione (5.0 gm) was dissolved in N-methylpyrrolidine (25 mL) at RT & to it was charged Chloranil (12.37 gm) at RT. The reaction mass was heated to 75 to 80° C. for 18 hours. The progress of the reaction is monitored on TLC. The reaction mass was cooled down to room temperature and methanol was added to it. The reaction mass was stirred for next 30 minutes and precipitated solid mass was filtered through buchner funnel and washed with methanol. All the filtrates were combined and suitably diluted. The product from aqueous solution was extracted in toluene. Combined toluene extracts was washed with 2% aqueous NaOH solution under stirring for 30 minutes. The toluene layer was separated and washed with water. Toluene layer was dried over sodium sulfate, filtered and evaporated at reduced pressure to get solid residue. The solid residue was treated with MTBE to get 3.0 gm solid product. HPLC Purity: 97%.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@:12]([CH2:19][CH:20]([CH3:22])[CH3:21])([CH3:18])[CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[CH3:24][CH:25]([N-]C(C)C)[CH3:26].C(Br)C=C>C1COCC1>[CH2:26]([C@@H:13]([C@@:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])([CH2:19][CH:20]([CH3:22])[CH3:21])[CH3:18])[C:14]([O:16][CH3:17])=[O:15])[CH:25]=[CH2:24]
Reactant: COC(=O)C[C@](C)(CC(C)C)NC(=O)OCc1ccccc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CC[C@H](C(=O)OC)[C@](C)(CC(C)C)NC(=O)OCc1ccccc1
Temperature: -80 °C
Reaction time: 0.33 h

Procedure:
500 mg (1.71 mmol) of methyl(S)-3-benzyloxycarbonylamino-3-isobutyl-butanoate, prepared according to the procedure described in Liebigs Ann., pp 1217-1228 (1995), is dissolved in 10 mL of dry THF and cooled under Argon to -80° C. 1.881 mL (3.762 mmol) of 2M LDA is added, and the mixture is stirred at -40° C. for 20 minutes. The reaction is cooled to -78° C., and 828 mg (6.84 mmol) of allyl bromide are added. The mixture is stirred at -78° C. for 5 hours and at room temperature overnight. The reaction is quenched with 20 mL of 1M pH 7 phosphate buffer. The pH is lowered to 2 with 1N HCl. The water layer is extracted with EtOAc. The combined organic layers are dried over MgSO4, and concentrated to provide the crude product, which is purified by chromatography using 70% hexanes/30% EtOAc as eluant to give the title compound.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[C:8](=[O:13])[CH2:7][CH2:6][CH2:5]2.C(N(CC)CC)C.[F:21][C:22]1[CH:23]=[C:24]([SH:28])[CH:25]=[CH:26][CH:27]=1.O>CC(OC)(C)C>[F:12][C:10]1[CH:11]=[C:2]([S:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([F:21])[CH:23]=2)[CH:3]=[C:4]2[C:9]=1[C:8](=[O:13])[CH2:7][CH2:6][CH2:5]2
Reactant: Fc1cccc(S)c1
Reactant: O=C1CCCc2cc(F)cc(F)c21
Solvent: COC(C)(C)C
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1CCCc2cc(Sc3cccc(F)c3)cc(F)c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 6,8-difluoro-3,4-dihydro-2H-naphthalen-1-one (50 g) in N,N′dimethylacetamide (100 ml) was treated with triethylamine (38.2 ml), followed by 3-fluorothiophenol (28.2 ml), keeping the temperature below 20° C. The reaction mixture was allowed to stir at ambient temperature for 18 hours. The reaction was diluted with MTBE (70 ml) and cooled on an ice-bath. Water (300 ml) was slowly added (keeping temperature below 25° C.) and the mixture aged for 1 hour. The product was collected by filtration and washed with water and cyclohexane, and dried to afford 8-fluoro-6-(3-fluoro-phenylsulfanyl)-3,4-dihydro-2H-naphthalen-1-one as a pale yellow solid yield (53.5 g, 95% pure by HPLC): MP=126.0-126.9° C.; MS (M+1)=291; H1 NMR (300 MHz): δ (DMSO): 1.97 (2H, pen, J=6.03 Hz), 2.55 (2H, t, J=6.03 Hz), 2.88 (2H, t, J=6.03), 6.84 (1H, dd, J=1.88, 12.06 Hz) 7.01 (1H, d, J=1.03 Hz), 7.31-7.44 (3H, m), 7.52-7.59 (1H, dd/d, J=6.03, 6.41 Hz).
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][C:25]2[NH:29][N:28]=[N:27][N:26]=2)=[CH:17][CH:16]=1)C1C=CC=CC=1>CO.ClCCl.[Pd]>[NH:29]1[C:25]([CH2:24][CH2:23][CH2:22][O:21][C:18]2[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][CH2:12][CH2:11][NH2:10])=[CH:16][CH:17]=2)=[N:26][N:27]=[N:28]1
Reactant: O=C(NCCCCc1ccc(OCCCc2nnn[nH]2)cc1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: NCCCCc1ccc(OCCCc2nnn[nH]2)cc1
Yield: 99.5 %

Procedure:
A solution of (4-{4-[3-(1H-tetrazol-5-yl)propoxy]phenyl}butyl)carbamic acid benzyl ester 3 (0.30 g, 0.73 mmol) in methanol (20 mL) and dichloromethane (5 mL) was stirred at room temperature overnight under hydrogen atmosphere in the presence of 10% palladium-on-carbon catalyst (0.1 g, 50% wet). The catalyst was removed by suction filtration, and the filtrate was concentrated in vacuo to give the desired product 4 as a white solid (200 mg, 99% yield) which was used for the next step without further purification. m/z (ESI): 276 [C14H21N5O+H]+.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[CH:21]([CH2:22][CH2:23][C:24]=2Br)[CH:20]([NH:26][C:27](=[O:36])[CH2:28][O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:19]3=[O:37])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[P:38]([O:49]CCCC)([O:44][CH2:45][CH2:46][CH2:47][CH3:48])[O:39][CH2:40][CH2:41][CH2:42][CH3:43]>C1(C)C=CC=CC=1.[Ni](Cl)Cl>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[CH:21]([CH2:22][CH2:23][C:24]=2[P:38]([O:39][CH2:40][CH2:41][CH2:42][CH3:43])([O:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:49])[CH:20]([NH:26][C:27](=[O:36])[CH2:28][O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:19]3=[O:37])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCOP(OCCCC)OCCCC
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(Br)CCC12
Agent: Cl[Ni]Cl
Solvent: Cc1ccccc1
Product: CCCCOP(=O)(OCCCC)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)COc3ccccc3)C2CC1
Yield: 24 %

Procedure:
A solution of 3-bromo-7-[(phenoxyacetyl)amino]-8-oxo-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (diphenylmethyl)ester (2 g, 3.6 mmol) in toluene (50 mL) was added tri-n-butyl phosphite (15 mL) and nickel(II)chloride (50 mg, 039 mmol). The reaction was brought to reflux under nitrogen. Each hour, the reaction was cooled and an additional portion of nickel(II)chloride (50 mg, 0.39 mmol) was added. This process was continued for a total of six hours. The reaction was concentrated in vacuo and the residue purified by flash chromatography on silica gel (25%-50% ethyl acetate/hexanes) to provide 7-[(Phenoxyacetyl)amino]-8-oxo-3-(dibutoxyphosphinyl)-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid (diphenylmethyl)ester (588 mg, 24%):
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=1.[CH:21]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)=[CH2:22].C(N(C(C)C)CC)(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[N:26]1[CH:27]=[CH:28][C:23](/[CH:21]=[CH:22]/[C:2]2[C:10]3[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=3)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=2)=[CH:24][CH:25]=1
Reactant: C=Cc1ccncc1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(C=O)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1nc(/C=C/c2ccncc2)c2ccc(C=O)cc21
Temperature: 100 °C
Yield: 49 %

Procedure:
A solution of 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (2.0 g, 4.98 mmol), 4-vinylpyridine (0.69 mL, 6.47 mmol), diisopropylethylamine (1.74 mL, 9.96 mmol) and DMF (50 mL) was purged with Ar gas for 20 min at which time Pd(OAc)2 (112 mg, 0.500 mmol) and P(o-tol)3 (457 mg, 1.50 mmol) were added and the reaction heated to 100° C. for 20 hours. The reaction was cooled to room temperature and partitioned between EtOAc and NH4Cl. The aqueous layer was extracted with EtOAc (3×) and the combined organics washed with water (2×) and brine (2×). The organic layer was dried over MgSO4 and the EtOAc removed in vacuo. The residue was purified by column chromatography (silica gel, 97:3 CH2Cl2/MeOH) to give 927 mg, 49% of the title compound which was used without further purification. MS ESI 380.2 [M+H]+, calcd for [C21H25N3O2Si+H]+ 380.18.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:18](Cl)(=[O:20])[CH3:19].Cl>CCOCC>[C:18]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: c1ccc2c(c1)CCCN2
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(=O)N1CCCc2ccccc21
Reaction time: 0.5 h

Procedure:
1,2,3,4-Tetrahydroquinoline (5 g, 0.038 mol) and triethylamine (4.55 g, 0.045 mol) were dissolved in 55 ml ether. Acetyl chloride (3.24 g, 0.041 mol) was added and the mixture stirred for 30 minutes, and poured into a mixture of 100 ml 1M HCl and 50 ml ether. The organic layer was separated, washed 1×100 ml 1M HCl and then 2×100 ml 5% NaHCO3, dried (K2CO3) and stripped to yield title product as an oil, 5.13 g.
Reaction SMILES: [Cl:1][CH:2]([Cl:28])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[N:20][C:21]([CH2:24]O)=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:27])[CH3:26])=[O:4].CCN(C(C)C)C(C)C.CS([Cl:42])(=O)=O>C(Cl)Cl>[Cl:28][CH:2]([Cl:1])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[N:20][C:21]([CH2:24][Cl:42])=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:26])[CH3:27])=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)O[C@H](c2ccc(-c3ccc(CO)nc3)cc2)[C@@H](CF)N1C(=O)C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)O[C@H](c2ccc(-c3ccc(CCl)nc3)cc2)[C@@H](CF)N1C(=O)C(Cl)Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.5 %

Procedure:
To a cooled (ice-water) solution of the product of step 1 (800 mg, 1.87 mmol) and DIPEA (0.675 mL, 3.75 mmol) in DCM (10 mL) is slowly added methanesulfonyl chloride (0.150 mL, 1.87 mmol). The reaction mixture is stirred at room temperature for 6 hours. The reaction is diluted with DCM (10 mL), washed with water (2×10 mL) dried over Na2SO4 and concentrated under reduced pressure to give the title compound (813 mg): LCMS m/z (Cl): 445 [M+H].