Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.C(OP([CH2:21][C:22]([OH:24])=[O:23])(OCC)=O)C.[NH2:25][C:26]1[C:27]2[C:34]([C:35]3[CH:40]=[CH:39][C:38]([O:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[CH:37][CH:36]=3)=[CH:33][N:32]([CH:48]3[CH2:53][CH2:52][C:51](=O)[CH2:50][CH2:49]3)[C:28]=2[N:29]=[CH:30][N:31]=1>O1CCCC1>[NH2:25][C:26]1[C:27]2[C:34]([C:35]3[CH:36]=[CH:37][C:38]([O:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[CH:39][CH:40]=3)=[CH:33][N:32]([CH:48]3[CH2:53][CH2:52][C:51](=[CH:21][C:22]([OH:24])=[O:23])[CH2:50][CH2:49]3)[C:28]=2[N:29]=[CH:30][N:31]=1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC(=O)CC1
Reactant: CCOP(=O)(CC(=O)O)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC(=CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70.7 %

Procedure:
A solution of diisopropylamine (1.40 g, 13.82 mmol) in tetrahydrofuran (60 mL) was added into a solution of 2.2 M n-BuLi (6.29 mL, 13.82 mmol) in tetrahydrofuran (20 mL) at −78° C. A solution of diethylphosphonoacetic acid (1.29 g, 6.59 mmol) in tetrahydrofuran (60 mL) was added at −78° C. under the atmosphere of nitrogen. The mixture was kept at −78° C. for 20 minutes and allowed to warm up to ambient temperature. The mixture was then transferred into a suspension of 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexanone (2.50 g, 6.28 mmol) in tetrahydrofuran (150 mL) at −78° C. quickly. The resulting mixture was allowed to warm up to ambient temperature overnight and the solvent was removed under reduced pressure. The residue was taken in water and adjusted PH to be 3-4 with 1M aqueous acetic acid followed by extraction with ethyl acetate three times. The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure to give 2-{4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyliden}acetic acid (1.96 g, 4.44 mmol) as a white solid: 1H NMR (DMSO-d6, 400 MHz) δ 11.98(br, 1H), 7.45(d, 2H), 7.41(s, 1H), 7.40(d, 2H), 7.16(t, 1H), 7.08(m, 4H), 6.10(br, 2H), 5.70(s, 1H), 4.80(m, 1H), 2.50-1.90(m, 8H); RP-HPLC (Hypersil C18, 5 μm, 100 A, 250×4.6 mm; 25%-100% acetonitrile-0.05M ammonium acetate over 10 min, 1 mL/min) Rt 9.70 min. MS: MH+ 441.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH3:14])[CH2:12][OH:13])=[N:8][C:7]([SH:15])=[N:6][C:5]=2[N:16]=1.Cl.Cl[CH2:19][C:20]1[N:21]=[C:22]([CH3:25])[S:23][CH:24]=1.CCN(C(C)C)C(C)C>CS(C)=O.CN1C(=O)CCC1>[NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH3:14])[CH2:12][OH:13])=[N:8][C:7]([S:15][CH2:19][C:20]3[N:21]=[C:22]([CH3:25])[S:23][CH:24]=3)=[N:6][C:5]=2[N:16]=1
Reactant: Cc1nc(CCl)cs1
Reactant: C[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1nc(CSc2nc(N[C@H](C)CO)c3sc(N)nc3n2)cs1
Reaction time: 1 h
Yield: 36.2 %

Procedure:
A stirred solution of the product of step (b) (0.05 g) in DMSO (4 ml) was treated with a solution of 4-chloromethyl-2-methylthiazole hydrochloride (0.029 g) and Hunig's base (0.025 g) in NMP (0.5 ml) and stirred for 1 hour. The solution was purified by reverse phase preparative HPLC on Nova-pak® C18 column, using 10 to 60% acetonitrile in 0.1% aqueous ammonium acetate at 50 ml/min over 10 min to give the titled compound (0.021 g)
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][C:17](=[O:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:8]=[CH:9][C:10]=1[O:11]C(=O)C)(=O)C.[OH-].[Na+].O.Cl>CO>[OH:4][C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][C:17](=[O:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:8]=[CH:9][C:10]=1[OH:11]
Reactant: CCCCCCC(=O)C=Cc1ccc(OC(C)=O)c(OC(C)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCC(=O)C=Cc1ccc(O)c(O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
In 10 ml of methanol was dissolved 830 mg of 1-(3,4-diacetoxyphenyl)-1-nonen-3-one and after adding 7.5 ml of an aqueous 1N-sodium hydroxide solution to the solution, the mixture was stirred for 30 minutes at room temperature. Then, the reaction mixture was ice-cooled and after adding thereto 25 ml of water, the mixture was acidified with the addition of 5 ml of an aqueous 1N-hydrochloric acid solution to form crystals, which were collected by filtration and washed with water to provide 580 mg of 1-(3,4-dihydroxyphenyl)-1-nonen-3-one.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].[CH:18]([C:20]1[CH:21]=[N:22][CH:23]=[N:24][CH:25]=1)=[CH2:19]>CN1CCCC1=O.O>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:19][CH2:18][C:20]3[CH:21]=[N:22][CH:23]=[N:24][CH:25]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: C=Cc1cncnc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CCc2cncnc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33.3 %

Procedure:
To a solution of 2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g. 0.49 mmol) in N-methyl 2-pyrolidone (1.0 mL) was added powdered potassium hydroxide (0.14 g, 2.5 mmol) and allowed to stir for 10 min at RT. 5-vinyl pyrimidine (0.132 g, 1.25 mmol) was added and stirred for further 5 h at 60 deg C. After completion (TLC), reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude was purified through column chromatography (7% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica approx. 5 inch), Then further purified by preparative TLC, to give the desired compound as yellow oil (0.050 g, 32.6% yield). 2,8-Dimethyl-5-(2-pyrimidin-5-yl-ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.040 g, 0.13 mol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.015 g, 0.119 mol) in THF (1.0 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.046 g, 90% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15](O)=[O:16])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:24])=O.CN(C=O)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([Cl:24])=[O:16])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc(NS(=O)(=O)c2ccc(Br)cc2)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccc(NS(=O)(=O)c2ccc(Br)cc2)c1
Temperature: 0 °C

Procedure:
A suspension of 3-(4-bromophenylsulfonamido)benzoic acid (2.30 g, 6.46 mmol) in DCM (50 mL) was stirred and cooled under argon to 0° C. Oxalyl chloride (676 μL, 7.11 mmol) was then added dropwise via a syringe, followed by DMF (50 μL). The resulting solution was then stirred overnight, allowing the reaction mixture to warm room temperature. The solution was used without further purification.
Reaction SMILES: [Br:1][CH2:2][C:3]1[N:8]=[C:7]2[CH:9]=[C:10]([Cl:12])[S:11][C:6]2=[CH:5][CH:4]=1.[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCOCC>[Br-:1].[Cl:12][C:10]1[S:11][C:6]2[C:7](=[N:8][C:3]([CH2:2][P+:19]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:4][CH:5]=2)[CH:9]=1
Reactant: Clc1cc2nc(CBr)ccc2s1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: Clc1cc2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)ccc2s1
Product: [Br-]
Yield: 90.3 %

Procedure:
A solution of bromide (0.304 g, 1.16 mmol) of Step 2 and triphenylphosphine (0.455 g, 1.73 mmol) in 6 mL of acetonetrile was stirred at r.t. for 20 hr. Ether was added and the solid was washed with ether to yield 0.550 g (91%) of the title phosphonium salt.
Reaction SMILES: O[C@@H:2]1[C:7]([CH3:9])([CH3:8])[O:6][C:5]2[CH:10]=[CH:11][C:12]([C:14]#[N:15])=[CH:13][C:4]=2[C@H:3]1[N:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])=[CH:18][C:17]1=[O:31].[H-].[Na+].O>O1CCCC1>[C:14]([C:12]1[CH:11]=[CH:10][C:5]2[O:6][C:7]([CH3:9])([CH3:8])[CH:2]=[C:3]([N:16]3[CH:21]=[CH:20][C:19]([CH2:22][O:23][Si:24]([C:27]([CH3:28])([CH3:30])[CH3:29])([CH3:25])[CH3:26])=[CH:18][C:17]3=[O:31])[C:4]=2[CH:13]=1)#[N:15]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](n2ccc(CO[Si](C)(C)C(C)(C)C)cc2=O)[C@@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)C=C(n2ccc(CO[Si](C)(C)C(C)(C)C)cc2=O)c2cc(C#N)ccc2O1
Yield: 82.1 %

Procedure:
In 50 ml of anhydrous tetrahydrofuran, is dissolved 1.32 g of trans-3-hydroxy-6-cyano-3,4-dihydro-2,2-dimethyl-4-(1,2-dihydro-2-oxo-4-t-butyldimethylsilyloxymethyl-1-pyridinyl)-2H-benzo[b]pyran obtained is Example 1. Then, 0.12 g of 60% oily sodium hydride is added to the solution at room temperature and reacted under reflux for 4 hours. After stopping the reaction by adding water, the reaction mixture is extracted with ether. The organic layer is successively washed with water and saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Then, the inorganic matter is filtered off and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography using 1/7 mixture of ethyl acetate/methylene chloride as a developing solvent. Thus, 1.04 g of 6-cyano-2,2-dimethyl-4-(1,2-dihydro-2-oxo-4-t-butyldimethylsilyloxymethyl-1-pyridinyl)-2H-benzo[b]pyran is obtained.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][S:14][CH2:15][C@H:16]([C:25]([OH:27])=O)[NH:17]C(OC(C)(C)C)=O)=O)C1C=CC=CC=1.[CH3:28][S:29]([Cl:32])(=[O:31])=[O:30].[S:33]1[CH2:37][CH2:36][NH:35][CH2:34]1>>[ClH:32].[NH2:17][C@@H:16]([C:25](=[O:27])[N:35]1[CH2:36][CH2:37][S:33][CH2:34]1)[CH2:15][S:14][CH2:13][CH2:12][NH:11][S:29]([CH3:28])(=[O:31])=[O:30]
Reactant: C1CSCN1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H](CSCCNC(=O)OCc1ccccc1)C(=O)O
Product: CS(=O)(=O)NCCSC[C@@H](N)C(=O)N1CCSC1
Product: Cl

Procedure:
Starting from (S)-3-(2-{[benzyloxycarbonyl]-amino}-ethylthio)-N-(tert-butyloxy-carbonyl)-alanine, methanesulphonyl chloride and 1,3-thiazolidine, the expected product is obtained according to the procedure described in Example 37.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:29]=[C:28]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([N:37]4[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]4)=[CH:33][N:32]=3)[C:27](=[O:44])[N:26]([CH3:45])[CH:25]=2)[C:5]([CH2:22][OH:23])=[C:6]([N:8]2[CH2:20][CH2:19][N:11]3[C:12]4[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=4[CH:18]=[C:10]3[C:9]2=[O:21])[CH:7]=1.[C:46]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:29]=[C:28]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([N:37]4[CH2:38][CH2:39][N:40]([CH3:43])[CH2:41][CH2:42]4)=[CH:33][N:32]=3)[C:27](=[O:44])[N:26]([CH3:45])[CH:25]=2)[C:5]([CH2:22][O:23][CH3:46])=[C:6]([N:8]2[CH2:20][CH2:19][N:11]3[C:12]4[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=4[CH:18]=[C:10]3[C:9]2=[O:21])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CN1CCN(c2ccc(Nc3cc(-c4cc(F)cc(N5CCn6c(cc7c6CCCC7)C5=O)c4CO)cn(C)c3=O)nc2)CC1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COCc1c(-c2cc(Nc3ccc(N4CCN(C)CC4)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Reaction time: 1 h
Yield: 79.9 %

Procedure:
To a solution of 2-(5-fluoro-2-(hydroxymethyl)-3-(1-methyl-5-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one 197 (200 mg, 0.33 mmol) and K2CO3(135 mg, 0.99 mmol) in DMF(30 mL) was added the solution of iodomethane (70 mg, 0.50 mmol) in DMF(5 mL) at room temperature. The reaction mixture was stirred for 1 h. It was then filtered and the residue was purified by prep-HPLC to afford 333 as a yellow solid (165 mg, 80%). MS: [M+H]+ 626. 1H NMR (500 MHz, DMSO) δ 8.59 (d, J=2.0, 1H), 8.49 (s, 1H), 7.97 (d, J=2.0, 1H), 7.44 (s, 1H), 7.39 (s, 1H), 7.32 (m, 2H), 7.17 (m, 1H), 6.52 (s, 1H), 4.31 (s, 2H), 4.14 (m, 3H), 3.88 (s, 1H), 3.56 (s, 3H), 3.54 (s, 4H), 3.44 (s, 4H), 3.12 (s, 6H), 2.58 (m, 2H), 2.46 (s, 2H), 1.79 (s, 2H), 1.68 (s, 2H).
Reaction SMILES: C([OH:3])C.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:14]2[N:19]=[C:18]([C:20]([N:22]3[CH2:27][C@@H:26]([CH3:28])[N:25]([C:29]4[CH:34]=[CH:33][C:32]([N+:35]([O-])=O)=[CH:31][CH:30]=4)[CH2:24][C@@H:23]3[CH3:38])=[O:21])[CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[Cl-:39].[NH4+]>O>[OH2:3].[ClH:39].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:14]2[N:19]=[C:18]([C:20]([N:22]3[C@H:23]([CH3:38])[CH2:24][N:25]([C:29]4[CH:30]=[CH:31][C:32]([NH2:35])=[CH:33][CH:34]=4)[C@@H:26]([CH3:28])[CH2:27]3)=[O:21])[CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: COc1ccc(-c2cccc(C(=O)N3C[C@@H](C)N(c4ccc([N+](=O)[O-])cc4)C[C@@H]3C)n2)cc1OC
Reactant: CCO
Reactant: [Cl-]
Agent: [NH4+]
Solvent: O
Product: COc1ccc(-c2cccc(C(=O)N3C[C@H](C)N(c4ccc(N)cc4)C[C@H]3C)n2)cc1OC
Product: Cl
Reaction time: 0.5 h

Procedure:
To an ethanol (37 ml) and water (13 ml) mixed solution of 1.42 g of (±)-trans-1-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]-2,5-dimethyl-4-(4-nitrophenyl)piperazine were added 0.16 g of ammonium chloride and 1.66 g of reduced iron, followed by 0.5 hour of heating under reflux. The reaction solution was filtered through celite and the filtrate was concentrated under reduced pressure. An aqueous saturated sodium hydrogen carbonate solution was added to thus obtained residue, followed by extraction with chloroform. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate, and thereafter, the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform-methanol) and the obtained compound was treated with a 4M hydrogen chloride/ethyl acetate solution to form its salt. Then, the solvent was evaporated and the residue was washed with ethyl acetate to obtain 582 mg of (±)-trans-4-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]-2,5-dimethylpiperazin-1-yl}aniline hydrochloride hydrate as pale yellow crystals.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[O:16][C:17]([CH3:20])=[N:18][N:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:27](O)(C(F)(F)F)=O.Cl.[CH3:35][O:36][C:37]1[CH:45]=[N:44][C:43]([C:46]2[CH:47]=[CH:48][N:49](C)[N:50]=2)=[C:42]2[C:38]=1[C:39]([C:52](=[O:56])C(O)=O)=[CH:40][NH:41]2.C(N(CC)CC)(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl>[C:21]1([C:14](=[C:11]2[CH2:10][CH2:9][N:8]([C:6](=[O:5])[C:52]([C:39]3[C:38]4[C:42](=[C:43]([C:46]5[CH:47]=[C:48]([CH3:27])[NH:49][N:50]=5)[N:44]=[CH:45][C:37]=4[O:36][CH3:35])[NH:41][CH:40]=3)=[O:56])[CH2:13][CH2:12]2)[C:15]2[O:16][C:17]([CH3:20])=[N:18][N:19]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1nnc(C(=C2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc2)o1
Reactant: COc1cnc(-c2ccn(C)n2)c2[nH]cc(C(=O)C(=O)O)c12
Agent: CCN(CC)C(C)C
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Product: COc1cnc(-c2cc(C)[nH]n2)c2[nH]cc(C(=O)C(=O)N3CCC(=C(c4ccccc4)c4nnc(C)o4)CC3)c12
Reaction time: 0.5 h
Yield: 6 %

Procedure:
To a solution of 4-[1-phenyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)methylene]piperidine-1-carboxylic acid tert-butyl ester (0.0430 g, 0.167 mmol) in CH2Cl2 (2 mL) was added TFA (0.3 mL) and the reaction mixture was stirred for 30 min. The solvent was then removed in vacuo and the residual material was dissolved in CHCl3 (2 mL). To this solution was added 4-methoxy-7-(2-methylpyrazol-5-yl)-6-azaindol-3-yl-oxoacetic acid hydrochloride salt (0.050 g, 0.167 mmol) and iPrNEt2 (0.145 mL, 0.833 mmol), followed by BOP—Cl (0.0590 g, 0.233 mmol). The mixture was allowed to stir at rt for 2 h and then the solvent was removed in vacuo. The residue was diluted with H2O and extracted with EtOAc (×3). The combined organic layers were washed (H2O, brine), dried (Na2SO4) and concentrated and the residue was purified by preparative HPLC (TFA) to give the title compound (0.0053 g, 6%) as a colorless solid:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1)=O.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH:30]=O>>[F:9][C:8]([F:11])([F:10])[C:7]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:2]=1[N:1]=[CH:30][C:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:22]([F:21])([F:32])[F:33])=[C:12]2[C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1
Reactant: O=CCc1ccccc1C(F)(F)F
Reactant: Nc1c(C(=O)c2cccc(O)c2)cccc1C(F)(F)F
Product: Oc1cccc(-c2c(-c3ccccc3C(F)(F)F)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from [2-amino-3-(trifluoromethyl)phenyl]-(3-hydroxy-phenyl)methanone and (2-Trifluoromethyl-phenyl)-acetaldehyde following the procedure of Example 457: MS (ES) m/z 431.9; HRMS: calcd for C23H13F6NO+H+, 434.09741; found (ESI, [M+H]+), 434.0961.
Reaction SMILES: [I-].[F:2][C:3]1([F:27])[O:7][C:6]2[CH:8]=[CH:9][C:10]([N:12]3[CH2:16][C:15](=[CH2:17])[S:14]/[C:13]/3=[N:18]\[C:19](N3C=C[N+](C)=C3)=[O:20])=[CH:11][C:5]=2[O:4]1.[CH3:28][CH:29]1[CH2:33][CH2:32][CH2:31][NH:30]1.CCN(C(C)C)C(C)C>C(#N)C.C(Cl)Cl>[F:27][C:3]1([F:2])[O:7][C:6]2[CH:8]=[CH:9][C:10]([N:12]3[CH2:16][C:15](=[CH2:17])[S:14]/[C:13]/3=[N:18]\[C:19]([N:30]3[CH2:31][CH2:32][CH2:33][CH:29]3[CH3:28])=[O:20])=[CH:11][C:5]=2[O:4]1
Reactant: CC1CCCN1
Reactant: C=C1CN(c2ccc3c(c2)OC(F)(F)O3)/C(=N/C(=O)n2cc[n+](C)c2)S1
Agent: [I-]
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C=C1CN(c2ccc3c(c2)OC(F)(F)O3)/C(=N/C(=O)N2CCCC2C)S1
Temperature: 60 °C

Procedure:
To a solution of 1-({[(2Z)-3-(2,2-difluoro-1,3-benzodioxol-5-yl)-5-methylene-1,3-thiazolidin-2-ylidene]amino}carbonyl)-3-methyl-1H-imidazol-3-ium iodide (Example 116, 0.1 g, 0.19 mmol) and 2-methylpyrrolidine (0.018 g, 0.19 mmol) in anhydrous acetonitrile (5 mL) was added Hunig's base (0.025 g), and then the solution was heated at 60° C. for 3 hours. After cooling to room temperature, the reaction was diluted with 50 mL of CH2Cl2, washed water and brine, dried over sodium sulfate, and evaporated under reduced pressure. The crude residue was choromatographed over silica using CH2Cl2 to give the titled compound. 1H NMR (CD3OD) δ ppm 1.00 (3H), 1.60 (1H), 1.90 (3H), 3.40 (2H), 3.90 (1H), 4.80 (2H), 5.20 (1H), 5.35 (1H), 7.30 (2H), 7.50 (1H); MS (ESI) 382(M+H)+.
Reaction SMILES: [C:1]([NH:4][C@:5]1([C:20](=[O:26])[NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C@@H:9]([CH2:10][CH:11]=[CH2:12])[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6]1)(=[O:3])[CH3:2].[CH3:27][C:28]1([CH3:35])[C:32]([CH3:34])([CH3:33])[O:31][BH:30][O:29]1>C(Cl)Cl.[Ir].ClC1CCC=CCCC=1.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([NH:4][C@:5]1([C:20](=[O:26])[NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:30]2[O:31][C:32]([CH3:34])([CH3:33])[C:28]([CH3:35])([CH3:27])[O:29]2)[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: C=CC[C@H]1CN(C(=O)OC(C)(C)C)C[C@@]1(NC(C)=O)C(=O)NC(C)(C)C
Reactant: CC1(C)OBOC1(C)C
Agent: [Ir]
Agent: ClC1=CCCC=CCC1
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CN(C(=O)OC(C)(C)C)C[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
A stirred solution of (3R,4S)-tert-butyl 3-acetamido-4-allyl-3-(tert-butylcarbamoyl)pyrrolidine-1-carboxylate (5.51 g, 15 mmol) in anhydrous methylene chloride (80 mL) under nitrogen was treated with chloro-1,5-cyclooctadiene iridium dimer (0.252 g, 0.375 mmol) and 1,2-bis(diphenylphosphino)ethane (0.299 g, 0.75 mmol), stirred for 30 min. and cooled (−20° C.). 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (3.30 mL, 22.5 mmol) was added dropwise, and the solution was placed in an ice bath and allowed to reach room temperature overnight (18 h). The mixture was quenched with water (75 mL), stirred 15 min, and extracted with ethyl acetate (400 mL, then 2×100 mL). The combined organic solution was washed with saturated aqueous sodium chloride (150 mL), dried (MgSO4), and concentrated. The solid was recrystallized (2 crops) from acetonitrile to afford (3R,4S)-tert-butyl 3-acetamido-3-(tert-butylcarbamoyl)-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-1-carboxylate (6.13 g, 82%) as a white solid. NMR (CDCl3) δ 6.40-6.60 (m, 1 H), 6.23 (s, 1 H), 3.95-4.05 (m, 1 H), 3.65-3.75 (m, 2 H), 2.90-3.20 (m, 2 H), 2.00 (s, 3 H), 1.45 (s, 9 H), 1.30-1.45 (m, 4 H), 1.33 (s, 9 H), 1.22 (s, 12 H), 0.70-0.80 (m, 2 H). MS (m+1): 496.4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:13])C(F)(F)F)[N:5]([CH3:7])[CH:6]=1.Cl.[OH-].[NH4+:16]>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH2:16])=[O:13])[N:5]([CH3:7])[CH:6]=1
Reactant: [NH4+]
Reactant: Cn1cc(Br)cc1C(=O)C(F)(F)F
Agent: Cl
Agent: [OH-]
Product: Cn1cc(Br)cc1C(N)=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 81 %

Procedure:
1-(4-bromo-1-methyl-1H-pyrrol-2-yl)-2,2,2-trifluoroethanone (5.0 g, 19.5 mmol) was dissolved in ammonium hydroxide (72.5 ml, 29.4% aqueous solution) and stirred at room temperature for 45 min. The solution was brought to pH=7 with 2N HCl. The solid precipitate was collected by filtration. The solid was washed with water and dried overnight under reduced pressure at 50° C. The aqueous layer was extracted twice with dichloromethane. The organic phase was concentrated in vacuo to afford more solid. Solid from the filtration and extraction were combined to afford 4-bromo-1-methyl-1H-pyrrole-2-carboxylic acid amide (3.2 g, 81%) as a white solid: LC/MS-ESI observed [M+H]+ 203 and 205.
Reaction SMILES: C([O:3][C:4](=[O:23])[C@:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:24][C:25]1[O:29][C:28]([C:30]2([CH3:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[N:27][C:26]=1[CH2:37][CH2:38]OS(C1C=CC(C)=CC=1)(=O)=O>>[F:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C@@:5]([CH3:14])([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:13][CH2:38][CH2:37][C:26]3[N:27]=[C:28]([C:30]4([CH3:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[O:29][C:25]=3[CH3:24])=[CH:11][CH:12]=2)[C:4]([OH:3])=[O:23])=[CH:21][CH:20]=1
Reactant: CCOC(=O)[C@](C)(Cc1ccc(O)cc1)Oc1ccc(F)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3(C)CCCCC3)oc2C)cc1
Product: Cc1oc(C2(C)CCCCC2)nc1CCOc1ccc(C[C@](C)(Oc2ccc(F)cc2)C(=O)O)cc1

Procedure:
The title compound was prepared from (S)-2-(4-fluorophenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-[5-methyl-2-(1-methylcyclohexyl)-oxazol-4-yl)-ethyl ester (95% ee; Chiralpak AD separation, 8×28 cm, 10% IPA/heptane, 275 nm) by the procedure described in Example 1.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH:5]([C:6]([O:8]CC)=O)[C:4]1([CH3:20])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1.[CH2:21]([NH2:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(=O)([O-])O.[Na+]>O>[CH2:21]([N:27]1[CH2:2][CH:3]2[CH:5]([C:4]2([CH3:20])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:6]1=[O:8])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCOC(=O)C1C(CCl)C1(C)c1cccc([N+](=O)[O-])c1
Reactant: CCCCCCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCCCCCN1CC2C(C1=O)C2(C)c1cccc([N+](=O)[O-])c1
Temperature: 100 °C

Procedure:
To a solution of ethyl 3-(chloromethyl)-2-methyl-2-(3-nitrophenyl)cyclopropane carboxylate (Preparation 5, 20 g, 67.2 mmol) in hexylamine (36 ml, 270 mmol) was added sodium hydrogen carbonate (5.64 g, 67.2 mmol), and the mixture was heated at 100° C. for 16 h. The rmixture was cooled, diluted with water (80 ml) and extracted with dichloromethane (3×150 ml). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica column chromatography, eluting with a gradient of 2:1 to 1:2 hexane/ethyl acetate. Appropriate fractions were combined and concentrated in vacuo to give the title compound as a very pale yellow oil (14.2 g, 67%).