Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C@H:4]1[C:8](=[O:9])[O:7][C@H:6]([C@@H:10]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:11][C@H:12]([CH2:16][C:17]2[CH:25]=[C:24]3[C:20]([CH:21]=[N:22][N:23]3[CH2:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:19][CH:18]=2)[CH:13]([CH3:15])[CH3:14])[CH2:5]1)([CH3:3])[CH3:2].OC1C=CC=CN=1.[NH2:46][CH2:47][C:48]([CH3:53])([CH3:52])[C:49]([NH2:51])=[O:50]>CCN(CC)CC>[NH2:51][C:49](=[O:50])[C:48]([CH3:53])([CH3:52])[CH2:47][NH:46][C:8]([C@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][C@H:6]([OH:7])[C@@H:10]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:11][C@H:12]([CH2:16][C:17]1[CH:25]=[C:24]2[C:20]([CH:21]=[N:22][N:23]2[CH2:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:19][CH:18]=1)[CH:13]([CH3:14])[CH3:15])=[O:9]
Reactant: COCCCn1ncc2ccc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H]3C[C@@H](C(C)C)C(=O)O3)C(C)C)cc21
Reactant: CC(C)(CN)C(N)=O
Agent: Oc1ccccn1
Solvent: CCN(CC)CC
Product: COCCCn1ncc2ccc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@H](C(=O)NCC(C)(C)C(N)=O)C(C)C)C(C)C)cc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
A mixture of tert-butyl (1S,3S)-1-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl)-3-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-4-methylpentylcarbamate (120 mg, 0.25 mmol), Et3N (1.5 mL), 2-hydroxypyridine (71.3 mg, 0.75 mmol), and 3-amino-2,2-dimethylpropanamide (87 mg, 0.75 mmol) was stirred at 80° C. overnight. The mixture was evaporated and purified by flash chromatography on silica gel to give tert-butyl (3S,5S,6S,8S)-8-(3-amino-2,2-dimethyl-3-oxopropylcarbamoyl)-6-hydroxy-3-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-2,9-dimethyldecan-5-ylcarbamate (120 mg, 65%). MS: 646 (M++1)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N:13]=[N:14][NH:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[C:26]#[N:27])#[N:2].[ClH:28].[CH2:29]([N:31]([CH2:38][CH3:39])[CH2:32][CH2:33][CH2:34][C:35](O)=[O:36])[CH3:30]>C(Cl)Cl>[ClH:28].[CH2:29]([N:31]([CH2:32][CH2:33][CH2:34][C:35]([N:13]([C:4]1[CH:5]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2])[N:14]=[N:15][C:16]1[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[CH:18][C:17]=1[C:26]#[N:27])=[O:36])[CH2:38][CH3:39])[CH3:30]
Reactant: CCN(CC)CCCC(=O)O
Reactant: N#Cc1ccc(C(F)(F)F)cc1N=NNc1cc(C(F)(F)F)ccc1C#N
Agent: Cl
Solvent: ClCCl
Product: CCN(CC)CCCC(=O)N(N=Nc1cc(C(F)(F)F)ccc1C#N)c1cc(C(F)(F)F)ccc1C#N

Procedure:
A solution of 10.0 g. (0.026 mol.) of 1,3-bis(2-cyano-5-trifluoromethylphenyl)triazene, 6.0 g. (0.029 mol.) of N,N-dicyclohexylcarbodiimide and 5.1 g. (0.026 mol.) of 4-diethylaminobutyric acid hydrochloride in 800 ml. of methylene chloride is stirred at 25° for 12 hours. The reaction mixture is filtered and the filtrate is concentrated under reduced pressure to give a residue which is washed with ether and recrystallized from benzene to give 3-[4-(N,N-diethylamino)butyryl]-1,3-bis(2-cyano-5-trifluoromethylphenyl)-triazene hydrochloride.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][O:20][C:21](=[O:61])[CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH2:58][CH3:59])([C:38]3[CH:43]=[CH:42][C:41]([C:44]#[C:45][C:46]4([O:52][Si](C)(C)C)[CH2:51][CH2:50][S:49][CH2:48][CH2:47]4)=[C:40]([CH3:57])[CH:39]=3)[CH2:36][CH3:37])=[CH:31][C:30]=2[CH3:60])[CH:28]=1.O>O1CCCC1>[CH3:19][O:20][C:21](=[O:61])[CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH2:36][CH3:37])([C:38]3[CH:43]=[CH:42][C:41]([C:44]#[C:45][C:46]4([OH:52])[CH2:47][CH2:48][S:49][CH2:50][CH2:51]4)=[C:40]([CH3:57])[CH:39]=3)[CH2:58][CH3:59])=[CH:31][C:30]=2[CH3:60])[CH:28]=1
Reactant: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCSCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(C#CC2(O)CCSCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Reaction time: 0.5 h
Yield: 71 %

Procedure:
Tetrabutylammonium fluoride (1 M solution in tetrahydrofuran, 0.2 mL, 0.2 mmol) was added to a solution of [5-(4-{1-ethyl-1-[3-methyl-4-(4-trimethylsilanyloxy-tetrahydro-thiopyran-4-ylethynyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester (Example 137-(1); 82 mg, 0.13 mmol) in tetrahydrofuran (1 mL) at 0° C., and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=1:3) to give the target compound as a colorless oil (50 mg, 69%).
Reaction SMILES: [C:1]1([C:7]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.O/[N:47]=[C:48](/[NH2:55])\[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>CN(C=O)C>[C:49]1([C:48]2[N:55]=[C:13]([C:7]3([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]3)[O:15][N:47]=2)[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: N/C(=N/O)c1ccccc1
Reactant: O=C(O)C1(c2ccccc2)CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(-c2noc(C3(c4ccccc4)CCCCC3)n2)cc1
Temperature: 95 °C
Yield: 4 %

Procedure:
A solution of 1-phenylcyclohexanecarboxylic acid (1 g, 4.9 mmol), EDAC (1.032 g, 5.39 mmol), HOBT (825 mg, 5.39 mmol), and N,N-diisopropylethylamine (2.57 mL, 14.69 mmol) in DMF (5 mL) was stirred at room temperature for 30 min under an argon atmosphere. (E)-N′-hydroxybenzimidamide (733 mg, 5.39 mmol) was added and the reaction mixture was heated to 95° C. for 8 h. The reaction mixture was cooled to room temperature and a portion (˜10%) was purified by automated preparative HPLC (PHENOMENEX® Luna Axia 21.2×100 mm 5 μm, Flow rate 20 mL/min, Gradient time 15 min, Mobile Phase: solvent A: 5% aq. MeOH, 0.05% TFA; solvent B: 95% aq. MeOH, 0.05% TFA). HPLC: tR=3.95 min, Waters Sunfire C18 4.6×50 mm, 4 min gradient, Detection Wave length 220 nm, Starting solvent: 10% aq. MeOH-0.1% TFA; Final solvent: 90% aq. MeOH-0.1% TFA to obtain 3-phenyl-5-(1-phenylcyclohexyl)-1,2,4-oxadiazole (60 mg). LC/MS: m/e 305.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.95-8.14 (2 H, m), 7.47-7.66 (3H, m), 7.31-7.44 (4 H, m), 7.17-7.31 (1H, m), 2.57-2.75 (2 H, m), 2.01-2.18 (2 H, m), 1.71 (2H, bs), 1.51-1.65 (1H, m), 1.27-1.51 (3 H, m).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18]CC3C=CC=CC=3)=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9](=[N:26]O)[CH2:8][CH:7]1[CH3:28])=[O:5])[CH3:2].[OH-].[K+]>C(O)C.[Al].[Ni]>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:18])=[C:13]([O:16][CH3:17])[CH:14]=2)[C@H:9]([NH2:26])[CH2:8][C@@H:7]1[CH3:28])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2cc(OC)c(OCc3ccccc3)cc2C(=NO)CC1C
Agent: [Ni]
Agent: [Al]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)N1c2cc(OC)c(O)cc2[C@H](N)C[C@@H]1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 25.9 %

Procedure:
To a stirred solution of 6-benzyloxy-4-hydroxyimino-7-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (2.05 g, 5.33 mmol), in ethanol (20 mL) and aqueous 2N KOH (16 mL, 32 mmol) was added aluminum-nickel alloy (1.82 g, 50% Ni, 21.2 mmol) in portions. The reaction was stirred at room temperature for 1.5 h, then additional aluminum-nickel alloy (1.82 g, 21.2 mmol) was added, and the reaction was stirred for 3 h. Additional aqueous 2N KOH (20 mL, 40 mmol) was added, and the reaction was stirred for 1 h. The mixture was then filtered through a bed of Celite®, rinsing with ethyl acetate. The filtrate was concentrated in vacuo, and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give 0.65 g crude product. Purification by silica gel chromatography using 0-5% methanol/dichloromethane as eluent afforded 387 mg of the title compound (26%).
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:39])[C@@H:24]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:18][C@:14]2([OH:40])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([OH:58])[C:5]([C@@:7]1([CH3:57])[C@H:12]([C@@H:13]2[O:41][C:42]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[O:43])[C@:11]2([O:52][C:53]([CH3:55])=[O:54])[CH2:50][O:51][C@@H:10]2[CH2:9][C@@H:8]1[OH:56])=[O:6].C(#N)C>O>[CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:39])[C@@H:24]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:18][C@@:14]2([OH:40])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([OH:58])[C:5]([C@@:7]1([CH3:57])[C@H:12]([C@@H:13]2[O:41][C:42]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[O:43])[C@:11]2([O:52][C:53]([CH3:55])=[O:54])[CH2:50][O:51][C@@H:10]2[CH2:9][C@@H:8]1[OH:56])=[O:6].[OH2:6].[OH2:6].[OH2:6]
Reactant: CC(=O)O[C@@]12CO[C@@H]1C[C@H](O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)c4ccccc4)C[C@@](O)([C@@H](OC(=O)c4ccccc4)[C@H]21)C3(C)C
Solvent: CC#N
Solvent: O
Product: CC(=O)O[C@@]12CO[C@@H]1C[C@H](O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)c4ccccc4)C[C@](O)([C@@H](OC(=O)c4ccccc4)[C@H]21)C3(C)C

Procedure:
In accordance with the third aspect of the present invention, a process of producing docetaxel trihydrate is provided. The process comprises a) combining anhydrous docetaxel, and acetonitrile; b) heating the mixture of step a) to about 30-60° C.; c) adding water to the mixture of the heated mixture of step d); cooling the mixture of c) to about 10-30° C. to obtain a slurry; and e) filtering, washing, and drying the slurry of step d) to obtain docetaxel trihydrate.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][C:13]([Br:18])=[C:14]([OH:17])[CH:15]=2)[N:10]([CH:19]2[CH2:21][CH2:20]2)[C:9]=1[CH3:22])=[O:7])[CH3:4].[CH3:23]I>CN(C=O)C.O.CCOCC>[CH2:3]([O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][C:13]([Br:18])=[C:14]([O:17][CH3:23])[CH:15]=2)[N:10]([CH:19]2[CH2:20][CH2:21]2)[C:9]=1[CH3:22])=[O:7])[CH3:4]
Reactant: CI
Reactant: CCOC(=O)c1c(C)n(C2CC2)c2cc(Br)c(O)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1c(C)n(C2CC2)c2cc(Br)c(OC)cc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 88.1 %

Procedure:
Sodium hydride (60% in mineral oil, 71 mg, 1.8 mmol) is added to a solution of 6-bromo-1-cyclopropyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester (200 mg, 0.590 mmol) in DMF (4.0 mL). The mixture is stirred for 20 minutes at room temperature. Methyl iodide (110 μL, 1.77 mmol) is added and the mixture is stirred for 1 h at room temperature. The mixture is diluted with water and ether. The layers are separated. The ether layer is washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue is triturated in ethyl acetate-hexane to give the title compound as an off-white solid (183 mg, 88%). ES/MS m/e 353.8 (M+1).
Reaction SMILES: [CH:1]1([C:7]([N:9]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)=[O:8])CCCCC1.N1C2C(=CC(S(N)(=O)=O)=CC=2)CC1.[Cl:35]CC(Cl)=O>>[Cl:35][CH2:1][C:7]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)=[O:8]
Reactant: O=C(Cl)CCl
Reactant: NS(=O)(=O)c1ccc2c(c1)CCN2C(=O)C1CCCCC1
Agent: NS(=O)(=O)c1ccc2c(c1)CCN2
Product: NS(=O)(=O)c1ccc2c(c1)CCN2C(=O)CCl
Yield: 23 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 55, indoline-5-sulfonamide (Intermediate 54A, 500 mg, 2.52 mmol) and 2-chloroacetyl chloride (221 μL, 2.77 mmol) were converted to the title compound (160 mg, 23%). 1H NMR (DMSO-d6) δ 8.13 (d, J=8.1 Hz, 1H), 7.68-7.66 (m, 2H), 7.24 (s, 2H), 4.58 (s, 2H), 4.20 (t, J=8.5 Hz, 2H), 3.24 (t, J=8.5 Hz, 2H); MS(ESI+) m/z 275.0 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([Cl:21])=[C:19]([Cl:22])[N:18]=[C:17]([Cl:23])[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[ClH:21].[ClH:21].[NH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[C:20]([Cl:21])=[C:19]([Cl:22])[N:18]=[C:17]([Cl:23])[N:16]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc(Cl)nc(Cl)c2Cl)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Clc1nc(Cl)c(Cl)c(NC2CCNCC2)n1

Procedure:
A solution of 4-(2,5,6-trichloro-pyrimidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.85 g, 2.23 mmol) in 4 M HCl in dioxane (100 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 283.4 [M+H]+.
Reaction SMILES: C([O:8][N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([F:25])[C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[N:19][C:12]=2[N:11]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])[C:10]1=[O:33])C1C=CC=CC=1>C1COCC1.[Pd]>[F:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[N:11]1[C:12]2[N:19]=[C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]([F:25])=[CH:16][C:13]=2[C:14](=[O:15])[N:9]([OH:8])[C:10]1=[O:33]
Reactant: O=c1c2cc(F)c(N3CCCC3)nc2n(-c2ccccc2F)c(=O)n1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=c1c2cc(F)c(N3CCCC3)nc2n(-c2ccccc2F)c(=O)n1O
Yield: 116.4 %

Procedure:
Using the method of Example 56, 20% Pd/C (25 mg), 3-benzyloxy-1-(2-fluorophenyl)-6-fluoro-7-pyrrolidin-1-yl-1H-pyrido[2,3-d]pyrimidine-2,4dione (Example T-4, 0.14 g, 0.31 mmol) were combined in 25 mL of THF, to give 0.13 g of the title compound as a solid, mp >250° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([S:20](=[O:23])(=[O:22])[NH2:21])=[CH:16][CH:15]=2)[C:11]#N)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].O=[CH:25][C:26](=C)[CH3:27]>>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20](=[O:23])(=[O:22])[NH2:21])=[CH:16][CH:15]=3)[CH:25]=[C:26]([CH3:27])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: C=C(C)C=O
Reactant: COc1ccc(C(C#N)Nc2ccc(S(N)(=O)=O)cc2)cc1F
Product: COc1ccc(-c2cc(C)cn2-c2ccc(S(N)(=O)=O)cc2)cc1F

Procedure:
Following a procedure similar to that described in Example 1(iii), but using α-(3-fluoro-4-methoxyphenyl)-α-(4-sulfamoylanilino) acetonitrile [prepared as described in step (ii) above] and methacrolein as starting materials, the title compound was obtained as a white powder (yield 28%), melting at 170-173° C.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[C:8]([NH:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH:14]([OH:18])[CH2:13]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[C:22]([F:35])[N:21]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:19][C:20]1[CH:25]=[C:24]([C:2]2[N:6]3[CH:7]=[C:8]([NH:11][CH:12]4[CH2:17][CH2:16][CH2:15][CH:14]([OH:18])[CH2:13]4)[CH:9]=[CH:10][C:5]3=[N:4][CH:3]=2)[CH:23]=[C:22]([F:35])[N:21]=1
Reactant: CC1(C)OB(c2cc(F)nc(Cl)c2)OC1(C)C
Reactant: OC1CCCC(Nc2ccc3ncc(Br)n3c2)C1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OC1CCCC(Nc2ccc3ncc(-c4cc(F)nc(Cl)c4)n3c2)C1
Temperature: 95 °C

Procedure:
To a solution of 3-trans-RS/RS (3-bromo-imidazo[1,2-a]pyridin-6-ylamino)-cyclohexanol [intermediate J step 2] (1 eq, 0.1 g), 2-Chloro-6-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (1.05 eq,82 mg), Na2CO3 (2 eq, 68 mg) in ethanol (2 ml) and water (0.2 ml), under an inert atmosphere of argon is added bis(triphenylphosphine)palladium II chloride (0.1 eq, 0.96 mmol, 22 mg). The reaction mixture is heated at 95° C. for 16 hours. The mixture is diluted with H2O (50 ml) and extracted with EtOAc. The combined organic portions are washed with brine, dried (MgSO4) and concentrated in vacuo. The residue is purified by chromatography on silica eluting with 0-10% MeOH in EtOAc to afford the title compound; [M+H]+=360.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([N+:16]([O-:18])=[O:17])[C:14]=1F)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.CN(C=O)C.[CH3:24][S-:25].[Na+].C(=O)(O)[O-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([N+:16]([O-:18])=[O:17])[C:14]=1[S:25][CH3:24])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: C[S-]
Reactant: O=[N+]([O-])c1c(F)c(Cl)cc2c1[nH]c1cnccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1c(Cl)cc2c([nH]c3cnccc32)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
A 250 ml round-bottom flask with magnetic stirrer was charged with 6-chloro-7-fluoro-8-nitro-β-carboline (Intermediate 5, 3.959 g, 14.9 mmol) and 100 ml anhydrous DMF. The resulting orange mixture was cooled to 0° C. (ice and water bath) and sodium thiomethoxide (1.809 g, 25.8 mmol) in powder form was added slowly thereto. The reaction mixture was stirred for 1 hr at 0° C., warmed to RT, and added slowly to a stirring mixture of 4:1H2O/saturated aqueous sodium bicarbonate (500 ml). The precipitated solid was collected via suction filtration and air-dried to afford 4.017 g of 6-chloro-7-methylsulfanyl-8-nitro-9H-β-carboline as an orange powder. The crude material was used directly in subsequent steps. 1H-NMR (300 MHz, Methanol-d4): δ 8.91 (1H, d) 8.63 (1H, s) 8.42 (1H, d) 8.17 (1H, dd) 2.54 (3H, s). LCMS (formic acid standard method) retention time=1.43 min. MS (M+H+): 294.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=1.BrCCBr.[Si:14]([O:21][CH2:22][C:23](N(OC)C)=[O:24])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>>[Si:14]([O:21][CH2:22][C:23]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=1)=[O:24])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CON(C)C(=O)CO[Si](C)(C)C(C)(C)C
Reactant: Fc1cccc(Br)c1
Agent: [Mg]
Solvent: BrCCBr
Product: CC(C)(C)[Si](C)(C)OCC(=O)c1cccc(F)c1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 95.9 %

Procedure:
To a suspension of magnesium turnings (2.10 g, 85.7 mmol) in anhydrous THY (120 mL), was added slowly at RT 1-bromo-3-fluorobenzene (10.0 g, 57.2 mmol) and 1,2-dibromoethane (0.10 mL). After stirring for 40 min under argon, the mixture was cooled to −78° C., and 2-(tert-butyldimethylsilyloxy)-N-methoxy-N-methylacetamide (9.3 g, 40 mmol) was added. The resulting mixture was warmed to 0° C. and stirred for 2 h. The reaction was quenched with saturated NH4Cl (5.0 mL), and the insoluble material was filtered. The filtrate was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (20:1) to afford 10.3 g (93%) of 2-(tert-butyldimethylsilyloxy)-1-(3-fluorophenyl)ethanone (58a) as oil. LCMS (ESI) m/z: 268.0[M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[C:20]3[C:15](=[C:16]([F:22])[CH:17]=[CH:18][C:19]=3[F:21])[O:14][CH2:13][CH:12]2[CH2:23][CH2:24][CH:25]=[O:26])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:27]([Mg]Br)[CH:28]=[CH2:29]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]2[C:20]3[C:15](=[C:16]([F:22])[CH:17]=[CH:18][C:19]=3[F:21])[O:14][CH2:13][CH:12]2[CH2:23][CH2:24][CH:25]([OH:26])[CH2:29][CH:28]=[CH2:27])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: C=CC[Mg]Br
Reactant: O=CCCC1COc2c(F)ccc(F)c2C1S(=O)(=O)c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: C=CCC(O)CCC1COc2c(F)ccc(F)c2C1S(=O)(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 65.7 %

Procedure:
A solution of 3-[4-(4-chloro-benzenesulfonyl)-5,8-difluoro-chroman-3-yl]-propionaldehyde (1.79 g, 4.47 mmol) in THF (45 mL) at −78° C. was treated with allylmagnesium bromide (1 M in Et2O, 5.8 mL, 5.8 mmol) and warmed to 0° C. over 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl, and extracted with EtOAc (2×). The combined organic extracts were washed saturated aqueous NaHCO3, brine, dried over MgSO4 and concentrated in vacuo. Flash chromatography (2→10% EtOAc/CH2Cl2) afforded the title compound (1.3 g, 66%): 1H NMR (CDCl3 400 MHz) δ 7.71 (dd, J=8.1, 1.5 Hz, 2H), 7.53 (dd, J=8.1, 1.5 Hz, 2H), 7.03 (m, 1H), 6.41 (m, 1H), 5.76 (m, 1H), 5.16-5.08 (m, 2H), 4.93 (ddd, J=11.7, 2.9, 2.9 Hz, 1H), 4.32 (dd, J=12.4, 2.2 Hz, 1H), 4.31 (s, 1H), 3.59 (m, 1H), 2.85 (m, 1H), 2.29-2.10 (m, 2H), 1.68-1.43 (m, 4H).
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:35](=[O:37])[CH3:36])[C:10]([O:16][CH2:17][CH2:18][CH2:19][O:20][C:21]3[C:26]([Cl:27])=[CH:25][C:24]([C:28](=[O:30])[CH3:29])=[C:23]([OH:31])[C:22]=3[CH2:32][CH2:33][CH3:34])=[CH:11][CH:12]=2)[CH:7]=1.[OH-].[Na+]>CO>[C:35]([C:9]1[C:10]([O:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[C:26]([Cl:27])=[CH:25][C:24]([C:28](=[O:30])[CH3:29])=[C:23]([OH:31])[C:22]=2[CH2:32][CH2:33][CH3:34])=[CH:11][CH:12]=[C:13]2[C:8]=1[CH:7]=[C:6]([O:5][CH2:4][C:3]([OH:38])=[O:2])[CH:15]=[CH:14]2)(=[O:37])[CH3:36]
Reactant: CCCc1c(O)c(C(C)=O)cc(Cl)c1OCCCOc1ccc2ccc(OCC(=O)OC)cc2c1C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(O)c(C(C)=O)cc(Cl)c1OCCCOc1ccc2ccc(OCC(=O)O)cc2c1C(C)=O
Yield: 73.4 %

Procedure:
A mixture of 1.3 g of [[8-acetyl-7-[3-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)propoxy]-2-naphthalenyl]oxy]acetic acid methyl ester, 48 ml of methanol and 24 ml of 1N sodium hydroxide was stirred at reflux for one hour and 20 minutes. The methanol was removed in vacuo the aqueous solution was acidified to pH 3. The sticky solid was extracted with chloroform, washed with water, dried over magnesium sulfate and concentrated in vacuo to give an oil which was crystallized from ether to yield 0.93 g (78%) of [[8-Acetyl-7-[3-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)propoxy]-2-naphthalenyl]oxy]acetic acid, mp 132°-134° C.
Reaction SMILES: C(O[CH2:10][C@H:11]([C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1)[CH2:12][CH:13]=[O:14])(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[N:21]1([C:18]2[CH:19]=[CH:20][C:15]([C@H:11]([CH3:10])[CH2:12][CH:13]=[O:14])=[CH:16][CH:17]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=CC[C@H](COC(=O)c1ccccc1)c1ccc(N2CCCC2)cc1
Solvent: ClC(Cl)Cl
Product: C[C@H](CC=O)c1ccc(N2CCCC2)cc1

Procedure:
A solution (R)-3-(4-pyrolidin-1-yl-phenyl)-butyraldehyde (201 mg, 0.923 mmol, 1.00 equiv) in CH2Cl2 (0.5 mL) was added to a stirring solution of sodium borohydride (37.1 mg, 1.00 mmol, 1.08 equiv) in ethanol (3.0 mL). After 5 min, the reaction was diluted with saturated aqueous NaHCO3 (50 mL) and CH2Cl2 (30 mL). The organic layer was separated and washed with saturated solutions of NaHCO3 and NaCl. The resulting solution was then dried over Na2SO4 and concentrated in vacuo. The residual oil (201 mg, 0.915 mmol, 1.00 equiv) was exposed to tert-butyldimethylsilyl chloride (276 mg, 1.83 mmol, 2.00 equiv), triethylamine (0.28 mL, 2.0 mmol, 2.2 equiv), and DMAP (10 mg) in CH2Cl2 (1.5 mL). After one hour, the reaction mixture was subjected directly to silica gel chromatography. Elution with 10% Et2O in hexanes followed by concentration of two fractions in vacuo afforded 35 mg of S3 as a colorless oil (0.10 mmol, 11% yield) that was spectroscopically identical in all respects to (S)-4-benzoyloxy-3-(4-pyrolidin-1-yl-phenyl)-butyraldehyde. [α]D (reference)=−28.7 (c=1.20, CHCl3); [α]D (observed)=−34.8 (c=0.994, CHCl3).