Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.N1C=CC=CC=1.C[O:9][C:10]1[CH:24]=[CH:23][C:13]([C:14]([C:16]2[NH:17][C:18](=[O:22])[NH:19][C:20]=2[CH3:21])=[O:15])=[CH:12][CH:11]=1>>[OH:9][C:10]1[CH:24]=[CH:23][C:13]([C:14]([C:16]2[NH:17][C:18](=[O:22])[NH:19][C:20]=2[CH3:21])=[O:15])=[CH:12][CH:11]=1
Reactant: COc1ccc(C(=O)c2[nH]c(=O)[nH]c2C)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1[nH]c(=O)[nH]c1C(=O)c1ccc(O)cc1
Reaction time: 0.5 h

Procedure:
To a melt of 26 g (0.23 mole) of pyridine hydrochloride at 200°-205° C. is added 5.3 g (0.023 mole) of 1,3-dihydro-4-(4-methoxybenzoyl)-5-methyl-2H-imidazol-2-one and the mixture is stirred mechanically for 30 minutes. The reaction mixture is poured on ice-2NHCl. The resulting precipitate is washed with water and recrystallized from isopropanol-water to give the title compound. M.P. >300° C. λ(max)(methanol) 320 nm (ε=13,200).
Reaction SMILES: [OH-].[K+].[C:3]1(/[C:9](/[C:19]2[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21][CH:20]=2)=[C:10](/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)\[CH2:11][CH3:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:27][C:28]#[N:29]>O>[C:3]1([C:9]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]=[CH:27][C:28]#[N:29])=[CH:21][CH:20]=2)=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH3:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=O)cc1)c1ccccc1
Reactant: CC#N
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCC(=C(c1ccccc1)c1ccc(C=CC#N)cc1)c1ccccc1
Yield: 57 %

Procedure:
A suspension of potassium hydroxide (85%, 260 mg, 3.9 mmol) in CH3CN (25 mL) was heated to reflux and (Z)-1,2-Diphenyl-1-(4-formylphenyl)-1-butene (4a) (Willson J. Med. Chem. 1994, 37, 1550-1552) (1.0 g, 3.18 mmol) was added in portions. After refluxing 5 min the mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, brine and dried (MgSO4). The solvent was removed under reduced pressure and the residue chromatographed (silica gel, 15% EtOAc/hexanes) to give the nitrile (4b) as a white solid (616 mg, 57%): 1H NMR (CDCl3) δ 7.39-7.07 (m, 13H), 6.91 (d, J=8.4 Hz, 2H), 5.69 (d, J=16.9 Hz, 1H), 2.48 (q, J=7.3 Hz, 2H), 0.94 (t, J=7.3 Hz, 3H); HRMS calcd. for C25H21N (M+H+) 335.1674; found 335.1679.
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][C@H:7]1[N:14]([C:15]([C:17]2[N:18]=[C:19]([CH3:29])[S:20][C:21]=2[C:22]2[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=2)=[O:16])[CH2:13][C@H:12]2[C@@H:8]1[CH2:9][CH:10]([CH3:30])[CH2:11]2)=O.C([O-])([O-])=O.[K+].[K+].CCOCC>CO>[NH2:5][CH2:6][C@H:7]1[N:14]([C:15]([C:17]2[N:18]=[C:19]([CH3:29])[S:20][C:21]=2[C:22]2[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=2)=[O:16])[CH2:13][C@H:12]2[C@@H:8]1[CH2:9][CH:10]([CH3:30])[CH2:11]2
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CO
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CN)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,2,2-trifluoro-N-[(1S,2S,5R)-3-(2-methyl-5-m-tolyl-thiazole-4-carbonyl)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-acetamide (1.96 g) was dissolved in MeOH (20 mL) and a sat. aq. K2CO3 solution was added (20 mL). The reaction mixture was stirred overnight at RT. Ether was added to the reaction mixture and the org. layer was extracted with aq. HCl (25%) and aq. HCl (1M). The org. phase was discarded and the aq. layers were basified with aq. 30% NaOH and then extracted with DCM. The combined org. extracts were washed with a sat. aq. NaHCO3 solution, dried over anh. MgSO4, filtered and concentrated to yield the title compound as a light orange oil which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][NH:8][N:7]=1)=[O:5])[CH3:2].Br[CH2:15][CH:16]1[CH2:18][CH2:17]1>>[CH2:1]([O:3][C:4]([C:6]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][N:8]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1n[nH]cc1[N+](=O)[O-]
Reactant: BrCC1CC1
Product: CCOC(=O)c1nn(CC2CC2)cc1[N+](=O)[O-]
Yield: 46 %

Procedure:
The product was obtained according to the method described in example 4, step 2 starting from 4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester and bromomethyl-cyclopropane as a mixture of regioisomers which were separated by silica gel chromatography using a heptane/ethyl acetate gradient to yield 88 mg (23%) of the desired regioisomer and 179 mg (46%) of 1-cyclopropylmethyl-4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[NH2:11][CH:12]1[C:36](=[O:37])[N:14]2[CH:15]([C:20]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH:16]([OH:19])[CH2:17][S:18][C@H:13]12.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:1]([NH:11][CH:12]1[C:36](=[O:37])[N:14]2[CH:15]([C:20]([O:22][CH:23]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH:16]([OH:19])[CH2:17][S:18][C@H:13]12)=[O:2]
Reactant: O=CO
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(O)CS[C@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: O=CNC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(O)CS[C@H]12
Temperature: 3 °C
Reaction time: 0.17 h

Procedure:
Formic acid (0.4 ml) and acetic anhydride (1 ml) were stirred at 40° C. for 30 minutes. The reaction mixture was cooled in an ice-water bath and added dropwise to a mixture of benzhydryl 7-amino-3-hydroxycepham-4-carboxylate (1.0 g) in methylene chloride (30 ml) at 3° C. The mixture was stirred at 3° C. for 10 minutes and adjusted to pH 7.0 with 5% aqueous solution of sodium bicarbonate, washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give benzhydryl 7-formamido-3-hydroxycepham-4-carboxylate (1.05 g) as powder.
Reaction SMILES: [CH3:1][C:2]1[NH:8][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH:3]=1.[H-].[Na+].[Br:16][CH2:17][CH2:18][CH2:19][CH2:20]Br.C(OCC)(=O)C>CN(C)C=O>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][N:8]1[C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH:3]=[C:2]1[CH3:1]
Reactant: BrCCCCBr
Reactant: CC1=COc2ccccc2C(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1=COc2ccccc2C(=O)N1CCCCBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
2.0 g of 3-methyl-4,5-dihydro-1,4-benzoxazepin-5-one was dissolved in 120 ml of dimethylformamide, then 548 mg (1.2 equivalents) of 60% sodium hydride was added under ice cooling. This was stirred at room temperature for 1 hour, then 4.1 ml (3 equivalents) of 1,4-dibromobutane was added and the mixture was stirred for 3 hours. Ice water was added to the reaction solution and extraction was performed with ethyl acetate. The ethyl acetate extract was washed with saline, then dried over anhydrous magnesium sulfate. The solvent was distilled off and the resultant crude product was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 3.0 g of the above-identified compound (yield 84%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].[N:11]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(CC)CC)C>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:14]2[CH2:13][CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15]2)=[C:6]([C:7]#[N:8])[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#Cc1cc(Br)ccc1F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)cc2C#N)CC1
Yield: 79.9 %

Procedure:
In a pressure tube, 5-bromo-2-fluorobenzonitrile (2500 mg, 12.5 mmol), tert-butyl piperazine-1-carboxylate (2444.45 mg, 13.12 mmol), triethylamine (5.23 ml, 37.5 mmol) in dimethylsulfoxide (10 ml) were combined and refluxed at 100 C for ovn. The mixture was cooled, and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was dried using sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel 5-60% ethyl acetate/hexane to provide a light brown oil, tert-butyl 4-(4-bromo-2-cyanophenyl)piperazine-1-carboxylate (3660 mg, 80%).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([OH:6])=[O:5].[NH2:8][C:9](=[S:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].O.C([O-])(O)=O.[Na+]>O1CCOCC1>[CH2:13]([O:12][C:10]([C:9]1[S:15][C:3]([C:4]([OH:6])=[O:5])=[CH:2][N:8]=1)=[O:11])[CH3:14]
Reactant: CCOC(=O)C(N)=S
Reactant: O=C(O)C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1ncc(C(=O)O)s1
Yield: 47.8 %

Procedure:
Bromopyruvic acid (22.7 g, 135.33 mmol) was added to a solution of ethyl 2-amino-2-thioxoacetate (Intermediate W, 18 g, 135.3 mmol) in dioxane (200 mL) and refluxed for 5 h. After completion the reaction mixture was poured into water (200 mL), the residue was basified with sat NaHCO3 and extracted with EtOAc (2×250 mL). The aqueous layer was acidified with 2N HCl and extracted with EtOAc (2×250 mL) The combined extracts were washed with water (250 mL), brine (250 mL), dried over anhydrous Na2SO4, filtered and evaporated to afford 2-(ethoxycarbonyl)thiazole-5-carboxylic acid (13 g crude). The crude was carried to next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:5][CH:6]=[C:7]([CH3:9])[N:8]=1.[CH3:18][C:19]1[CH:36]=[CH:35][C:22]([CH2:23][O:24][C:25](=O)[O:26]N2C(=O)CCC2=O)=[CH:21][CH:20]=1>>[CH3:18][C:19]1[CH:36]=[CH:35][C:22]([CH2:23][O:24][C:25]([N:15]2[CH2:16][CH2:17][CH:12]([CH2:11][NH:10][C:4]3[C:3]([O:2][CH3:1])=[N:8][C:7]([CH3:9])=[CH:6][N:5]=3)[CH2:13][CH2:14]2)=[O:26])=[CH:21][CH:20]=1
Reactant: COc1nc(C)cnc1NCC1CCNCC1
Reactant: Cc1ccc(COC(=O)ON2C(=O)CCC2=O)cc1
Product: COc1nc(C)cnc1NCC1CCN(C(=O)OCc2ccc(C)cc2)CC1

Procedure:
The above compound was prepared in a similar manner as described in EXAMPLE 130 from 4-[(3-methoxy-5-methyl-pyrazin-2-ylamino)-methyl]-piperidine (EXAMPLE 130, STEP 2) using N-(4-methylbenzyloxycarbonyloxy)succinimide (INTERMEDIATE 1A). M.S.(M+1): 385.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[N:11]3[C:12]4[C:17]([N:18]=[C:19]([NH:20][CH2:21][CH2:22][CH2:23][OH:24])[C:10]3=[N:9][CH:8]=2)=[CH:16][C:15]([C:25]([F:28])([F:27])[F:26])=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[S:29](Cl)([CH3:32])(=[O:31])=[O:30].C(#N)C>ClCCl>[CH3:32][S:29]([N:1]1[CH2:2][CH:3]=[C:4]([C:7]2[N:11]3[C:12]4[C:17]([N:18]=[C:19]([NH:20][CH2:21][CH2:22][CH2:23][OH:24])[C:10]3=[N:9][CH:8]=2)=[CH:16][C:15]([C:25]([F:26])([F:28])[F:27])=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCNc1nc2cc(C(F)(F)F)ccc2n2c(C3=CCNCC3)cnc12
Solvent: ClCCl
Solvent: CC#N
Product: CS(=O)(=O)N1CC=C(c2cnc3c(NCCCO)nc4cc(C(F)(F)F)ccc4n23)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 15 %

Procedure:
To a solution of 3-[1-(1,2,3,6-tetrahydro-pyridin-4-yl)-7-trifluoromethyl-imidazo[1,2-a]quinoxalin-4-ylamino]-propan-1-ol as prepared in example 27 (50.0 mg; 0.132 mmol; 1 eq) in anhydrous dichloromethane (660 μL) are successively added N,N′-dimethylaminopyridine (16.1 mg; 0.132 mmol; 1 eq) and mesyl chloride (10.3 μL; 0.132 mmol; 1 eq). The solution is allowed to stir at room temperature for 17 hours after which period the reaction is almost complete. The reaction mixture is concentrated under vacuum and the resulting residue is taken-up with ethyl acetate (10 mL). The organic solution is washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated in vacuum. Two successive column chromatography on silica gel (eluent column 1: ethyl acetate/methanol/triethylamine 8:2:0.2; eluent column 2: dichloromethane/methanol 95:5) and one column chromatography on reversed-phase (C18, acetonitrile) affords the title compound as a white solid (9 mg; 0.020 mmol; 15%)
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][C@@H:11]2[CH3:29])=[O:9])=[C:4]([CH3:30])[CH:3]=1.[NH:31]1[CH2:34][CH2:33][CH2:32]1>C(O)(C)C>[N:31]1([C:2]2[N:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([S:16]([C:19]4[CH:20]=[CH:21][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:23][CH:24]=4)(=[O:18])=[O:17])[CH2:12][C@@H:11]3[CH3:29])=[O:9])=[C:4]([CH3:30])[CH:3]=2)[CH2:34][CH2:33][CH2:32]1
Reactant: Cc1cc(F)ncc1C(=O)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)C[C@@H]1C
Reactant: C1CNC1
Solvent: CC(C)O
Product: Cc1cc(N2CCC2)ncc1C(=O)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)C[C@@H]1C
Temperature: 120 °C
Yield: 92.6 %

Procedure:
(2S)-1-[(6-Fluoro-4-methyl-3-pyridinyl)carbonyl]-2-methyl-4-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (may be prepared as described in Example 27) (67 mg, 0.15 mmol) was weighed into a microwave vial and dissolved in isopropanol (1.5 ml). Azetidine (0.203 ml, 3.01 mmol) was added and the mixture was heated in the microwave to 120° C. for 12 h with stirring. The reaction mixture was concentrated to give the crude material as a colourless gum (˜187 mg). This was purified by MDAP to give the title compound as a pale yellow gum (67 mg). The gum was redissolved in MeOH, water was added, and the mixture was concentrated under a flow of argon then dried in vacuo to give the title compound as a colourless solid.
Reaction SMILES: C([O:3][C:4](=[O:39])[C@@H:5]([NH:15][C@H:16]([C:31](=[O:38])[NH:32][C:33]1[NH:37][N:36]=[N:35][N:34]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)=[CH:20][CH:19]=1)[CH2:6][O:7]CC1C=CC=CC=1)C>CCOC(C)=O.CCO.[Pd]>[Cl:30][C:26]1[CH:25]=[C:24]([C:21]2[CH:20]=[CH:19][C:18]([CH2:17][C@H:16]([NH:15][C@@H:5]([CH2:6][OH:7])[C:4]([OH:39])=[O:3])[C:31](=[O:38])[NH:32][C:33]3[NH:37][N:36]=[N:35][N:34]=3)=[CH:23][CH:22]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)[C@H](COCc1ccccc1)N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)Nc1nnn[nH]1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)[C@H](CO)N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)Nc1nnn[nH]1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
To a solution of (S)-3-benzyloxy-2-[(S)-2-(3′-chloro-biphenyl-4-yl)-1-(1H-tetrazol-5-ylcarbamoyl)-ethylamino]-propionic acid ethyl ester (Example 32-8: 47 mg, 0.090 mmol) in EtOAc (1 mL) and EtOH (1 mL) was added 5% Pd—C (9.6 mg, 0.0045 mmol). H2 gas was loaded with a balloon and the reaction mixture was stirred at 50° C. for 6 hours. The reaction mixture was filtered through celite pad and the filtrate was concentrated. The residue was purified by reverse phase HPLC (Sunfire C-18 column, eluent: 0.1% TFA in H2O/CH3CN) to give (S)-2-[(S)-2-(3′-chloro-biphenyl-4-yl)-1-(1H-tetrazol-5-ylcarbamoyl)-ethylamino]-3-hydroxy-propionic acid and (S)-2-[(S)-2-biphenyl-4-yl-1-(1H-tetrazol-5-ylcarbamoyl): ethylamino]-3-hydroxy-propionic acid.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@@H:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1)=O.O.[NH2:19][NH2:20]>C(O)CCC>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:11][C@@H:8]1[CH2:9][CH2:10][C@H:5]([C:3]([NH:19][NH2:20])=[O:2])[CH2:6][CH2:7]1
Reactant: COC(=O)[C@H]1CC[C@@H](Oc2ccccn2)CC1
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: NNC(=O)[C@H]1CC[C@@H](Oc2ccccn2)CC1
Temperature: 125 °C

Procedure:
A mixture of cis-4-(pyridin-2-yloxy)-cyclohexanecarboxylic acid methyl ester (0.39 g, 1.6 mmol) and hydrazine hydrate (0.40 ml, 8.2 mmol) in n-butanol (0.5 ml) was heated at 125° C. over night. After cooling to room temperature the reaction mixture was partitioned between dichloromethane (75 ml) and water (75 ml). The aqueous layer was washed with dichloromethane/75 ml). The combined organic layers were washed with water (75 ml) and brine (75 ml), dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound (0.35 g, 91%) as colorless oil, which was used in the next step without further purification. MS m/e: 236 (M+H+)
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[CH2:24][CH2:25][OH:26].CN([CH:30]=[O:31])C>C1COCC1>[F:16][C:17]1[C:18]([CH2:24][CH2:25][OH:26])=[C:19]([F:23])[CH:20]=[CH:21][C:22]=1[CH:30]=[O:31]
Reactant: CN(C)C=O
Reactant: OCCc1c(F)cccc1F
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(F)c(CCO)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,2,6,6-Tetramethylpiperidine (5 mL) was added to a solution of butyllithium (1.6M in hexanes, 19 mL) in THF (25 mL) at −70° C. A solution of 2-(2,6-difluorophenyl)ethanol (example 45, step a) (1.6 g) in THF (25 mL) was added dropwise and the resulting mixture stirred for 2 h. DMF (3.9 mL) was then added and the mixture stirred for 1 h at −70° C. The mixture was then allowed to warm to RT and stirred for 70 h. The reaction was quenched with HCl solution (2M, 50 mL), diluted with ethyl acetate (100 mL) and the layers separated. The aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organics were washed with brine (100 mL), dried over magnesium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with 4:1 to 2:1 isohexane:ether gradient. The fractions containing product were combined and evaporated. The resulting oil was dissolved in ethyl acetate (50 mL) and washed with HCl solution (2M, 30 mL), brine (30 mL), dried over magnesium sulphate, filtered and evaporated to give the subtitled compound as a clear oil. Yield 1.1 g.
Reaction SMILES: CON(C)[C:4](=[O:48])[CH2:5][CH2:6][C@H:7]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C@@H:10]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]3[O:31][CH2:30][CH2:29][N:28]([CH2:32][CH2:33][CH2:34][O:35][CH3:36])[C:27]=3[CH:37]=2)[CH2:9][N:8]1[S:38]([C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=1)(=[O:40])=[O:39].[CH3:50][Mg]Br>>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([C@@H:11]2[C@@H:10]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]4[O:31][CH2:30][CH2:29][N:28]([CH2:32][CH2:33][CH2:34][O:35][CH3:36])[C:27]=4[CH:37]=3)[CH2:9][N:8]([S:38]([C:41]3[CH:42]=[CH:43][C:44]([CH3:47])=[CH:45][CH:46]=3)(=[O:40])=[O:39])[C@@H:7]([CH2:6][CH2:5][C:4](=[O:48])[CH3:50])[CH2:12]2)=[CH:18][CH:17]=1
Reactant: C[Mg]Br
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CCC(=O)N(C)OC)C[C@@H]3c3ccc(OC)cc3)cc21
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CCC(C)=O)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
Similar to example 29b, 1.68 g of N-methoxy-3-[(2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-N-methylpropionamide and 4.3 ml of methylmagnesium bromide (1N solution in tetrahydrofuran) are used to afford the title compound as a colourless oil. Rf=0.23 (EtOAc-heptane 1:1); Rt=5.25.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:15]4[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:14]=4[CH2:13][CH2:12][C:11]=3[C:10]([C:24]([O:26]CC)=[O:25])=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:15]4[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:14]=4[CH2:13][CH2:12][C:11]=3[C:10]([C:24]([OH:26])=[O:25])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nn(-c2ccc(Br)cc2)c2c1CCc1ccc([N+](=O)[O-])cc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)c1nn(-c2ccc(Br)cc2)c2c1CCc1ccc([N+](=O)[O-])cc1-2
Reaction time: 8 h
Yield: 97.1 %

Procedure:
A suspension of ethyl 1-(4-bromophenyl)-8-nitro-4,5-dihydro-1H-benzo[g]indazole-3-carboxylate (4.4 g) in THF (80 mL) was treated with 1 N aq. NaOH (80 mL) and stirred vigorously overnight. The reaction mixture was diluted with ethyl acetate and acidified to pH=2 with 1 N aq. HCl. The organic layer was separated and the aqueous fraction extracted with EtOAc (3×). Combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford 4.0 g (97%) of 1-(4-bromophenyl)-8-nitro-4,5-dihydro-1H-benzo[g]indazole-3-carboxylic acid as a solid: MS(ESI+) 414 [M+H]+. 1H NMR (400 MHz, d6 DMSO) δ 8.07 (dd, 1H), 7.83 (d, 2H), 7.66 (d, 1H), 7.56 (d, 2H), 7.42 (d, 1H), 3.10 (m, 2H), 2.99 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]2[O:29][C:28]([C:30](O)=[O:31])=[CH:27][C:26]=2[CH:33]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:30]([C:28]1[O:29][C:25]2[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:33][C:26]=2[CH:27]=1)=[O:31]
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Reactant: COc1ccc2oc(C(=O)O)cc2c1
Product: COc1ccc2oc(C(=O)Nc3ccc(N4CCC(N5CCCC5C)C4)cc3C)cc2c1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 5-methoxy-benzofuran-2-carboxylic acid. MS: 434.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)=[CH:13][C:12]=3[CH2:25][CH2:26][CH3:27])=[N:9][O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:28].[C:29]([O:34]C)(=[O:33])[C@@H:30]([CH3:32])O>>[Cl:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)=[CH:13][C:12]=3[CH2:25][CH2:26][CH3:27])=[N:9][O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[O:28][C@@H:30]([CH3:32])[C:29]([OH:34])=[O:33]
Reactant: CCCc1cc(Oc2ccc(Cl)cc2)ccc1-c1noc2ccc(O)c(Cl)c12
Reactant: COC(=O)[C@@H](C)O
Product: CCCc1cc(Oc2ccc(Cl)cc2)ccc1-c1noc2ccc(O[C@@H](C)C(=O)O)c(Cl)c12

Procedure:
The phenol product from Step 1 (0.38 g, 0.9 mmol) and methyl (R)-lactate (0.16 g, 1.5 mmol) was reacted according the general procedure described in Step 11 of Example 1 to give the title compound as a white solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.C[N+]1([O-])CCOCC1>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: CCOC(=O)C1CCC(O)CC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: CCOC(=O)C1CCC(=O)CC1
Yield: 94.5 %

Procedure:
To a vigorously stirring suspension of ethyl 4-hydroxycyclohexanecarboxylate (2.0 g, 12 mmol, Aldrich) and activated 4 Å MS (1.0 g) in acetonitrile (70 mL) at 23° C. was sequentially added 4-methylmorpholine-N-oxide (2.0 g, 17 mmol) and tetrapropylammonium perruthenate (410 mg, 1.2 mmol). After stirring the resulting black suspension for 30 min, the mixture was concentrated in vacuo, and the resulting residue was filtered through a plug of silica gel (30% ethyl acetate in hexanes) to provide ethyl 4-oxocyclohexanecarboxylate as a clear oil (1.93 g, 98%). MS (AP CI) 171 (M+H).
Reaction SMILES: [CH2:1]1[CH:6]2[CH2:7][NH:8][CH2:9][CH2:10][N:5]2[CH2:4][CH:3]([C:11]2[N:19]3[C:14]([C:15]([NH2:20])=[N:16][CH:17]=[N:18]3)=[C:13]([C:21]3[CH:22]=[CH:23][C:24]4[C:28]([CH:29]=3)=[N:27][N:26]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:25]=4)[CH:12]=2)[O:2]1.I[CH3:37]>>[CH3:37][N:8]1[CH2:9][CH2:10][N:5]2[CH:6]([CH2:1][O:2][CH:3]([C:11]3[N:19]4[C:14]([C:15]([NH2:20])=[N:16][CH:17]=[N:18]4)=[C:13]([C:21]4[CH:22]=[CH:23][C:24]5[C:28]([CH:29]=4)=[N:27][N:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:25]=5)[CH:12]=3)[CH2:4]2)[CH2:7]1
Reactant: Nc1ncnn2c(C3CN4CCNCC4CO3)cc(-c3ccc4cn(-c5ccccc5)nc4c3)c12
Reactant: CI
Product: CN1CCN2CC(c3cc(-c4ccc5cn(-c6ccccc6)nc5c4)c4c(N)ncnn34)OCC2C1
Yield: 52 %

Procedure:
In a manner similar to the procedure described for the preparation of Example 103 and using 7-(octahydropyrazino[2,1-c][1,4]oxazin-3-yl)-5-(2-phenyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine and iodomethane as the starting materials, 27 mg (52%) of the desired product was isolated. 1H NMR (300 MHz, DMSO-d6) 9.16 (s, 1 H), 8.10 (d, 2 H), 7.94 (s, 1 H), 7.85 (d, 1 H), 7.68 (s, 1 H), 7.59 (t, 2 H), 7.44 (t, 1 H), 7.21 (dd, 1H), 6.78 (s, 1H), 5.12 (dd, 1H), 3.78 (dd, 1H), 3.39-3.30 (m, 1H), 3.00 (dd, 1H), 2.71-2.67 (m, 2H), 2.61-2.54 (m, 1H), 2.48-2.38 (m, 1H), 2.27-2.19 (m, 2H), 2.15 (s, 3H), 2.10-2.02 (m, 1H), 1.63 (t, 1H); LC-MS [M+H]+=481, RT=1.08 min.