Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:16])([C:9]1[CH:14]=[CH:13][C:12](C)=[CH:11][CH:10]=1)[CH2:7][OH:8].BrCCCCC(C)(C1C=CC=CC=1)C(OCC)=O.[Li+].[BH4-].CO>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:16])([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:7][OH:8]
Reactant: Cc1ccc(C(C)(CO)CCCCBr)cc1
Agent: CCOC(=O)C(C)(CCCCBr)c1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: ClCCl
Product: CC(CO)(CCCCBr)c1ccccc1
Yield: 84 %

Procedure:
According to the procedure given for the synthesis of 206e, 205d (52.0 g, 166.0 mmol) was reacted with LiBH4 (5.4 g, 247.9 mmol) and methanol (82 g, 255.9 mmol) in CH2Cl2 (180 mL) to afford 206d (38.0 g, 84%) as an oil. 1H NMR (CDCl3): δ 7.5-7.1 (m, 5H), 3.60 (d, 1H, J=10.8), 3.53 (d, 1H, J=10.8), 3.34 (t, 2H, J=7.0), 1.90-1.78 (m, 3H), 1.62-1.26 (m, 3H), 1.35 (s, 3H), 1.14 (m, 1H). 13C NMR (CDCl3): δ 144.4, 128.4, 126.5, 126.1, 72.4, 43.2, 37.4, 33.5, 33.3, 22.5, 21.4.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[CH3:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[CH2:16][NH:17][O:18][CH3:19]>>[CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8]([N:17]([O:18][CH3:19])[CH2:16][C:15]2[CH:20]=[CH:21][CH:22]=[CH:23][C:14]=2[CH3:13])=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CONCc1ccccc1C
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Product: CON(Cc1ccccc1C)C(=O)C=C1OC(C)(C)OC1=O
Yield: 100 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(2-methylbenzyl)-O-methyl-hydroxylamine as described in the preparation of compound 1-A gave the title amide as white crystals (100% yield): mp 96-97° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.78 (6H, s, CH3), 2.4 (3H, s, CH3), 3.59 (3H, s, OCH3), 4.89 (2H, s, NCH2), 6.44 (1H, s, CH), 7.2-7.28 (4H, m, aromatics). Anal. calcd. for C16H19NO5: C, 62.94; H, 6.27; N, 4.59. Found: C, 62.90; H, 6.21; N, 4.52.
Reaction SMILES: [C:1]1([CH:7]2[O:12][C:11]3[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:10]=3[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]1([CH:7]2[O:12][C:11]3[CH:13]=[CH:14][C:15]([O:17][C:19]4[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][N:20]=4)=[CH:16][C:10]=3[O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Oc1ccc2c(c1)OCC(c1ccccc1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)OCC(c2ccccc2)O3)nc1

Procedure:
A solution of 2,3-dihydro-2-phenyl-benzo[1,4]dioxin-6-ol (80 mg), 2-chloro-5-nitropyridine (56 mg) and potassium carbonate (52 mg) in dimethylformamide (1.0 ml) was stirred at 120° C. for 2 hrs. After cooling the mixture water (10 ml) was added and the precipitated product was filtered, washed with water and 2-propanol and dried under reduced pressure. Yield is 60 mg and mp 163-170° C. 1H NMR (DMSO-d6) δ 4.16 (dd, J 8.5, 11.6 Hz, 1H), 4.47 (dd, J 11.6, 2.6 Hz, 1H), 5.28 (dd, J 2.6, 8.5 Hz, 1H), 6.75 (dd, J 2.6, 8.8 Hz, 1H), 6.88 (d, J 2.6 Hz, 1H), 7.05 (d, J 8.8 Hz, 1H), 7.21 (d, J 9.1 Hz, 1H), 7.39-7.52 (m, 5H), 8.60 (dd, J 2.8, 9.1 Hz, 1H), 9.05 (d, J 2.8 Hz, 1H).
Reaction SMILES: [OH-:1].[Na+].[CH:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[C:5]([OH:12])[CH:4]=1.[C:13](Cl)(=[O:23])[C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>O.C(Cl)Cl>[N+:9]([C:8]1[CH:7]=[CH:6][C:5]([O:12][C:13](=[O:23])[C:14]2[CH:22]=[CH:21][C:17]([C:18]([O:1][C:5]3[CH:4]=[CH:3][C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=3)=[O:19])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1)([O-:11])=[O:10]
Reactant: [OH-]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 0.25 h

Procedure:
A 300-ml r.b. flask, equipped with a magnetic stirring bar was charged with 7.85 g sodium hydroxide (Fisher, 0.197 moles) in 75 ml of deionized water and then, to the stirred solution, 27.40 g of p-nitrophenol (Aldrich, 98%, 0.197 moles) was added. The solution turned orange and a considerable amount of yellow solid was present. A solution of 20.04 g of terephthaloyl chloride (Aldrich, 97%, 0.0987 moles assuming 100% purity) in methylene chloride was dripped into the flask from a dropping funnel. The flask was stirred another 15 min and the mixture filtered through a Whatman's #1 filter paper disk on a Buchner funnel. The filtrate was almost clear and the solid on the filter was washed with a few portions of water in the funnel and with two small portions of acetone. The solid was dried by briefly drawing air through it in a vacuum funnel and then, broken into finer pieces, in a 65° C. vacuum oven. The crude product weighed 36.1 g (theory, 40.2 g) and melted at 228°-243° C.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4].[N:20]1([C:26]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][C:27]=2[C:28](Cl)=[O:29])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[CH2:1]([O:5][C:6](=[O:19])[C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:14][CH2:15][N:16]([C:28](=[O:29])[C:27]3[CH:31]=[C:32]([N+:35]([O-:37])=[O:36])[CH:33]=[CH:34][C:26]=3[N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH2:17][CH2:18]2)=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Reactant: CCCCOC(=O)c1ccc(N2CCNCC2)cc1
Product: CCCCOC(=O)c1ccc(N2CCN(C(=O)c3cc([N+](=O)[O-])ccc3N3CCOCC3)CC2)cc1
Yield: 16 %

Procedure:
The title compound was prepared according to the procedure described for example 46 from 4-piperazin-1-yl-benzoic acid butyl ester (CAS: 86620-18-0) and 2-Morpholin-4-yl-5-nitro-benzoyl chloride (example B) (yield: 16%, MS (m/e): 497.3 (M+H, 100%)
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[NH:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[C:10](=O)[C:11]([O:13][CH3:14])=[O:12]>CO>[CH3:2][O:3][N:4]=[C:10]([C:6]1[NH:5][CH:9]=[CH:8][CH:7]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: CON
Reactant: COC(=O)C(=O)c1ccc[nH]1
Agent: Cl
Solvent: CO
Product: CON=C(C(=O)OC)c1ccc[nH]1

Procedure:
97.5 g (1.2 eq) of methoxyamine hydrochloride are added to a solution of 148.8 g (0.97 mol) of methyl pyrrol-2-ylglyoxylate (prepared by a method similar to that described by B. Lindstrom et al., Acta Chem. Scand. 27 (1973), 7) in 1 l of methanol, and the solution is refluxed for 2.5 hours. After evaporation in a rotary evaporator, the residue is taken up in ethyl acetate and the solution is washed with water, dried and evaporated down. 81 g (46%) of the pyrrole remained in the form of an oil.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].CCN(CC)CC.[NH2:19][NH2:20]>CCO>[NH2:11][C:10]1[C:8]2[C:9](=[CH:2][C:3]([C:4]#[N:5])=[CH:6][CH:7]=2)[NH:20][N:19]=1
Reactant: N#Cc1ccc(C#N)c(F)c1
Reactant: NN
Solvent: CCO
Solvent: CCN(CC)CC
Product: N#Cc1ccc2c(N)n[nH]c2c1

Procedure:
To a solution of 2-fluoroterephthalonitrile (500 mg) and Et3N (572 μl) in EtOH (20 ml) was added hydrazine (monohydrate), followed by reaction at 60° C. for 16 hours, and concentrated. The residue was washed with diethyl ether to obtain 3-amino-1H-indazole-6-carbonitrile (488 mg) as a yellow solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:12](=[O:15])[CH:13]=[CH2:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]=[O:30].C(N(CC)CC)C>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:12](=[O:15])[CH2:13][CH2:14][C:29]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=2)=[O:30])=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(C)(=O)=O)cc1
Reactant: O=Cc1ccccn1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2ccccn2)cc1
Temperature: 25 °C
Yield: 79 %

Procedure:
To a solution of 4-[4-(methylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (500 mg) in ethanol (5 mL) were added pyridine-2-carbaldehyde (180 μL), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (46 mg) and triethylamine (95 μL), and the mixture was stirred with heating under reflux for 2 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (525 mg, yield 79%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (3:1, volume ratio). MS: 430 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[Al+3].[Cl-].[Cl-].[Cl-].[Cl:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[O:24][CH3:25].Cl>ClCCCl>[Cl:23][C:22]1[C:17]([Cl:16])=[C:18]([O:24][CH3:25])[CH:19]=[CH:20][C:21]=1[C:5]([C:4]1[CH:8]=[CH:9][C:10]([Cl:11])=[C:2]([Cl:1])[CH:3]=1)=[O:6]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: COc1cccc(Cl)c1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc(C(=O)c2ccc(Cl)c(Cl)c2)c(Cl)c1Cl
Temperature: 60 °C

Procedure:
To a solution of 57.6 g of 3,4-dichlorobenzoylchloride in 1,2-dichloroethane (150 ml) is added 36.7 g of AlCl3 in portions over a 30 minute period. To the resultant mixture is added dropwise 44.26 g of 2,3-dichloroanisole in 1,2-dichloroethane (150 ml). There is an evolution of gas and the reaction mixture is heated to 60° C. for one hour. The mixture is then poured over 150 ml of concentrated HCl and 150 ml of ice and then extracted with CHCl3 and then ethanol. The resultant organic layer is washed with 10% aqueous K2CO3, then water, dried over (Na2SO4) and evaporated to yield 2,3-dichloro-4-methoxy-3',4'-dichlorobenzophenone, mp 113°-140° C.
Reaction SMILES: [C:1]([C@:3]1([OH:10])[CH2:7][CH2:6][N:5]([CH3:8])[C:4]1=[O:9])#[CH:2].Br[C:12]1[CH:13]=[CH:14][C:15]2[O:21][CH2:20][CH2:19][N:18]3[C:22]([CH2:28][O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:36])=[C:23]([C:25]([NH2:27])=[O:26])[N:24]=[C:17]3[C:16]=2[CH:37]=1>CS(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[O:29][CH2:28][C:22]1[N:18]2[CH2:19][CH2:20][O:21][C:15]3[CH:14]=[CH:13][C:12]([C:2]#[C:1][C@:3]4([OH:10])[CH2:7][CH2:6][N:5]([CH3:8])[C:4]4=[O:9])=[CH:37][C:16]=3[C:17]2=[N:24][C:23]=1[C:25]([NH2:27])=[O:26]
Reactant: C#C[C@]1(O)CCN(C)C1=O
Reactant: NC(=O)c1nc2n(c1COc1ccccc1Cl)CCOc1ccc(Br)cc1-2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Product: CN1CC[C@@](O)(C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(COc4ccccc4Cl)n2CCO3)C1=O
Yield: 23 %

Procedure:
Similar to as described in General Procedure E with the exceptions of using Pd(PPh3)4 in DMSO, 10-bromo-3-((2-chlorophenoxy)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one to give the titled compound as a colorless solid (12 mg, 23%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[C:17]([O:16][C:13](=[O:15])[CH2:14][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][Br:21])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(=O)OC(C)(C)C
Reactant: BrCCCCCBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)CCCCCCBr
Reaction time: 0.25 h

Procedure:
To 6.94 ml of diisopropylamine in 100 ml of anhydrous tetrahydrofuran was added dropwise 34 ml of a 1.45 M solution of n-butyl lithium in hexane at -70° C. and the mixture was stirred for 15 minutes. To the solution was added dropwise a solution of 6.63 ml of t-butyl acetate in 30 ml of anhydrous tetrahydrofuran and the mixture was stirred for 30 minutes, and then 8 ml of 1,5-dibromopentane in 10 ml of anhydrous tetrahydrofuran were added thereto and the mixture was stirred for 5 minutes. To it was added 17 ml of hexamethylphosphamide, the mixture was stirred at -78° C. for 1 hour and at from -40° C. to -30° C. for 30 minutes. To the reaction mixture was added an aqueous solution of ammonium chloride, and was separated aqueous layer from organic layer. The aqueous layer was extracted with diethyl ether, and the extract was added that organic layer and washed with water, a saturated aqueous solution of ammonium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of methylene chloride and cyclohexane (1:1) as an eluent to give 8.5 g of the title compound having the following physical characteristic:
Reaction SMILES: C(OC([N:8]([C:13]1[CH:52]=[CH:51][C:16]2[N:17]([CH2:21][C:22]([O:24][C@H:25]([C:36]3[CH:41]=[CH:40][C:39]([O:42][CH:43]([F:45])[F:44])=[C:38]([O:46][CH2:47][CH:48]4[CH2:50][CH2:49]4)[CH:37]=3)[CH2:26][C:27]3[C:32]([Cl:33])=[CH:31][N+:30]([O-:34])=[CH:29][C:28]=3[Cl:35])=[O:23])[C:18](=[O:20])[O:19][C:15]=2[CH:14]=1)[S:9]([CH3:12])(=[O:11])=[O:10])=O)(C)(C)C.Cl.C1COCC1>C(Cl)Cl>[Cl:33][C:32]1[CH:31]=[N+:30]([O-:34])[CH:29]=[C:28]([Cl:35])[C:27]=1[CH2:26][C@@H:25]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH:43]([F:44])[F:45])=[C:38]([O:46][CH2:47][CH:48]2[CH2:50][CH2:49]2)[CH:37]=1)[O:24][C:22](=[O:23])[CH2:21][N:17]1[C:16]2[CH:51]=[CH:52][C:13]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])=[CH:14][C:15]=2[O:19][C:18]1=[O:20]
Reactant: CC(C)(C)OC(=O)N(c1ccc2c(c1)oc(=O)n2CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)S(C)(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccc2c(c1)oc(=O)n2CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 79.9 %

Procedure:
To a solution of (S)-4-(2-(2-(6-(N-(tert-butoxycarbonyl)methylsulfonamido)-2-oxobenzo[d]oxazol-3(2H)-yl)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (0.200 g, 0.254 mmol) in DCM (10 ml) cooled to 0° C., HCl 4M in THF (0.634 ml, 2.54 mmol) was added, and the mixture was warmed to room temperature and stirred for 48 hours. A white solid precipitated. The precipitate was collected by filtration and washed with DCM affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(6-(methylsulfonamido)-2-oxobenzo[d]oxazol-3(2H)-yl)acetoxy)ethyl)pyridine 1-oxide (0.140 g, 0.203 mmol, 80% yield). MS/ESI+ 688.1 [MH]+; [αD]=−31.04, c=0.46, MeOH; 1H NMR (300 MHz, DMSO-d6) δ ppm 9.66 (br. s., 1H), 8.43 (s, 2H), 7.25 (d, 1H), 7.19 (d, 1H), 7.15 (d, 1H), 7.08 (d, 1H), 7.05 (dd, 1H), 6.96 (dd, 1H), 7.07 (t, 1H), 6.04 (dd, 1H), 4.82 (d, 1H), 4.70 (d, 1H), 3.92 (d, 2H), 3.40 (dd, 1H), 3.22 (dd, 1H), 2.99 (s, 3H), 1.07-1.41 (m, 1H), 0.48-0.70 (m, 2H), 0.25-0.44 (m, 2H).
Reaction SMILES: C(O)(=O)C.[C:5]([O:9][C:10]([N:12]1[CH2:18][CH2:17][C:16](=O)[CH:15]([CH2:20][C:21]([OH:23])=O)[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].[CH3:24][NH:25][NH2:26]>C1COCC1.O>[C:5]([O:9][C:10]([N:12]1[CH2:18][CH2:17][C:16]2=[N:26][N:25]([CH3:24])[C:21](=[O:23])[CH2:20][CH:15]2[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: CNN
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(CC(=O)O)CC1
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN1N=C2CCN(C(=O)OC(C)(C)C)CCC2CC1=O

Procedure:
36 mL acetic acid was added to 10.5 g 4-carboxymethyl-5-oxo-azepane-1-carboxylic acid tert-butyl ester in 75 mL THF at 5° C. 3.1 mL methylhydrazine was added to the mixture and refluxed for 3 h. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine. The crude product was purified by column chromatography on silica gel to yield 6.9 g of the desired product. (M+H)+: 282
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH2:31][O:32][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[N:10]([CH:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]3=[O:30].[C-]#N.[Na+].[CH3:36][N:37]1CCCC1=O>C(OCC)(=O)C.O.O.O.O.O.O.[Ni](Cl)Cl>[C:18]1([CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]3([C:5]4[CH:6]=[CH:7][C:2]([C:36]#[N:37])=[CH:3][C:4]=4[O:32][CH2:31]3)[C:9]2=[O:30])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN1CCCC1=O
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc(Br)ccc12
Agent: Cl[Ni]Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ccc2c(c1)OCC21C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Temperature: 25 °C
Yield: 100 %

Procedure:
A 10 mL microwave reaction vessel was charged with 6-bromo-1′-(diphenylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (0.51 g, 1.1 mmol), nickel chloride hexahydrate (0.25 g, 1.1 mmol), sodium cyanide (0.10 g, 2.1 mmol) and 1-methyl-2-pyrrolidinone (1 mL). The solution was irradiated at 200° C. for 20 min in a microwave reactor. The solution was allowed to cool to ambient temperature, diluted with ethyl acetate (25 mL) and filtered. The filtrate was washed with brine (3×15 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with a 15% to 50% gradient of ethyl acetate in hexanes to afford 1′-(diphenylmethyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-6-carbonitrile (0.50 g, 100%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.44-7.22 (m, 10H), 7.21-7.18 (m, 1H), 7.14-6.93 (m, 5H), 6.72 (d, J=7.8 Hz, 1H), 6.55 (d, J=7.5 Hz, 1H), 5.07 (d, J=9.2 Hz, 1H), 4.80 (d, J=9.2 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1([C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)[CH2:4][CH2:3]1.CO.[CH3:16][Si](C=[N+]=[N-])(C)C.CCCCCC>C1COCC1>[NH2:1][C:2]1([C:5]2[CH:13]=[CH:12][C:8]([C:9]([O:11][CH3:16])=[O:10])=[CH:7][CH:6]=2)[CH2:4][CH2:3]1
Reactant: NC1(c2ccc(C(=O)O)cc2)CC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(C2(N)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 87 %

Procedure:
4-(1-aminocyclopropyl)benzoic acid (1.75 g, 0.00988 mol) was stirred in THF (20 mL) and Methanol (10 mL) over ice/water bath. 2.00 M of trimethylsilyldiazomethane in hexane (9.9 mL, 0.020 mol) was added and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated down to viscous oil which solidified upon standing to give a crystalline solid. Crude material was dried on high vacuum line for 12 hours to give methyl 4-(1-aminocyclopropyl)benzoate (1.65 g, 87%) as pale brown solid. Step 2:
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[N:18]([CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=43)[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].[CH:36]([S:38]([CH:41]=C)(=[O:40])=[O:39])=[CH2:37]>>[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[C:23]4[CH:26]=[CH:27][C:28]([CH:30]5[CH2:35][CH2:34][N:33]([CH2:37][CH2:36][S:38]([CH3:41])(=[O:40])=[O:39])[CH2:32][CH2:31]5)=[CH:29][C:22]=4[O:21][CH2:20][CH2:19][N:18]3[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCNCC3)cc1OCC2
Reactant: C=CS(=O)(=O)C=C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCN(CCS(C)(=O)=O)CC3)cc1OCC2

Procedure:
Following the procedure for 152, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene trifluoroacetic acid salt was reacted with vinyl sulfone to give 225 as a white solid. 1H NMR δ (ppm) (DMSO-d): 8.27 (1H, d, J=8.29 Hz), 7.86-7.84 (2H, m), 7.00 (1H, dd, J=8.37, 1.76 Hz), 6.85 (1H, d, J=1.70 Hz), 5.88-5.78 (1H, m), 4.44 (4H, q, J=5.99 Hz), 3.26 (3H, m), 3.00 (3H, s), 2.95 (2H, d, J=11.00 Hz), 2.68 (2H, t, J=6.79 Hz), 2.02 (2H, t, J=11.39 Hz), 1.72 (2H, d, J=12.62 Hz), 1.57 (2H, qd, J=12.27, 3.58 Hz), 1.42 (6H, d, J=6.60 Hz). LCMS: RT=2.68 min, M+H+=485
Reaction SMILES: [C:1]1([OH:8])[CH:6]=[CH:5][C:4]([OH:7])=[CH:3][CH:2]=1.[N:9]([CH2:12][CH3:13])=[C:10]=[O:11].C(N(CC)CC)C>O1CCOCC1>[OH:7][C:4]1[CH:5]=[CH:6][C:1]([O:8][C:10](=[O:11])[NH:9][CH2:12][CH3:13])=[CH:2][CH:3]=1
Reactant: CCN=C=O
Reactant: Oc1ccc(O)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCNC(=O)Oc1ccc(O)cc1

Procedure:
Benzene-1,4-diol Compound 25a was reacted with isocyanato-ethane and a catalytic amount of triethylamine in 1,4-dioxane at room temperature to provide ethyl-carbamic acid 4-hydroxy-phenyl ester Compound 25b.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]([CH3:12])=[CH:9][CH2:10]Br.[CH3:13][C:14]1[C:19](=[S:20])[CH2:18][CH:17]=[CH:16][C:15]=1[C:21]([O:23][CH3:24])=[O:22]>CC(C)=O>[CH3:7][C:8]([CH3:12])=[CH:9][CH2:10][S:20][C:19]1[C:14]([CH3:13])=[C:15]([CH:16]=[CH:17][CH:18]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: CC(C)=CCBr
Reactant: COC(=O)C1=C(C)C(=S)CC=C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(SCC=C(C)C)c1C
Temperature: 25 °C
Reaction time: 10 h

Procedure:
37.9 g (0.275 mol) of potassium carbonate and 43.5 g (0.275 mol) of 3-methyl-2-butenyl bromide were added dropwise to 50 g (0.275 mol) of methyl 3-thio-2-methylbenzoate in 250 ml of acetone, and the mixture was stirred at room temperature for 10 hours. The solvent was distilled off, the residue was taken up in water/ethyl acetate and the organic phase was dried, filtered off and concentrated.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:15]=[CH:14][C:11]([C:12]#N)=[CH:10][C:9]=1[C:16]([F:19])([F:18])[F:17].[OH-:20].[Na+].Cl.C[OH:24]>O>[CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:15]=[CH:14][C:11]([C:12]([OH:24])=[O:20])=[CH:10][C:9]=1[C:16]([F:19])([F:18])[F:17]
Reactant: CO
Reactant: C[C@@H]1CCCCN1c1ccc(C#N)cc1C(F)(F)F
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: C[C@@H]1CCCCN1c1ccc(C(=O)O)cc1C(F)(F)F
Temperature: 100 °C

Procedure:
4-[(2R)-2-methylpiperidin-1-yl]-3-(trifluoromethyl)benzonitrile (1.40 g; 5.22 mmol; 1 eq.) was dissolved in MeOH (7 mL) to which was added NaOH (5 N solution in water, 7 mL). The reaction mixture was heated to 100° C. for 7 hours. The reaction mixture was acidified to pH 2 with 5N HCl solution in water. The resulting precipitate was filtered and washed with water to give a light brown solid. It was recrystallized from Et2O/cHex to give a beige solid.