Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1C(O)=O.[Br:14]Br>C(Cl)(Cl)(Cl)Cl>[Br:14][C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[Cl:1]
Reactant: BrBr
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cccc(Br)c1Cl
Temperature: 90 °C
Yield: 99.9 %

Procedure:
To an oven dried round-bottom flask fitted with stir bar and an oven dried condenser under N2 at room temperature was added 2-chloro-3-nitrobenzoic acid (6.0 g, 29.8 mmol), mercuric oxide, red (9.67 g, 44.7 mmol) and carbon tetrachloride (200 mL). The reaction mixture heated to 90° C. for 30 minutes with irradiation from a 150 W TYPE A utility light bulb. The reaction mixture was then cooled to approximately 60° C. and bromine (2.30 mL, 44.7 mmol) added dropwise via syringe and the nitrogen inlet was replaced with an Ar balloon. The reaction mixture was heated again to 90° C. for 4 hours under constant irradiation from the light bulb. The reaction was allowed to cool to room temperature, quenched with saturated aqueous NaHCO3 solution and DCM and stirred for 30 minutes. The phases partitioned upon standing and then were separated. The aqueous portion was extracted with DCM. The combined organic phases were washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo to afford 7.04 g of 1-bromo-2-chloro-3-nitrobenzene: 1H NMR (400 MHz, CDCl3) δ 7.31 (t, J=8.0 Hz, 1H) 7.74 (dd, J=8.2, 1.2 Hz, 1H) 7.87 (dd, J=8.0, 1.4 Hz, 1H).
Reaction SMILES: C[N:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]1=O.[CH3:15][C:16]1(C)[CH2:20]C[CH2:18][C:17]1=O.N>CO>[CH3:15][C:16]1([CH3:20])[C:7]2=[N:2][CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=[C:6]2[CH2:18][CH2:17]1
Reactant: CC1(C)CCCC1=O
Reactant: Cn1cc([N+](=O)[O-])cc([N+](=O)[O-])c1=O
Agent: N
Solvent: CO
Product: CC1(C)CCc2cc([N+](=O)[O-])cnc21
Yield: 23.8 %

Procedure:
A mixture of 1-methyl-3,5-dinitro-2-pyridone (0.8 g, 4.0 mmol), 2,2-dimethyl-cyclopentanone (0.45 g, 4.0 mmol) and ammonia solution (2.0M) in methanol (40 mL) was refluxed overnight. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The soluble portion was flash chromatographed over silica gel (eluent 90:10 v/v ethyl acetate-hexane) to give a yellow solid (0.183 g, 24% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:7]([CH3:9])([CH3:8])[O:6][C:5](OC2C=CC([N+]([O-])=O)=CC=2)=[N:4][S:3]1(=[O:21])=[O:20].Cl.[NH2:24][C@H:25]([C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[C:32]#[N:33])[CH2:26][CH2:27][OH:28]>ClCCl.C(N(CC)C(C)C)(C)C>[OH:28][CH2:27][CH2:26][C@@H:25]([C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[C:32]#[N:33])[NH:24][C:5]1[O:6][C:7]([CH3:8])([CH3:9])[C:2]([CH3:1])([CH3:22])[S:3](=[O:20])(=[O:21])[N:4]=1
Reactant: CC1(C)OC(Oc2ccc([N+](=O)[O-])cc2)=NS(=O)(=O)C1(C)C
Reactant: N#Cc1cccc([C@@H](N)CCO)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)OC(N[C@@H](CCO)c2cccc(C#N)c2)=NS(=O)(=O)C1(C)C
Yield: 59.3 %

Procedure:
100 mg of 5,5,6,6-tetramethyl-2-(4-nitrophenoxy)-5,6-dihydro-1,4,3-oxathiazine 4,4-dioxide and 97 mg of 3-((S)-1-amino-3-hydroxypropyl)benzonitrile hydrochloride were dissolved in 5 ml of dichloromethane and 0.25 ml of N,N-diisopropylethylamine, and the mixture was stirred at room temperature for 16 hours. Subsequently, the reaction solution was diluted with 20 ml of dichloromethane, and washed with 10 ml of 10% aqueous ammonia solution and with 10 ml of 1 N aqueous hydrochloric acid. The two aqueous phases were extracted once again with 20 ml of ethyl acetate, and the combined organic phases were dried over Na2SO4 and concentrated by rotary evaporation. The residue was purified in a purification laboratory by means of preparative HPLC. After lyophilization of the product-containing fractions, the product (66 mg) was thus obtained with a molecular weight of 365.5 g/mol (C17H23N3O4S); MS (ESI): m/e=366 (M+H+).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[C:19]1([OH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O.CN(C)C=O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([O:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:3][C:4]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:8][CH:9]=1
Reactant: Oc1ccccc1
Reactant: O=C(O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CCc1oc(Oc2ccccc2)nc1-c1ccc(Cl)cc1
Temperature: 140 °C
Reaction time: 3 h
Yield: 93.1 %

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionic acid (1.43 g), phenol (0.94 g), potassium carbonate (2.10 g) and N,N-dimethylformamide (10 ml) was stirred at 140° C. for 3 hours. Water was added to the reaction mixture, which was then acidified with 6N hydrochloric acid. The crystals thus precipitated were collected by filtration to obtain 4-(4-chlorophenyl)-2-phenoxy-5-oxazolepropionic acid (1.60 g, 93%). This was recrystallized from ethyl acetate to give colorless needles. mp 136-137° C.
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].[CH2:8]([O:10][CH:11](OCC)OCC)[CH3:9].C(OC(=O)C)(=O)C.C(O)(=O)C>C(O)C>[CH2:8]([O:10][CH:11]=[CH:2][C:1]([CH2:4][C:5](=[O:7])[CH3:6])=[O:3])[CH3:9]
Reactant: CC(=O)CC(C)=O
Reactant: CCOC(OCC)OCC
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCOC=CC(=O)CC(C)=O
Reaction time: 2.5 h

Procedure:
253 g (2.5 moles) of acetylacetone, 1,110 g (7.5 moles) of orthoformic acidtriethyl ester and 8 g of acetic anhydride are heated to ebullition in a flask with vigorous stirring. During the reaction, about 23 g of acetic acid is added and the ethanol formed is distilled off. After 2 to 3 hours the reaction is completed. The unreacted orthoformic acid triethyl ester is distilled out at reduced pressure (5 to 1 Torr) through the top of the column and fed back to the next batch. Following this, 355 g of ethoxymethylene acetylacetone is evaporated, separated from the residue through a simple distillation bridge at 0.1 to 0.3 Torr. The yield, referred to acetylacetone, was 91% of theory.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([Mg]Br)=[CH:12][CH:11]=1.N1C=CN=CC=1>C1COCC1>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)=[CH:12][CH:11]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: BrC1CCCCC1
Solvent: C1CCOC1
Solvent: c1cnccn1
Product: COc1ccc(C2CCCCC2)cc1
Yield: 96 %

Procedure:
Bromocyclohexane (81.8 mg, 0.5 mmol) and a THF solution (0.85 mL, 0.88 M, 0.75 mmol) of 4-methoxyphenylmagnesium bromide were used as starting materials, and reacted as in Entry 1. Conditions: The THF solution of 4-methoxyphenylmagnesium bromide was added dropwise at 25° C. over 20 minutes. 1H-NMR analysis was conducted using pyrazine (19.0 mg, 0.24 mmol) as an internal standard (yield 96%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([CH:14]([NH:20][C:21]([C@@H:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:29](=[O:45])[CH2:30][CH2:31][CH:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)[CH2:24]2)=[O:22])[CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:11]=[N:12][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:53][CH2:54][F:55]>O1CCCC1.O>[F:55][CH2:54][CH2:53][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([CH:14]([NH:20][C:21]([C@@H:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:29](=[O:45])[CH2:30][CH2:31][CH:32]3[CH2:33][CH2:34][N:35]([C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[CH2:36][CH2:37]3)[CH2:24]2)=[O:22])[CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:11]=[N:12][CH:13]=1
Reactant: FCCI
Reactant: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(-c2ccccc2O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(-c2ccccc2OCCF)c1
Temperature: 25 °C
Reaction time: 90 h
Yield: 59.8 %

Procedure:
124 mg (0.20 mmol) tert-butyl 4-{3-[(3R)-3-({1-[5-(2-hydroxyphenyl)pyridin-3-yl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate were dissolved in 2.2 ml tetrahydrofurane. 130 mg (0.40 mmol) cesium carbonate and 66 mg (0.38 mmol) 1-iodo-2-fluoroethane were added. The mixture was stirred at room temperature for 90 hours. 66 mg (0.38 mmol) 1-iodo-2-fluoroethane were added and the mixture stirred at room temperature for 20 hours. 66 mg (0.38 mmol) 1-iodo-2-fluoroethane were added and the mixture stirred at room temperature for 60 hours, diluted with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuum. Chromatography over 10 g silica gel (dichloromethane/ethanol 100/0-90/10) gave 80 mg (54%) tert-butyl 4-(3-{(3R)-3-[(1-{5-[2-(2-fluoroethoxy)phenyl]pyridin-3-yl}-3-methoxy-3-oxopropyl)carbamoyl]piperidin-1-yl}-3-oxopropyl)piperidine-1-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[CH:20]=[C:21]([C:24]5[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.Cl.C(N(CC)CC)C>CO>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[CH:20]=[C:21]([C:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(OCc3nnc4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)cn34)ccnc2c1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc2c(OCc3nnc4ccc(C5=CCNCC5)cn34)ccnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.6 %

Procedure:
tert-Butyl 4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.113 g, 0.23 mmol) was dissolved in methanol (3 mL) then added concentrated hydrochloric acid (0.500 ml, 6.0 mmol). The reaction mixture was stirred at room temperature overnight then concentrated under vacuum. The remaining solid was suspended in methanol (1 mL) then added triethylamine (0.40 ml, 2.9 mmol). The clear solution was stirred at room temperature for 2 hours then concentrated under vacuum. The sample was purified by flash chromatography eluting with 8% 7N ammonia in methanol/dichloromethane to afford 7-methoxy-4-((6-(1,2,3,6-tetrahydropyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)quinoline (0.038 g, 42% yield) as a tan solid.
Reaction SMILES: [CH:1]([C:3]1[N:8]2[CH:9]=[N:10][CH:11]=[C:7]2[CH:6]=[CH:5][CH:4]=1)=O.[BH4-].[Na+].OCC1N2C=NC=C2C=CC=1.S(Cl)([Cl:27])=O>>[Cl:27][CH2:1][C:3]1[N:8]2[CH:9]=[N:10][CH:11]=[C:7]2[CH:6]=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=Cc1cccc2cncn12
Agent: OCc1cccc2cncn12
Agent: [BH4-]
Agent: [Na+]
Product: ClCc1cccc2cncn12

Procedure:
5-Chloromethylimidazo[1,5-a]pyridine is prepared from 5-formylimidazo-[1,5-a]pyridine by reduction with sodium borohydride to 5-hydroxymethylimidazo[1,5-a]pyridine and subsequent treatment with thionyl chloride.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:11][C:12](=[O:16])[C:13]([OH:15])=O)[CH:8]=2)[NH:3]1.[O:17]([CH:24]1[CH2:29][CH2:28]N(C)CC1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCC)C>[O:15]=[C:13]([N:3]1[CH2:4][CH2:28][CH:29]([CH2:24][O:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:10][CH2:2]1)[C:12]([NH:11][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2](=[O:1])[CH2:10]2)=[O:16]
Reactant: CN1CCC(Oc2ccccc2)CC1
Reactant: O=C1Cc2cc(NC(=O)C(=O)O)ccc2N1
Solvent: CCOCC
Product: O=C1Cc2cc(NC(=O)C(=O)N3CCC(COc4ccccc4)CC3)ccc2N1

Procedure:
The title compound is prepared from N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-oxalamic acid (Example 101b) and 4-phenoxy-methyl-piperidine according to the method described in Example 1c. Melting Point: 200-202° C. (diethylether)
Reaction SMILES: CS(O)(=O)=O.CS(O)(=O)=O.[NH2:11][C@@H:12]1[CH2:15][NH:14][C@H:13]1[CH3:16].C(N(CC)CC)C.[F:24][C:25]1[C:43](F)=[CH:42][C:28]2=[N:29][C:30]3[N:31]([CH3:41])[CH:32]=[C:33]([C:38]([OH:40])=[O:39])[C:34](=[O:37])[C:35]=3[CH:36]=[C:27]2[CH:26]=1.O>CS(C)=O>[NH2:11][C@@H:12]1[CH2:15][N:14]([C:43]2[C:25]([F:24])=[CH:26][C:27]3[C:28]([CH:42]=2)=[N:29][C:30]2[N:31]([CH3:41])[CH:32]=[C:33]([C:38]([OH:40])=[O:39])[C:34](=[O:37])[C:35]=2[CH:36]=3)[C@H:13]1[CH3:16]
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Reactant: C[C@@H]1NC[C@H]1N
Agent: CS(=O)(=O)O
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: C[C@H]1[C@H](N)CN1c1cc2nc3c(cc2cc1F)c(=O)c(C(=O)O)cn3C
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 78.1 %

Procedure:
A solution of 18 g of trans-3-amino-2-methylazetidine dimethanesulphonate and 12.7 g of triethylamine in 150 cm3 of dimethyl sulphoxide is heated with stirring to approximately 70° C. for 20 minutes. At the same temperature, 14.5 g of 7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid are added in small portions in the course of 10 minutes, and the mixture is heated to approximately 90° C. for 2 hours. After cooling to approximately 20° C., the reaction mixture is poured into 400 cm3 of water at the same temperature. The insoluble matter is drained, washed with twice 100 cm3 of water and twice 100 cm3 of ethanol and recrystallized in 300 cm3 of dimethylformamide. 13.9 g of 8-(trans-3-amino-2-methyl-1-azetidinyl)-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid, which decomposes at 265°-267° C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.C(N(CC)CC)C.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>C(Cl)Cl>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([N:6]2[CH2:5][CH2:4][NH:3][C@H:2]([CH3:1])[CH2:7]2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CN(S(=O)(=O)c2ccc(Cl)cc2)CCN1
Temperature: 25 °C
Reaction time: 48 h
Yield: 78.7 %

Procedure:
To a solution of 1,1-dimethylethyl (2R)-2-methyl-1-piperazinecarboxylate (1.5 g, 07.5 mmol) in dry DCM (40 mL) was added triethylamine (2.59 mL, 18.8 mmol) and 4-chlorobenzenesulfonyl chloride (3.15 g, 10.5 mmol) and the reaction stirred at room temperature for 48 h. To the reaction was added resin supported-triamine (5 g) and the mixture stirred for 4 h. The reaction mixture was filtered and the filtrate washed with 0.5 M HCl (aq., 100 mL) followed by water (100 mL) before it was dried (MgSO4), filtered and the solvent removed in vacuo. The crude product was dissolved in DCM (40 mL) and TFA (10 mL) was added. The solution was stirred for 20 min. The solvent was evaporated and the residue tajen up in DCM (40 mL) and washed with 50% aqueous sodium bicarbonate (100 mL) followed by water (100 mL). The organic phase was dried (MgSO4), filtered and the solvent removed in vacuo to give the title compound (1.62 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@@H:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:7][NH:6]1)=[O:4].[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:7][N:6]1[S:16]([CH3:15])(=[O:18])=[O:17])=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H]1CC[C@H](C(=O)OC)NC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)C1CCC(C(=O)OC)N(S(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
6-ring: To rac-cis-Piperidine-2,5-dicarboxylic acid dimethyl ester [Frank J., J. Heterocyclic Chem. 32, 857–861 (1995)] (36.2 g) dissolved in dichloromethane (720 ml) were added 4-dimethylaminopyridine (33.0 g) and, dropwise, methanesulphonyl chloride (28.6 g) within 10 minutes and room temperature. The temperature rose to 35° C. The reaction mixture was stirred 1 h at room temperature, washed with 2 molar HCl, sodium carbonate-solution and brine, dried over magnesium sulphate and concentrated to dryness to obtain (2RS,5RS)-1-methanesulfonyl-piperidine-2,5-dicarboxylic acid dimethyl ester (46.8 g) as a syrup, MS: 220 (M+-59).
Reaction SMILES: [CH2:1]([C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:20]=[CH:19]C(C#N)=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[OH-:21].[K+].Cl.C(O)CO[CH2:27][CH2:28][OH:29]>>[CH2:1]([C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:20]=[CH:19][C:27]([C:28]([OH:29])=[O:21])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: OCCOCCO
Reactant: C=CCCCC[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Product: C=CCCCC[C@H]1CC[C@H](c2ccc(C(=O)O)cc2)CC1

Procedure:
A mixture of 2.61 g of p-[trans-4-(5-hexenyl)cyclohexyl]benzonitrile and 20 g of potassium hydroxide in 200 ml of diethylene glycol was boiled at 180° C. for 1 hour while gassing with argon in a round flask equipped with a magnetic stirrer and a reflux condenser. After cooling the brown reaction mixture was made acid with 35 ml of 36 percent hydrochloric acid and partitioned between 100 ml of methylene chloride and 100 ml of water. The aqueous phase was back-extracted three times with 100 ml of methylene chloride each time. The organic phases were washed twice with 100 ml of water each time and dried over magnesium sulphate and active charcoal. After separating the solvent in a rotary evaporator there were obtained 2.93 g (104%) of p-[trans-4-(5-hexenyl)cyclohexyl]benzoic acid as brownish, not quite pure crystals; Rf value 0.38 (ethyl acetate/petroleum ether vol. 3:7).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.CO.[NH4+].[Cl-]>[Fe].O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([NH2:15])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Nc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Nc1ccc(Cl)cc1Nc1ccccc1
Temperature: 90 °C
Yield: 81.9 %

Procedure:
To a mixture of (5-chloro-2-nitrophenyl)phenylamine (1.36 g, 5.47 mmol) in a 3:1 mixture of MeOH:water (120 mL) were added NH4Cl (1.76 g, 32.81 mmol) and iron powder (1.22 g, 21.88 mmol) and the reaction mixture heated at 90° C. for 2 h. After cooling to RT, the solid was filtered through a pad of Celite® and washed with additional MeOH. The filtrate was concentrated in vacuo and the resulting residue partitioned between EtOAc and water. The aqueous phase was further extracted with EtOAc and the combined organic fractions washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-100% DCM in cyclohexane) to afford the title compound as a brown oil (980 mg, 82%). LCMS (Method C): RT 3.57 min [M+H]+ 219.0
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][Si:8]([CH:15]([CH3:17])[CH3:16])([CH:12]([CH3:14])[CH3:13])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.O1CCCC1.C([Li])CCC.[C:30]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH:35]=[O:36])#[N:31]>[Cl-].[NH4+].C(OCC)(=O)C>[OH:36][CH:35]([C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][Si:8]([CH:15]([CH3:17])[CH3:16])([CH:12]([CH3:14])[CH3:13])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1)[C:34]1[CH:33]=[C:32]([CH:39]=[CH:38][CH:37]=1)[C:30]#[N:31]
Reactant: CC(C)[Si](OCc1ccc(Br)cc1)(C(C)C)C(C)C
Reactant: N#Cc1cccc(C=O)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)[Si](OCc1ccc(C(O)c2cccc(C#N)c2)cc1)(C(C)C)C(C)C
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 74.4 %

Procedure:
Stir a solution of (4-bromo-benzyloxy)-triisopropyl-silane (72 g, 209.7 mmol) and tetrahydrofuran (500 mL) at −78° C. Add a 1.6 M solution of n-butyllithium in hexanes (143 mL) over 10 min. After addition, allow the reaction mixture to reach −20° C. and stir for 5 minutes. Cool the reaction mixture to −78° C. In another flask, stir a solution of 3-cyanobenzaldehyde (25 g, 190.6 mmol) and tetrahydrofuran (250 mL) at −78° C. Add the lithium anion solution to the aldehyde solution via large cannula at a rate such that the internal aldehyde temperature does not rise above −50° C. After addition is complete, stir the reaction mixture 18 hours at room temperature. Dilute the reaction mixture with aqueous saturated ammonium chloride (500 mL) and ethyl acetate (200 mL). Separate the layers, and extract the aqueous layer with ethyl acetate (3×100 mL). Combine the organic layers, dry over anhydrous magnesium sulfate, filter, and concentrate. Purify the residue via silica gel chromatography eluting with hexanes to 9:1 hexanes:ethyl acetate to afford the title compound (56.1 g, 75%) as a colorless oil. LCMS (m/z) 396 M+1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1.C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.Cl.[CH:45]12[CH2:54][CH:49]3[CH2:50][CH:51]([CH2:53][CH:47]([CH2:48]3)[CH:46]1[NH2:55])[CH2:52]2>ClCCl>[CH:45]12[CH2:54][CH:49]3[CH2:50][CH:51]([CH2:53][CH:47]([CH2:48]3)[CH:46]1[NH:55][C:36]([N:18]1[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:2]4[N:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[CH:14][CH:13]=3)[CH2:16][CH2:17]1)=[O:42])[CH2:52]2
Reactant: c1cnc(COc2ccc(N3CCNc4ccccc43)cc2)nc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NC1C2CC3CC(C2)CC1C3
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1C2CC3CC(C2)CC1C3)N1CCN(c2ccc(OCc3ncccn3)cc2)c2ccccc21
Temperature: 25 °C
Yield: 57.9 %

Procedure:
0.095 g of 1-[4-(pyrimidin-2-ylmethoxy)phenyl]-1,2,3,4-tetrahydroquinoxaline is placed in 3 ml of dichloromethane at 0° C. under nitrogen. 0.09 ml of triethylamine and 0.031 g of triphosgene are added. The mixture is stirred at ambient temperature for 2 h 30, 0.01 g of triphosgene is then added and stirring is maintained for 2 h. 0.12 ml of triethylamine and 0.062 g of adamantan-2-ylamine hydrochloride are then added. Stirring is maintained at ambient temperature for 1 h. After hydrolysis, the reaction medium is extracted with ethyl acetate until the aqueous phase has been completely extracted. The organic phases are combined, washed with a saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated to dryness. The crude product obtained is chromatographed on silica gel, elution being carried out with a gradient of methanol in dichloromethane varying from 0% to 9/1. 0.03 g of 4-[4-(pyrimidin-2-ylmethoxy)phenyl]-3,4-dihydro-2H-quinoxaline-1-carboxylic acid adamantan-2-ylamide is obtained, which is triturated from a mixture of ethyl acetate and diisopropyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:27]3[CH2:26][CH2:25][CH2:24][NH:23][C:22]=3[CH:21]=[N:20]2)=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([N:23]2[CH2:24][CH2:25][CH2:26][C:27]3[N:19]([C:16]4[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=4)[N:20]=[CH:21][C:22]2=3)=[O:11])=[CH:6][CH:7]=1
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Product: O=C(Cc1ccc(Cl)cc1)N1CCCc2c1cnn2-c1ccc(F)cc1

Procedure:
The compound was from prepared from 4-chlorophenylacetic acid and 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine using General Method A. The product mixture was crystallized from 4:1 CH3CN:H2O to give the title compound as an off-white crystalline solid (37.6 mg). 1H NMR (400 MHz, MeOD-d4, mixture of rotamers) δ 8.18 (s, 0.9H), 7.84 (s, 0.1H), 7.56 (m, 2H), 7.25-7.37 (m, 6H), 4.02 (s, 0.2H), 3.92 (s, 1.8H), 2.81 (t, J=6.2 Hz, 2H), 2.49 (m, 2H), 1.90 (m, 2H); MS: (ES) m/z calculated for C20H18ClFN3O [M+H]+ 370.1, found 370.1.