Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Br:9])[C:3]=1[NH2:4].[OH:10]O>C(O)(=O)C>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Br:9])[C:3]=1[N:4]=[O:10]
Reactant: Nc1c(Br)cccc1Br
Reactant: OO
Solvent: CC(=O)O
Product: O=Nc1c(Br)cccc1Br
Reaction time: 48 h

Procedure:
To a solution of 2,6-dibromoaniline (10 g, 40 mmol) in glacial acetic acid (160 mL) was added 30% hydrogen peroxide (30 mL). The mixture was left for 48 h at which point crystals had precipitated. The crystals were collected by filtration, washed with acetic acid and water then dried under high vacuum to give 2,6-dibromonitrosobenzene (6.24 g). This material (2.6 g, 10 mmol) was dissolved in DMSO (25 mL) along with sodium azide (650 mg, 10 mmol). The mixture was heated to 100° C. for 1 h then cooled to rt and diluted with ethyl acetate and water. The layers were separated and the organic phase was washed with water and brine, then dried over sodium sulfate and concentrated. FC (75 g silica, 10/1 hexane/ethyl acetate) afforded the title compound (1.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1.C(N(C(C)C)C(C)C)C.Br[CH2:38][C:39]([O:41]CC)=[O:40].[OH-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:38][C:39]([OH:41])=[O:40])[CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: CCOC(=O)CBr
Reactant: O=C(c1cccnc1Oc1cc(Cl)ccc1Cl)N1CCNc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(O)CN1CCN(C(=O)c2cccnc2Oc2cc(Cl)ccc2Cl)c2ccccc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 21.8 %

Procedure:
To a solution of [2-(2,5-dichloro-phenoxy)-pyridin-3-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanone (30 mg, 0.075 mmol, 1.0 equiv; Example 122) in anhydrous DMF (0.5 mL) was added N-ethyldiisopropylamine (48 mg, 65 μL, 0.375 mmol, 5.0 equiv; [CAS RN 7087-68-5]) and ethyl bromoacetate (27.6 mg, 19 μL, 0.165 mmol, 2.2 equiv; [CAS RN 105-36-2]) and the reaction mixture heated by microwave irradiation to 100° C. After 2 h, a 5 M solution of sodium hydroxide (0.5 mL, 2.5 mmol, 33 equiv; [CAS RN 1310-73-2]) was added and the reaction mixture stirred at rt over night. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 7.5 mg (22%) of the title compound as a light yellow powder. MS (ISP): 458.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1([C:9]([OH:11])=[O:10])[CH2:6][CH2:5][CH2:4][CH:3]1[O:7][CH3:8].[C:12](O)([CH3:15])([CH3:14])[CH3:13].C1(N=C=NC2CCCCC2)CCCCC1>CCOCC.CNC1(NC)C=CN=CC1>[C:12]([O:10][C:9]([C:2]1([F:1])[CH2:6][CH2:5][CH2:4][CH:3]1[O:7][CH3:8])=[O:11])([CH3:15])([CH3:14])[CH3:13]
Reactant: COC1CCCC1(F)C(=O)O
Reactant: CC(C)(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CNC1(NC)C=CN=CC1
Solvent: CCOCC
Product: COC1CCCC1(F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.6 %

Procedure:
The 1-fluoro-2-hydroxy 1-cyclopentanecarboxylic acid methyl ester in cis form (compound number 2a) synthesized in Example 1 was methylated in the same manner as in Example 10 and further hydrolyzed in the same manner as in Example 11 to obtain 1-fluoro-2-methoxy-1-cyclopentanecarboxylic acid in cis form (compound number 12a). 0.4 g (2.7 mmol) of this carboxylic acid, 0.20 g (2.7 mmol) of tertiary butyl alcohol, 0.56 g (3.7 mmol) of dicyclohexylcarbodiimide and 15 mg of 4,4-dimethylaminopyridine were mixed in 5 ml of ether and stirred at room temperature for 2 hours. The reaction solution was filtered, ether was added to the filtrate, and the mixture was successively washed with a diluted hydrochloric acid solution, saturated saline, a saturated aqueous sodium bicarbonate solution and saturated saline. The ether layer was dried over anhydrous magnesium sulfate, and the solvent was distilled away to obtain 0.31 g (yield: 56%) of the objective 2-methoxy-1-fluoro-1-cyclopentanecarboxylic acid tertiary butyl ester in cis form (compound number 20a).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([O:11][CH:12]([CH3:16])[CH2:13][O:14][CH3:15])[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:15][O:14][CH2:13][CH:12]([CH3:16])[O:11][C:4]1[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=[C:2]([O:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:3]=1
Reactant: Oc1ccccc1
Reactant: COCC(C)Oc1cc(Cl)cnc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCC(C)Oc1cc(Oc2ccccc2)cnc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 22 %

Procedure:
5-Chloro-3-(2-methoxy-1-methyl-ethoxy)-2-nitro-pyridine (2 mmol) is dissolved in DMF (15 ml), phenol (3 eq.) and K2CO3 (4 eq.) is added. The reaction is heated to 100° C. in the microwave for 45 min. The reaction solution is pored into water and extracted with methyl-tert.-butyl ether. The combined organic layers are washed with brine, dried over MgSO4 and the solvent is removed in vacuo. 3-(2-Methoxy-1-methyl-ethoxy)-2-nitro-5-phenoxy-pyridine is obtained after column chromatography (heptane/ethyl acetate) as yellow oil in a yield of 22%. HPLC (method C): 2.03 min; LC-MS (method A): 1.99 min, 305.15 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:34][CH3:35])[N:6]2[CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21]CN1C(OCC1C=CC=CC=1)=O.BrCCC1CCC[N:41]([C:45]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:46])[CH2:40]1.FC(F)(F)C(O)=O.C(OC1N=C2C(N=C(OC)N2)=C(N)N=1)CCC>>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:34][CH3:35])[N:6]2[CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][N:41]([C:45]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:46])[CH2:40]1
Reactant: O=C(OCc1ccccc1)N1CCCC(CCBr)C1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCCCN3C(=O)OCc3ccccc3)c2n1
Agent: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCC3CCCN(C(=O)OCc4ccccc4)C3)c2n1

Procedure:
Prepared similarly to Intermediate 27 from phenylmethyl 3-(2-bromoethyl)-1-piperidinecarboxylate and 2-(butyloxy)-8-(methyloxy)-9H-purin-6-amine trifluoroacetate.
Reaction SMILES: C([Mg]Br)C.[CH:5]#[C:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH:19]([CH:21]=[CH2:22])=[O:20].[Cl-].[NH4+]>C(OCC)C.O>[CH2:22]=[CH:21][CH:19]([OH:20])[C:5]#[C:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: C#CCCCCCCCCCCCC
Reactant: C=CC=O
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: C=CC(O)C#CCCCCCCCCCCCC
Temperature: -10 °C

Procedure:
To freshly prepared ethyl magnesium bromide (from 58.95 mmoles of bromoethane and 49.36 mmoles of magnesium) in diethyl ether (125 ml) was added 1-tetradecyne (44.5 mmoles) in diethyl ether (25 ml) dropwise at ambient temperature. After 3 hours the reaction mixture was cooled to -10° C. and freshly distilled acrolein (59.86 mmoles) in diethyl ether (25 ml) was added dropwise. After 30 minutes saturated ammonium chloride (100 ml) and water (50 ml) were added. The organic phase was separated, washed with brine (100 ml) and dried over anhydrous magnesium sulfate. The desired compound was purified by flash chromatography on silica gel eluted with 90:10 hexane:ethyl acetate.
Reaction SMILES: [C:1]([C:3]1[C:7](I)=[CH:6][N:5]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:4]=1)#[N:2].C([Li])CCC.[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1.C(=O)([O-])O.[Na+]>O1CCCC1>[C:1]([C:3]1[C:7]([C:29]([CH:26]2[CH2:28][CH2:27]2)=[O:30])=[CH:6][N:5]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:4]=1)#[N:2]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1I
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C(=O)C1CC1
Temperature: 25 °C

Procedure:
To a stirred solution of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (0.22 g) in tetrahydrofuran (5 ml) at -78° C. under an atmosphere of nitrogen was added, at such a rate that the temperature of the reaction mixture did not exceed -65° C., n-butyllithium (0.21 ml of a 2.5M solution in hexanes). After stirring for a further 5 minutes cyclopropanecarbonyl chloride (0.13 ml) was added and the mixture allowed to warm to room temperature. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution (5 ml) and extracted twice with ether (25 ml). The combined organic layers were washed with water (50 ml), dried (Na2SO4) and evaporated to give a brown oil which was purified by column chromatography on silica gel (40 g) eluted with dichloromethane. Combination and evaporation of suitable fractions gave the title compound as a white solid, m.p. 195-197° C.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[C:23]([CH3:33])=[CH:24][C:25]([O:31][CH3:32])=[C:26]([CH:30]=1)[C:27]([OH:29])=O.[CH3:34][C:35]1[CH:40]=[C:39]([CH3:41])[N:38]=[C:37]([C:42]2([NH2:45])[CH2:44][CH2:43]2)[N:36]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[CH3:41][C:39]1[CH:40]=[C:35]([CH3:34])[N:36]=[C:37]([C:42]2([NH:45][C:27]([C:26]3[C:25]([O:31][CH3:32])=[CH:24][C:23]([CH3:33])=[C:22]([C:3]4[CH:4]=[CH:5][C:6]5[O:10][C:9]([C:11]6[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=6)=[C:8]([C:18]([NH:19][CH3:20])=[O:21])[C:7]=5[C:2]=4[F:1])[CH:30]=3)=[O:29])[CH2:43][CH2:44]2)[N:38]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)c(F)c12
Reactant: Cc1cc(C)nc(C2(N)CC2)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5nc(C)cc(C)n5)CC4)c(OC)cc3C)c(F)c12
Reaction time: 8 h

Procedure:
To a mixture of 5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (50 mg, 0.11 mmol), crude 1-(4,6-dimethylpyrimidin-2-yl)cyclopropanamine (100 mg) in 2 ml DMF at room temperature was added BOP (100 mg, 0.22 M, 2.0 eq.) and triethyl amine (0.046 ml 0.33 M, 3.0 eq.), and the mixture stirred overnight under an N2 atmosphere. The mixture was poured into crushed ice, and the solid precipitate was filtered and dried. The product obtained was further purified by preparative HPLC. Yield: 15 mg (24%) 1H NMR (400 MHz, CD3OD): δ 7.97-7.94 (m, 2H), 7.89 (s, 1H), 7.51 (d, J=8.5 Hz, 1H), 7.31-7.25 (m, 3H), 7.19 (s, 1H), 7.14 (s, 1H), 4.11 (s, 3H), 2.96 (s, 3H), 2.48 (s, 6H), 2.31 (s, 3H), 1.86-1.83 (m, 2H), 1.55-1.52 (m, 2H). 19F NMR (376.57 MHz, CD3OD) δ−77.40 (TFA), −112.33, −122.75 (CFCl3 as reference).
Reaction SMILES: [N:1]1([C:6]2[CH:19]=[CH:18][C:9]([CH2:10][N:11]3[CH2:16][CH2:15][NH:14][CH2:13][C:12]3=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(N(C(C)C)CC)(C)C.Cl[S:30]([CH2:33][C:34]([O:36][CH3:37])=[O:35])(=[O:32])=[O:31]>ClCCl>[N:1]1([C:6]2[CH:19]=[CH:18][C:9]([CH2:10][N:11]3[CH2:16][CH2:15][N:14]([S:30]([CH2:33][C:34]([O:36][CH3:37])=[O:35])(=[O:32])=[O:31])[CH2:13][C:12]3=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)CS(=O)(=O)Cl
Reactant: O=C1CNCCN1Cc1ccc(-n2ccnc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CS(=O)(=O)N1CCN(Cc2ccc(-n3ccnc3)cc2)C(=O)C1
Yield: 19.7 %

Procedure:
To a solution of 1-[4-(1-imidazolyl)benzyl]piperazin-2-one (586 mg) and diisopropylethylamine (388 mg) in dichloromethane (10 ml) was added dropwise, under ice-cooling, a solution of methyl chlorosulfonylacetate (380 mg) in dichloromethane (10 ml), and the mixture was stirred at room temperature overnight. The reaction solution was washed with 0.5N hydrochloric acid and saturated brine, dried and concentrated, and the residue was purified with silica gel column chromatography (eluent: methanol/dichloromethane=1/10) to give colorless oil of 1-[4-(1-imidazolyl)benzyl]-4-methoxycarbonylmethylsulfonyl-2-oxopiperazine (0.170 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([NH:12][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[CH2:6][CH2:5]2.Br[CH2:23][CH:24]1[CH2:26][CH2:25]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([NH:12][C:13](=[O:21])[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:23][CH:24]3[CH2:26][CH2:25]3)=[CH:18][CH:19]=1)[CH2:6][CH2:5]2
Reactant: O=C(N[C@H]1CCc2cc(Br)ccc2C1)c1ccc(O)cc1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CCc2cc(Br)ccc2C1)c1ccc(OCC2CC2)cc1
Temperature: 75 °C

Procedure:
A mixture of N—((S)-6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)-4-hydroxybenzamide (5.00 g), bromomethylcyclopropane (2.20 g), cesium carbonate (5.5 g) and DMF (50 ml) was heated to 75° C. for 12 hours. The cooled reaction mixture was admixed with water and extracted with ethyl acetate. The organic phase was washed three times with water, dried over magnesium sulfate and concentrated. The product was thus obtained with the molecular weight of 400.32 (C21H22BrNO2); MS (ESI): 400 (M+H+).
Reaction SMILES: [CH2:1]([C:10]1[C:11]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[C:12]([S:20]([OH:23])(=[O:22])=[O:21])[C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C(=O)([O-])[O-].[Ca+2:37].C(=O)=O>CCCCCCC.C(O)(C)C>[CH2:1]([C:10]1[C:11]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[C:12]([S:20]([O-:23])(=[O:21])=[O:22])[C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[Ca+2:37].[CH2:1]([C:10]1[C:11]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[C:12]([S:20]([O-:23])(=[O:21])=[O:22])[C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCc1cc2ccccc2c(S(=O)(=O)O)c1CCCCCCCCC
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [Ca+2]
Solvent: CC(C)O
Solvent: CCCCCCC
Product: CCCCCCCCCc1cc2ccccc2c(S(=O)(=O)[O-])c1CCCCCCCCC

Procedure:
Two hundred grams of dinonylnaphthalene sulfonic acid solution of the composition used in Example 1 is placed in a 1000 ml. flask fitted with a stirrer, thermometer and condenser. The flask is heated and 8.55 g. of powdered calcium carbonate (10% excess based on the sulfonic acid) is added with agitation. After a few minutes, carbon dioxide evolution ceases. The mixture is refluxed for 30 minutes, then the solids are allowed to settle. A 10 ml. sample diluted with a mixture of heptane and isopropanol as described in Example 1, and then filtered to remove the excess carbonate, has a pH of about 6.0, indicating that the carbonate/acid equilibrium has been reached. Then 2.0 g. of calcium hydroxide in 98 g. of mineral oil is prepared and 2 mls. of the mixture is added (0.02 g. of strong base). Finally, 60 g. of mineral oil is added, and the heptane and water are distilled off. The remaining fluid is filtered hot, at 130°-140° C., through a pressure filter. There is produced a completely neutral solution of calcium dinonylnaphthalene sulfonate in mineral oil.
Reaction SMILES: II.I[CH2:4]I.[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[CH2:11]>C1(C)C=CC=CC=1.[Cu]>[Br:6][C:7]1[CH:8]=[C:9]([CH:10]2[CH2:4][CH2:11]2)[CH:12]=[CH:13][CH:14]=1
Reactant: C=Cc1cccc(Br)c1
Reactant: ICI
Agent: [Cu]
Agent: II
Solvent: Cc1ccccc1
Product: Brc1cccc(C2CC2)c1
Yield: 10.6 %

Procedure:
Iodine (0.335 g, 1.32 mmol), diiodomethane (4.3 mL, 53.0 mmol) and 3-bromostyrene (5 g, 26.4 mmol) were added successively to a suspension of copper (7.5 g, 118.8 mmol) in toluene (50 mL). The mixture was refluxed for 140 h, then filtered and concentrated in vacuo. The residue was distilled under reduced pressure to afford 3-bromo-1-cyclopropylbenzene (0.55 g, 10%) as a colorless oil.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH:6]([C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)([CH3:8])[CH3:7].CN([CH:24]=[O:25])C>CCOC(C)=O>[CH:6]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH:24]=[O:25])=[CH:15][CH:14]=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)([CH3:8])[CH3:7]
Reactant: CN(C)C=O
Reactant: CC(C)c1cc2ccc([N+](=O)[O-])cc2[nH]1
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)c1[nH]c2cc([N+](=O)[O-])ccc2c1C=O
Reaction time: 0.33 h

Procedure:
POCl3 (0.12 ml, 1.4 mmol) was added dropwise to anhydrous DMF (1.5 ml) at 0° C. under argon. After stirred for 20 min, a solution of 2-isopropyl-6-nitro-1H-indole (Compound 120, 115 mg, 0.56 mmol) in anhydrous DMF (1.5 ml) was added slowly to the above reaction and stirred for 1 h at 0° C. and 2 h at room temperature. The reaction was diluted with EtOAc, washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2([C:16]3([N:19]4[CH:23]=[N:22][C:21]([Cl:24])=[N:20]4)[CH2:18][CH2:17]3)[CH2:15][O:14]2)=[CH:9][CH:8]=1>C(#N)C>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:16]2([N:19]3[CH:23]=[N:22][C:21]([Cl:24])=[N:20]3)[CH2:18][CH2:17]2)([OH:14])[CH2:15][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:9][CH:8]=1
Reactant: Clc1ccc(C2(C3(n4cnc(Cl)n4)CC3)CO2)cc1
Reactant: c1c[nH]cn1
Solvent: CC#N
Product: OC(Cn1ccnc1)(c1ccc(Cl)cc1)C1(n2cnc(Cl)n2)CC1
Yield: 32 %

Procedure:
A mixture of 13 g (191 mmol) of imidazole and 1 g (9 mmol) of potassium tert.-butylate in 100 ml of acetonitrile is refluxed under a nitrogen atmosphere. To this mixture there is added dropwise a solution of 18 g (61 mmol) of 2-(4-chlorophenyl)-2-[1-(3-chloro-1,2,4-triazol-1-yl)-cyclopropyl]-oxirane in 30 ml of acetonitrile. The reaction mixture is refluxed for a further 10 hours and then concentrated by stripping off the solvent under reduced pressure. The residue which remains is taken up in ethyl acetate and washed with water. The organic phase is dried over sodium sulphate and then concentrated by stripping off the solvent under reduced pressure. The residue which remains is chromatographed on silica gel using a mixture of dichloromethane/ethanol=90:10 as the eluent. Concentration of the eluate gives 7.1 g (32% of theory) of 1-(4-chlorophenyl)-1-[1-(3-chloro-1,2,4-triazol-1-yl)-cyclopropyl]-2-(imidazol-1-yl)-ethan-1-ol in the form of a solid of melting point 231° C.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:8]([NH2:9])=[CH:7][S:6][CH:5]=1.C(N(CC)CC)C.Cl.[CH3:18][O:19][CH2:20][C:21](=N)OCC.C(=O)([O-])O.[Na+]>C(O)C>[CH3:18][O:19][CH2:20][C:21]1[NH:3][C:4]2=[CH:5][S:6][CH:7]=[C:8]2[N:9]=1
Reactant: Nc1cscc1N
Reactant: CCOC(=N)COC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: COCc1nc2cscc2[nH]1
Temperature: 25 °C
Reaction time: 70 h
Yield: 58 %

Procedure:
[step 1] 3,4-Diaminothiophene dihydrochloride (300 mg, 1.60 mmol) was suspended in ethanol (12 mL), triethylamine (0.45 mL, 3.21 mmol) and ethyl 2-methoxyacetimidate monohydrochloride (Journal of Medicinal Chemistry, 1991, vol. 34, p 2468; 906 mg, 4.01 mmol) were added, and the mixture was stirred at room temperature for 70 hr. To the mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted 3 times with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 v/v-0/100 v/v) to give 2-(methoxymethyl)-1H-thieno[3,4-d]imidazole (156 mg, 58%).
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:4]([O:6][CH3:7])=[O:5].Cl[CH2:18][CH2:19][N:20]([CH2:25][CH2:26]Cl)[S:21]([CH3:24])(=[O:23])=[O:22].O>C(N(CC)C(C)C)(C)C>[C:13]([O:12][C:10]([NH:9][CH2:8][C@@H:3]([N:2]1[CH2:26][CH2:25][N:20]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:19][CH2:18]1)[C:4]([O:6][CH3:7])=[O:5])=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CS(=O)(=O)N(CCCl)CCCl
Reactant: COC(=O)[C@H](N)CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)[C@@H](CNC(=O)OC(C)(C)C)N1CCN(S(C)(=O)=O)CC1
Reaction time: 18 h
Yield: 44.1 %

Procedure:
A solution of 6 g (23.6 mmol) of methyl (R)-2-amino-3-tert-butoxycarbonylaminopropanoate hydrochloride and 5.2 g (23.6 mmol) of N,N-bis(2-chloroethyl)methanesulphonamide in 80 ml of N,N-diisopropylethylamine is heated at 125° C. with vigorous stirring for 18 h. After addition of water, the product is extracted with ethyl acetate. The organic phases are combined, washed with water, dried over magnesium sulphate, filtered and concentrated under vacuum. The crude product obtained is purified by chromatography over silica gel eluted with a 5/5 heptane/ethyl acetate mixture. 3.8 g (44%) of methyl (R)-3-tert-butoxycarbonylamino-2-(4-methanesulphonylpiperazin-1-yl)propanoate are obtained in the form of a white solid.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([CH:17]=O)[N:14]=[CH:13]2)=[CH:8][CH:7]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH:16]=[C:15]([CH:17]3[O:4][CH2:1][CH2:2][O:3]3)[N:14]=[CH:13]2)=[CH:10][CH:11]=1
Reactant: OCCO
Reactant: O=Cc1cn(-c2ccc(Cl)cc2)cn1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Product: Clc1ccc(-n2cnc(C3OCCO3)c2)cc1
Temperature: 25 °C
Yield: 41.2 %

Procedure:
A solution of ethane-1,2-diol (0.081 mL, 1.45 mmol, 1.5 equiv), 1-(4-chlorophenyl)-1H-imidazole-4-carbaldehyde (200 mg, 0.968 mmol), and camphorsulfonic acid (45 mg, 0.19 mmol, 0.2 equiv) in toluene (10 mL) was heated at reflux with a Dean-Stark apparatus for 1 hour. The reaction was cooled to room temperature and quenched with saturated aqueous sodium bicarbonate (30 mL). The mixture was extracted with ethyl acetate (30 mL) and the organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. Silica gel column chromatography (EtOAc with 7% methanol) provided 1-(4-chlorophenyl)-4-(1,3-dioxolan-2-yl)-1H-imidazole (0.100 g, tan solid) in 41% yield. 1H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 7.46 (d, J=8.4 Hz, 2H), 7.36 (s, 1H), 7.33 (d, J=8.4 Hz, 2H), 5.96 (s, 1H), 4.20 (m, 2H), 4.05 (m, 2H). MS m/z 251.0 (M+H)+; Rt-0.53 min.
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([NH2:12])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O[CH:17]1[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:24][C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)(=O)C>C1(C)C=CC=CC=1>[CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([NH:12][CH:17]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=4[O:24][C:25]4[C:30]3=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCN(C2CCCCC2)C1
Reactant: CC(=O)OC1c2ccccc2Oc2ccccc21
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)Oc1ccccc1C2NC1CCN(C2CCCCC2)C1

Procedure:
Refluxing N-cyclohexyl-3-aminopyrrolidine with 9-acetoxyxanthene in dry toluene for 24 hours, then working up as in Example 1 gives N-(N-cyclohexyl-3-pyrrolidinyl)-9-xanthenylamine.