Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[C:21]2[C:16]([CH2:17][CH2:18][CH:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[O:20]2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)P(N(C)C)(N(C)C)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].I[CH2:50][CH3:51]>C1COCC1>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[C:21]2[C:16]([CH2:17][CH2:18][C:19]([CH2:50][CH3:51])([C:23]([O:25][CH2:26][CH3:27])=[O:24])[O:20]2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCI
Reactant: CCOC(=O)C1CCc2ccc(OCCCOCc3ccccc3)cc2O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C1(CC)CCc2ccc(OCCCOCc3ccccc3)cc2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
To a 85 ml anhydrous THF solution of ethyl 7-(3-benzyloxypropoxy)-chromane-2-carboxylate (5.0 g, 13.5 mmol) and hexamethylphosphoramide (3.1 ml, 17.8 mmol) was added sodium bis(trimethylsilyl) amide 1.0M/THF solution (16.2 ml, 16.2 mmol) was added upon cooling in a dry ice-acetone bath. After stirring for 30 min at that temperature, to it was added iodoethane (3.3 ml, 41.3 mmol). The cooling bath was removed allowing the reaction mixture to warm to rt overnight. The solvent was removed under reduced pressure. The residue was diluted with AcOEt and sat. NH4Claq. The organic layer was separated, and the aqueous layer was extracted twice with AcOEt. The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and chromatographed on silica gel eluting with 10% methyl-tert-butyl ether/hexanes to give the title compound as a clear oil 3.76 g (70%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4](I)[CH:3]=1.C(N(CC)CC)C.[C:17]([Si:19]([CH3:22])([CH3:21])[CH3:20])#[CH:18]>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:18]#[C:17][Si:19]([CH3:22])([CH3:21])[CH3:20])=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Nc1ccc(Cl)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#CNc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
To a stirred solution of 4-chloro-2-iodo-phenylamine (5 g, 19.73 mmol) in THF (40 ml) was added triethyl amine (6.836 ml, 49.32 mmol), and ethynyl-trimethyl-silane (5.576 ml, 39.45 mmol) at 25° C. The mixture was purged with argon for 10 min, followed by the addition of PdCl2(PPh3)2 (0.692 g, 0.99 mmol) and CuI (113 mg, 0.59 mmol) at 25° C. The reaction mixture was stirred at room temperature for 2 h and was subsequently diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude residue which was purified by flash column chromatography (2-5% ethyl acetate in hexane) to afford 4-chloro-2-trimethylsilanylethynyl-phenylamine (3.6 g, 82%) as a brown solid. GC-MS: 223 (M).
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=1.S(Cl)([Cl:16])=O>ClCCl>[ClH:16].[Cl:16][CH2:2][C:3]1[N:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1cccc(CO)n1
Solvent: ClCCl
Product: CCOC(=O)c1cccc(CCl)n1
Product: Cl

Procedure:
As for Reaction 1, using 45.14 g of ethyl 6-(hydroxymethyl)-2-pyridinecarboxylate and 33 g thionyl chloride in 500 ml dichloromethane. Yield 59.9 g
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[OH:19])[C:12]([C:20]([N:22]3[CH2:27][CH2:26][N:25]([CH2:28][CH3:29])[CH2:24][CH2:23]3)=[O:21])=[CH:11]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH2:31][CH2:32][F:33]>CN(C)C=O>[CH:3]1([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[O:19][CH2:31][CH2:32][F:33])[C:12]([C:20]([N:22]3[CH2:23][CH2:24][N:25]([CH2:28][CH3:29])[CH2:26][CH2:27]3)=[O:21])=[CH:11]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: FCCBr
Reactant: CCN1CCN(C(=O)c2cn(CC3CCCCC3)c3c(O)cccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1CCN(C(=O)c2cn(CC3CCCCC3)c3c(OCCF)cccc23)CC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 18.5 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 65 mg, 1.62 mmol) was added portionwise with stirring under a stream of nitrogen to a solution of 4-{[1-(cyclohexylmethyl)-7-hydroxy-1H-indole-3-yl]carbonyl}-1-ethylpiperazine (200 mg, 0.54 mmol) in dimethylformamide (5 ml). After 30 minutes, 1-bromo-2-fluoroethane (49 μl, 0.65 mmol) was added. The mixture was heated to 60° C. with stirring for 48 hours. The reaction was quenched with 2-propanol (10 ml) and then concentrated. The resulting brown gum was partitioned between dichloromethane (50 ml) and 5% sodium hydrogen carbonate solution (50 ml). The organic layer was washed with water (50 ml), dried over sodium sulfate and concentrated. The crude intermediate was purified by flash chromatography using 95% dichloromethane, 5% methanol as eluent to afford the title compound (54 mg, 0.1 mmol). 1H NMR (400 MHz, CD3OD) δH 1.05 (2H, m), 1.19 (3H, m), 1.39 (3H, t, J 7.5), 1.56 (2H, m), 1.69 (3H, m), 1.92 (1H, m), 2.48 (2H, q, J 7.0), 2.53 (4H, m), 3.75 (4H, t, J 5.0), 4.26 (2H, d, J 7.5), 4.32 (1H, m), 4.39 (1H, m), 4.75 (1H, m), 4.87 (1H, m), 6.73 (1H, d, J 8.0), 7.06 (1H, t, J 8.0), 7.26 (1H, d, J 8.0), 7.44 (1H, s); EIMS: m/z=416.2 [M+H]+.
Reaction SMILES: [N:1]#[C:2]Br.[CH3:4][N:5]1[C:9]([CH2:10][N:11]2[CH2:15][CH:14]([CH2:16][CH2:17][CH3:18])[CH2:13][C:12]2=[O:19])=[CH:8][N:7]=[CH:6]1>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:4][N:5]1[C:9]([CH2:10][N:11]2[CH2:15][CH:14]([CH2:16][CH2:17][CH3:18])[CH2:13][C:12]2=[O:19])=[CH:8][N:7]=[C:6]1[C:2]#[N:1]
Reactant: N#CBr
Reactant: CCCC1CC(=O)N(Cc2cncn2C)C1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CCCC1CC(=O)N(Cc2cnc(C#N)n2C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33.2 %

Procedure:
In a 2 l, three-necked flask fitted with a magnetic stirrer and reflux condenser under inert atmosphere, DMAP (60.4 g, 0.495 mol) is dissolved in DMF (900 ml) and the solution is cooled to 0° C. Cyanogen bromide (54.4 g, 0.495 mol) is added by portions while the temperature is maintained between 0 and 10° C. The mixture is stirred for 0.5 h at this temperature and a solution of 1-[(1-methyl-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one 121 (36.5 g, 0.165 mol) in DMF (500 ml) is added. The mixture is heated at 40° C. overnight. The DMAP-BrCN complex (0.165 mol) in 350 ml of DMF is added at 5° C. (after being stirred for 1 h) and the mixture is heated at 45° C. overnight. One equivalent of the DMAP-BrCN complex in DMF (150 ml) is prepared again and added to the mixture at a temperature comprised between 0° C. and 10° C. The mixture is stirred at 45° C. overnight. The solvent is evaporated, the residue is dissolved in AcOEt, then the organic phase is washed with a saturated solution of NaHCO3 and brine, dried over MgSO4 and concentrated to dryness. Purification by preparative chromatography on silicagel affords 13.5 g 1-methyl-5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazole-2-carbonitrile 125.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[N:23]=[CH:22][C:21]([N:24]4[CH2:28][CH2:27][NH:26][C:25]4=[O:29])=[CH:20][CH:19]=3)=[O:17])[CH2:12][CH2:11]2)=[N:4][C:5]([CH3:9])=[C:6]([CH3:8])[CH:7]=1.[CH3:30]I>>[CH3:30][N:26]1[CH2:27][CH2:28][N:24]([C:21]2[CH:22]=[N:23][C:18]([C:16]([N:13]3[CH2:12][CH2:11][N:10]([C:3]4[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[C:5]([CH3:9])[N:4]=4)[CH2:15][CH2:14]3)=[O:17])=[CH:19][CH:20]=2)[C:25]1=[O:29]
Reactant: CI
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCNC4=O)cn3)CC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)cn3)CC2)nc1C

Procedure:
Using 1-{6-[4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carbonyl]pyridin-3-yl}imidazolidin-2-one (136 mg) described in Example 397 and methyl iodide (26 μL) and by the reaction and treatment in the same manner as in Example 36, the title compound (109 mg) was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([OH:9])[C:5]2[CH:10]=[CH:11][O:12][C:4]=2[CH2:3]1.[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1F>>[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[O:9][CH:6]1[CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][C:4]2[O:12][CH:11]=[CH:10][C:5]1=2
Reactant: CN1CCC(O)c2ccoc2C1
Reactant: Fc1cccc(Cl)c1Cl
Product: CN1CCC(Oc2cccc(Cl)c2Cl)c2ccoc2C1

Procedure:
The same method as in Example 1 was conducted using 7-methyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 19) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2,3-dichloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([O:11][CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:26]1(O)[CH2:30][CH:29]([OH:31])[CH2:28][CH2:27]1.O[CH2:34]CC1CCN(C(OC(C)(C)C)=O)CC1>>[OH:31][C@H:29]1[CH2:28][CH2:27][C@H:34]([O:1][C:2]2[C:7]3[C:8]([O:11][CH2:12][CH:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]4)=[N:9][O:10][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:26][CH2:30]1
Reactant: OC1CCC(O)C1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2noc3cccc(O)c23)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Product: CC(C)(C)OC(=O)N1CCC(COc2noc3cccc(O[C@H]4CC[C@H](O)CC4)c23)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 2 of EXAMPLE 7 using tert-butyl 4-{[(4-hydroxy-1,2-benzisoxazol-3-yl)oxy]methyl}piperidine-1-carboxylate (EXAMPLE 17, step 2) and 1,4-cyclopentanediol (mixture of isomers, cis: trans=ca. 1:1) instead of 4-(benzyloxy)-1,2-benzisoxazol-3-ol and tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2Cl.[CH3:16][N:17]1[CH2:21][CH2:20][CH:19]([N:22]2[CH:26]=[C:25]([NH2:27])[CH:24]=[N:23]2)[CH2:18]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:27][C:25]1[CH:24]=[N:23][N:22]([CH:19]2[CH2:20][CH2:21][N:17]([CH3:16])[CH2:18]2)[CH:26]=1
Reactant: CN1CCC(n2cc(N)cn2)C1
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Product: CC(=O)c1cnc2ccc(Br)cc2c1Nc1cnn(C2CCN(C)C2)c1
Yield: 86.9 %

Procedure:
Following general procedure C, 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (285 mg, 1.0 mmol) was reacted with 1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-amine (0.28 g, 1.68 mmol) to afford the desired product (360 mg, 87%) as a light yellow solid. ESI MS m/z 414 [C19H20BrN5O+H]+
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[CH:11][CH:10]=1)#[N:2].[CH3:27][O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]1[NH:35][C:36]1[NH:40][C:39]([CH3:41])=[N:38][N:37]=1>>[CH3:27][O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]1[N:35]1[C:17](=[O:18])[C:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([C:4]3[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:10][CH:11]=2)=[C:22]([CH2:23][CH2:24][CH3:25])[N:37]2[N:38]=[C:39]([CH3:41])[N:40]=[C:36]12
Reactant: COC1CCCCC1Nc1nnc(C)[nH]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCCCC2OC)c2nc(C)nn12
Temperature: 250 °C
Reaction time: 0.25 h
Yield: 45.8 %

Procedure:
A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (0.83 g) and N-(2-methoxycyclohexyl)-5-methyl-4H-1,2,4-triazol-3-amine (0.25 g) was stirred at 250° C. for 15 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.27 g, 46%).
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[C:8]([CH3:24])[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([O:18][CH3:19])=[O:17])[C:10](=[O:12])[CH:11]=1.C1C(=O)N([Br:37])C(=O)C1>ClCCl>[Br:37][C:11]1[C:10](=[O:12])[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([O:18][CH3:19])=[O:17])[C:8]([CH3:24])=[N:7][C:6]=1[O:5][CH2:4][C:3]1[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(F)cc3F)cc2=O)c1
Solvent: ClCCl
Product: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77.2 %

Procedure:
A mixture of methyl 3-[4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoate (0.41 g, 0.001 mol, from Step 3) and NBS (0.2 g, 0.0011 mol) in dichloromethane (5.0 mL) is stirred at room temperature for 1.5 h under argon atmosphere. The reaction mixture is purified by flash chromatography using 30% EtOAc in hexanes to furnish the title compound (0.37 g, 75%) as a white amorphous powder: 1H NMR (CD3OD/400 MHz) δ 8.04 (d, 1H, J=1.6 Hz), 7.89 (d, 1H, J=1.6 Hz), 7.62 (m, 2H), 7.01 (m, 2H), 5.56 (s, 2H), 3.89 (s, 3H), 2.15 (s, 3H), and 2.133 (s, 3H); ES-HRMS m/z 479.0412 (M+H calcd for C21H18N2O4F2Br requires 479.0413). 19F NMR(CD3OD/400 MHz) −111.870 (m) and −115.95 (m).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[F:7])=[O:5].[Mg+2].[Br-].[Br-].C(N(CC)CC)C.[N:26]1[CH:31]=[CH:30][CH:29]=[N:28][C:27]=1[C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1>C1COCC1>[CH2:2]([O:3][C:4](=[O:5])/[C:6](/[F:7])=[CH:36]/[C:35]1[CH:34]=[CH:33][C:32]([C:27]2[N:26]=[CH:31][CH:30]=[CH:29][N:28]=2)=[CH:39][CH:38]=1)[CH3:1]
Reactant: O=Cc1ccc(-c2ncccn2)cc1
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Agent: [Br-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)/C(F)=C/c1ccc(-c2ncccn2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
Triethyl 2-fluoro-2-phosphonoacetate (1.55 mL, 7.64 mmol) was added to a suspension of MgBr2 (1.68 g, 9.12 mmol) in THF (20 mL). The resulting mixture was cooled to 0° C., triethylamine (1.20 mL, 8.61 mmol) was added, and stirring was continued for 1 h at 0° C. A solution of 4-(2-pyrimidinyl)-benzaldehyde (1.00 g, 5.43 mmol, prepared as described in WO 9828264) in THF (10 mL) was aded via cannula and an additional amount of THF (5 mL) was used to rinse the transfer flask and cannula. The resulting mixture was stirred for 3 h at 0° C., quenched with 10% aq. ammonium chloride (5 mL), and concentrated to a small volume. The concentrate was diluted with ethyl acetate (50 mL), washed with 10% aq. ammonium chloride, sat. aq. NaHCO3, and brine (50 mL each), dried (MgSO4), and concentrated. Purification by chromatography (SiO2, 3:1 hexane/ethyl acetate) provided 1.27 g of the title compound as a 3:1 mixture with its E isomer. Recrystallization from 2-propanol provided 0.76 g (51%) of the title compound containing ca. 1% of the E isomer. MS 273 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:13]([O:23][CH2:24][CH3:25])(=[O:22])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:24]([O:23][C:13](=[O:22])[CH:14]=[C:15]([C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:25]
Reactant: CCOC(=O)C=Cc1ccccc1
Reactant: COc1cc(Br)c2cc[nH]c2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCOC(=O)C=C(c1ccccc1)c1cc(OC)cc2[nH]ccc12
Temperature: 100 °C

Procedure:
A mixture of 4-bromo-6-methoxy-indole CXIV (920 mg, 4.1 mmol), ethyl cinnamate (1.03 ml, 6.1 mmol), TEA (850 μl, 6.1 mmol), Pd(OAc)2 (46 mg, 0.20 mmol) and (o-Tol)3P (120 mg, 0.41 mmol) was heated in a sealed vial to 100° C. for 27 hours; The reaction mixture was cooled to room temperature, diluted with DCM, and the mixture was filtered through celite. The filtrate was concentrated and purified via flash chromatography (hexane/EtOAc) to afford 3-(6-methoxy-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester CXVI as a yellow-brown waxy solid (440 mg, 34% yield).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=1>C(O)C>[ClH:2].[C:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N+:9]([O-:11])=[O:10])=[CH:14][CH:15]=1)(=[O:21])[CH3:20]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CC(=O)c1ccc(N)cc1
Agent: Cl
Solvent: CCO
Product: CC(=O)c1ccc(Nc2ccncc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-chloro-3-nitropyridine hydrochloride (9.75 g, 50 mmol) in ethanol (40 ml) was added to a slurry of p-aminoacetophenone (6.76 g, 50 ml) in ethanol (25 ml), and the mixture was stirred at room temperature overnight. The mixture was chilled in ice, and the yellow solid filtered off and dried in vacuo. Yield 10.1 g (69%), m.p. 197°-200° C.
Reaction SMILES: [Cl:1][CH:2]([Cl:12])[C:3]1[CH:8]=[CH:7][C:6](C(Cl)Cl)=[CH:5][CH:4]=1.CC1C=CC(C=O)=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl>>[Cl:1][CH:2]([Cl:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClC(Cl)c1ccc(C(Cl)Cl)cc1
Agent: Cc1ccc(C=O)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: ClC(Cl)c1ccccc1
Yield: 96.5 %

Procedure:
JP79125629 (1979) discloses a method for preparing α,α,α′,α′-tetrachloro-p-xylene by reacting 4-methyl benzaldehyde with PCl5, forming an intermediate product 4-methyl, 1-(dichloromethyl)benzene, and conducting a photochlorination reaction. This prior art method has the following reaction formula: The abovementioned reaction is a two-step reaction. Even though the first step reaction has a yield of 96.5%, the second step reaction has a very low yield. The product mixture is very difficult to be purified.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:10]>>[NH2:10][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[Cl:1][C:2]1[N:7]=[C:6]([NH2:10])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: [NH4+]
Agent: [OH-]
Product: Nc1ccnc(Cl)n1
Product: Nc1nccc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2,4-Dichloropyrimidine (1.0 g, 6.7 mmol) was added 28% w/v ammonium hydroxide solution (20 mL). The mixture was stirred overnight at ambient temperature then concentrated in vacuo. The residue was dry loaded and purified by FCC eluting with 2-10% EtOH in CHCl3 to afford 2-amino-4-chloropyrimidine and 2-chloro-4-aminopyrimidine.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.CO.[OH-].[Na+]>C1COCC1>[CH2:30]([O:29][C:26]1[CH:25]=[CH:24][C:23]([S:20]([C:6]2([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=3)[CH2:8][CH2:7]2)(=[O:21])=[O:22])=[CH:28][CH:27]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(C)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(C)cc3)CC2)cc1

Procedure:
4-(4-Butoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-Butoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4-carboxylic ethyl ester (10.0 g, 22 mmol) dissolved in THF:Methanol (50:50 ml) and 10N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 7.2 g (72%); off white solid, mp 244° C.; MS: 446.3 (M+H)+
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([S:55]([C:58]([CH3:61])([CH3:60])[CH3:59])(=[O:57])=[O:56])=[C:10]([CH2:12][N:13]([CH3:54])[C:14]([CH:16]([NH:28][C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[C:35]([N:39]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[N:34][CH:33]=[CH:32]3)[C:17]2[CH:22]=[CH:21][C:20]([C@@H:23]([CH3:26])[CH2:24][OH:25])=[C:19]([CH3:27])[CH:18]=2)=[O:15])[CH:11]=1>C(#N)C.C(Cl)Cl>[C:42]([O:41][C:40]([N:39]([C:35]1[C:36]2[C:31](=[CH:30][C:29]([NH:28][CH:16]3[C:14](=[O:15])[N:13]([CH3:54])[CH2:12][C:10]4[CH:11]=[C:6]([CH:7]=[CH:8][C:9]=4[S:55]([C:58]([CH3:61])([CH3:60])[CH3:59])(=[O:57])=[O:56])[NH:5][C:1](=[O:2])[O:25][CH2:24][C@H:23]([CH3:26])[C:20]4[CH:21]=[CH:22][C:17]3=[CH:18][C:19]=4[CH3:27])=[CH:38][CH:37]=2)[CH:32]=[CH:33][N:34]=1)[C:47](=[O:48])[O:49][C:50]([CH3:52])([CH3:53])[CH3:51])=[O:46])([CH3:43])([CH3:44])[CH3:45]
Reactant: Cc1cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)N(C)Cc2cc(N)ccc2S(=O)(=O)C(C)(C)C)ccc1[C@@H](C)CO
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cc2ccc1[C@@H](C)COC(=O)Nc1ccc(S(=O)(=O)C(C)(C)C)c(c1)CN(C)C(=O)C2Nc1ccc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.4 %

Procedure:
Phosgene (201 mg, 0.406 mmol) was added dropwise to a solution of 22D (297 mg, 0.369 mmol) in acetonitrile (4 mL)/CH2Cl2 (4 mL) at 0° C. The bath was removed and the mixture was stirred at rt for 30 min. Ar was bubbled though the solution (10 min) to remove excess phosgene. The resulting solution was added to a solution of TEA (0.257 mL, 1.847 mmol) in CH2Cl2 (40 mL) at 40° C. over 5 h via a syringe pump. The reaction was stirred at rt overnight, quenched with H2O (1 mL) and MeOH (5 mL) and then concentrated. The crude product was purified by flash chromatography to give a mixture of diastereoisomers. The diastereomers were separated by a prep chiral HPLC (R,R-Whelk-O column 21.1×250 mm) to give 22E (75 mg, 0.090 mmol, 24.46% yield). MS (ESI) m/z: 830.8 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].F[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17].C([O-])([O-])=O.[K+].[K+].O>C1COCC1.C(OCC)(=O)C>[N+:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6])([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: COC(=O)CCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CCNc1ccccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
A mixture of methyl 3-aminopropanoate hydrochloride (15 g, 0.107 mol), 1-fluoro-2-nitrobenzene (14.9 g, 0.107 mol) and K2CO3 (36.6 g, 0.265 mol) in THF (50 mL) was heated at 90° C. and stirred overnight. After cooled to room temperature, water (20 mL) and ethyl acetate (40 mL) were added, and the separated organic layer was dried over Na2SO4, concentrated, and the resulting residue was purified by CombiFlash (PE:EA=4:1) to give methyl 3-((2-nitrophenyl)amino)propanoate (21.4 g, 90%). 1H NMR (300 MHz, CD3OD): δ 2.72 (t, J=6.6 Hz, 2H), 3.64-3.69 (m, 5H), 6.64-6.70 (m, 1H), 7.01-7.04 (m, 1H), 7.46-7.52 (m, 1H), 8.09-8.13 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].C(N(CC)CC)C.[NH2:19][C:20]1[CH:41]=[CH:40][C:23]([C:24]([N:26]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[CH2:30][N:29]3[CH:37]=[CH:38][CH:39]=[C:28]3[CH2:27]2)=[O:25])=[CH:22][CH:21]=1>C(Cl)Cl>[CH:39]1[CH:38]=[CH:37][N:29]2[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[N:26]([C:24]([C:23]3[CH:22]=[CH:21][C:20]([NH:19][C:5](=[O:6])[C:4]4[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=4[O:2][CH3:1])=[CH:41][CH:40]=3)=[O:25])[CH2:27][C:28]=12
Reactant: COc1ccccc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reaction time: 0.05 h
Yield: 59.6 %

Procedure:
To a stirred solution of 0.362 g of 2-methoxybenzoyl chloride 5 ml of methylene chloride is added 0.346 g of triethylamine at 0° C. After stirring for 3 minutes, 0.500 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added and stirring continued for 18 hours at room temperature. The reaction mixture is diluted with 45 ml of methylene chloride and washed with water, 2N citric acid, 1M NaHCO3, and brine. The reaction mixture is dried with Na2SO4, filtered through hydrous magnesium silicate and evaporated in vacuo to give a solid which is purified by crystallization from ethyl acetate to give 0.430 g of the desired product as a crystalline solid, m.p. 185°-188° C.