Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][C@@H:8]([CH2:12][CH2:13][C:14]([NH:16][CH2:17][NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[NH:15])[C:7]1=[O:29])[CH3:2].[CH2:31]([O:38][C:39](ON1C(=O)CCC1=O)=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:39]([O:38][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:40])[C@@H:8]([CH2:12][CH2:13][C:14]([NH:16][CH2:17][NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)(=[O:20])=[O:21])=[NH:15])[C:7]1=[O:29])=[O:30])[CH3:2]
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CCOC(=O)CN1CCN[C@@H](CCC(=N)NCNS(=O)(=O)c2ccc(C)cc2)C1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CN1CCN(C(=O)OCc2ccccc2)[C@@H](CCC(=N)NCNS(=O)(=O)c2ccc(C)cc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
A mixture of the compound of Example 10 (0.43 mmol), N-(benzyloxycarbonyloxy)succinimide (107 mg, 0.43 mmol) and triethylamine (0.24 mL, 1.72 mmol) in DMF (3 mL) was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and the organic layer was washed with water three times, dried over anhydrous Na2SO4, filtered and evaporated to give the title compound (195 mg).
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=O.[NH2:12][CH2:13][C:14]1[CH:41]=[CH:40][C:17]([CH2:18][N:19]([CH2:30][C:31]2[NH:35][C:34]3[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=3[N:32]=2)[CH:20]2[C:29]3[N:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH2:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1.CCN(CC)CC>O=S(Cl)Cl.CN(C1C=CN=CC=1)C>[NH:32]1[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=[C:31]1[CH2:30][N:19]([CH2:18][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][NH:12][C:4](=[O:6])[C:3]2[C:7]([CH3:11])=[CH:8][CH:9]=[N:10][C:2]=2[CH3:1])=[CH:41][CH:40]=1)[CH:20]1[C:29]2[N:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:23][CH2:22][CH2:21]1
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Reactant: Cc1ccnc(C)c1C(=O)O
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccnc(C)c1C(=O)NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.8 %

Procedure:
A solution of 2,4-dimethyl-nicotinic acid (54 mg, 0.35 mmol) in SOCl2 (˜2 mL, excess) was heated to 80° C. for 4 hours. The condenser was removed and the mixture was flushed with N2 at 80° C. for ˜5 minutes and then dried in vacuo for 10 minutes. The resulting syrup was dissolved in CH2Cl2 (2.4 mL) and added to a stirring mixture of (4-aminomethyl-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (187 mg, 0.47 mmol), Et3N (0.33 mL, 2.35 mmol) and a catalytic amount of DMAP. The reaction mixture was stirred overnight at room temperature. Purification of the crude yellow foam (240 mg) by radial chromatography on silica gel (2 mm plate, CH2Cl2/MeOH/NH4OH, 100:2:1) followed by radial chromatography on silica gel (1 mm plate, EtOAc/MeOH/NH4OH, 400:3:3) afforded the desired amide (61 mg, 33%) as a white foam.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][C:8]=1[C:9]([OH:11])=O)=[O:5])[CH3:2].[I-].ClC1C=CC=C[N+]=1C.[F:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2([CH:45]3[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][NH2:53])[CH2:47][CH2:46]3)[O:44][CH2:43][CH2:42][O:41]2)=[CH:36][CH:35]=1>O.ClCCl.C(N(CC)CC)C>[F:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2([CH:45]3[CH2:46][CH2:47][N:48]([CH2:51][CH2:52][NH:53][C:9]([C:8]4[CH:12]=[C:13]([O:16][CH2:17][C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[CH:14]=[CH:15][C:7]=4[NH:6][C:4](=[O:5])[O:3][CH2:1][CH3:2])=[O:11])[CH2:49][CH2:50]3)[O:41][CH2:42][CH2:43][O:44]2)=[CH:36][CH:35]=1
Reactant: CCOC(=O)Nc1ccc(OCc2ccccc2)cc1C(=O)O
Reactant: NCCN1CCC(C2(c3ccc(F)cc3)OCCO2)CC1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)Nc1ccc(OCc2ccccc2)cc1C(=O)NCCN1CCC(C2(c3ccc(F)cc3)OCCO2)CC1
Reaction time: 0.08 h
Yield: 67 %

Procedure:
To a stirred suspension of 19.6 parts of 2-[(ethoxycarbonyl)amino]-5-(phenylmethoxy)benzoic acid in 520 parts of dichloromethane were added 12.6 parts of N,N-diethylethanamine and the whole was stirred for 5 minutes. 15.9 Parts of 2-chloro-1-methylpyridinium iodide were added and stirring was continued for 90 minutes. A solution of 18.2 parts of 4-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]-1-piperidineethanamine in 390 parts of dichloromethane was added dropwise to the whole. Upon completion, stirring was continued for 2.50 hours at room temperature. 150 Parts of water were added to the reaction mixture. The organic layer was separated, washed with a sodium hydrogen carbonate solution 10%, dried, filtered and evaporated. The oily residue was purified by HPLC over silica gel using a mixture of methylbenzene and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 24.7 parts (67%) of ethyl [2-[[2-[4[ 2-(4-fluorophenyl)-1,3-dioxolan-2-yl]-1-piperidinyl]ethyl]aminocarbonyl]-4-(phenylmethoxy)phenyl]carbamate as a residue (25).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][CH2:12][CH2:13][NH:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:6][C:5]=1[OH:23].[H][H]>CO.[C].[Pd]>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])=[CH:6][C:5]=1[OH:23]
Reactant: [H][H]
Reactant: COC(=O)c1ccc(C=CCCNCC(=O)OC(C)(C)C)cc1O
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(CCCCNCC(=O)OC(C)(C)C)cc1O
Yield: 95 %

Procedure:
A solution of the compound (0.845 g) obtained in (1) above in methanol (20 ml) was vigorously stirred in the presence of 10% palladium-carbon (0.106 g) in a stream of hydrogen. After filtering through Celite, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=4/1 v/v) to give the title compound (0.810 g, yield 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=C(C#N)[CH:5]=[CH:4][N:3]=1.[CH3:10][Mg]Cl.Cl.C([O:16][CH2:17][CH3:18])C>>[C:17]([C:18]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=1)(=[O:16])[CH3:10]
Reactant: C[Mg]Cl
Reactant: CCOCC
Reactant: N#Cc1ccnc(Cl)c1
Agent: Cl
Product: CC(=O)c1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
24.61 g (177.62 mmol) of 2-chloro-4-cyano-pyridine are placed in 1.25 liters of diethyl ether under nitrogen, and 120 ml (22% in tetrahydrofuran, 353 mmol) of methylmagnesium chloride are added. The red suspension is stirred for 40 h at RT, poured onto 1.25 liters of ice/water and 250 ml of 6N hydrochloric acid and stirred for 14 h at RT. Extraction with diethyl ether and methylene chloride, drying with MgSO4 and concentration give 4-acetyl-2-chloro-pyridine; Rf =0.5 (methylene chloride:methanol=9:1).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[CH3:14])[CH:2]=[CH2:3].[OH-].[Na+].[CH3:17]I>CS(C)=O>[CH2:1]([N:4]([CH3:17])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[CH3:14])[CH:2]=[CH2:3]
Reactant: CI
Reactant: C=CCNc1ccc([N+](=O)[O-])cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: C=CCN(C)c1ccc([N+](=O)[O-])cc1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99 %

Procedure:
20 g (104 mmol) of N-allyl-2-methyl-4-nitroaniline were dissolved in 600 ml of dimethyl sulfoxide. 41.6 g (1.04 mol) of sodium hydroxide powder were added to the resultant solution, whereupon the solution became deep red. 44.3 g (19.6 ml, 312 mmol) of methyl iodide were added in one portion, and the solution became red-brown. The red-brown solution was stirred at room temperature for from 1 to 2 hours, poured into 3 l of ice water and then extracted three times with 500 ml of dichloromethane in each case. The combined dichloromethane phases were subsequently washed three times with 500 ml of water in each case, dried over sodium sulfate, filtered and evaporated under reduced pressure, to give a brown oil (21.4 g, corresponding to a yield of 99%), which was purified by chromatography on silica gel (eluent: n-hexane/ethyl acetate 15/1), to give N-allyl-N-methyl-2-methyl-4-nitroaniline (compound I-8 according to the invention) in a yield of 19.5 g, corresponding to 90%.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11].[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C(C)=CC=CC=1>[Br-:1].[CH3:11][CH:10]([CH3:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][P+:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)CCCCCCCCBr
Solvent: Cc1ccccc1C
Product: CC(C)CCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]

Procedure:
A solution of 1-bromo-9-methyldecane (1.0 g) and triphenylphosphine (1.7 g) in xylene (50 ml) was heated under relfux for 24 hours. The mixture was cooled, the supernatant was decanted and the residue was washed with ether and further dried by addition of benzene and evaporation to give the title compound as a pale gum.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:19]=1)[CH:15]=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH:31]([C:33]1[CH:49]=[CH:48][C:36]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][O:44][C:45](=[O:47])[CH3:46])=[CH:35][CH:34]=1)=O.[NH:50]1[CH:54]=[CH:53][CH:52]=[CH:51]1>>[C:45]([O:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][O:37][C:36]1[CH:48]=[CH:49][C:33]([C:31]2[C:54]3[NH:50][C:51]([C:15]([C:14]4[CH:17]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:19]=[C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:13]=4)=[C:51]4[N:50]=[C:54]([C:15]([C:14]5[CH:17]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:19]=[C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:13]=5)=[C:54]5[NH:50][C:51](=[C:15]([C:14]6[CH:13]=[C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:17]=6)[C:51]6[CH:52]=[CH:53][C:54]=2[N:50]=6)[CH:52]=[CH:53]5)[CH:53]=[CH:52]4)=[CH:52][CH:53]=3)=[CH:34][CH:35]=1)(=[O:47])[CH3:46]
Reactant: c1cc[nH]c1
Reactant: CCCCCCCCCCOc1cc(C=O)cc(OCCCCCCCCCC)c1
Reactant: CC(=O)OCCCCCCOc1ccc(C=O)cc1
Product: CCCCCCCCCCOc1cc(OCCCCCCCCCC)cc(-c2c3nc(c(-c4cc(OCCCCCCCCCC)cc(OCCCCCCCCCC)c4)c4ccc([nH]4)c(-c4cc(OCCCCCCCCCC)cc(OCCCCCCCCCC)c4)c4nc(c(-c5ccc(OCCCCCCOC(C)=O)cc5)c5ccc2[nH]5)C=C4)C=C3)c1

Procedure:
The title compound was prepared according to the method described in Example 15 above from 3,5-didecyloxy-benzaldehyde (see Example 13), acetic acid 6-(4-formyl-phenoxy)-hexyl ester (see Example 7) and pyrrole.
Reaction SMILES: [CH2:1]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH:4]=[CH2:5].C(Cl)(=O)C(Cl)=O.[CH3:21][C:22]([CH3:25])([O-])[CH3:23].[Li+]>C1C=CC=CC=1.O1CCCC1>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([O:12][C:22]([CH3:25])([CH3:23])[CH3:21])=[O:11])=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: CC(C)(C)[O-]
Reactant: C=CCCCc1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Li+]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: C=CCCCc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-(4-pentenyl)benzoic acid (42 g, 0.22 mol) in benzene (250 ml) was added dropwise to a solution of oxalyl chloride (60 ml) in benzene (200 ml) over 1 hour. The solution was stirred for 1 hour at room temperature and then heated under reflux for 2 hours. The solvent and excess oxalyl chloride was evaporated off under reduced pressure to give an oily residue which was dissolved in dry tetrahydrofuran (250 ml) and added dropwise over 1 hour to a stirred solution of lithium t-butoxide [prepared from t-butanol (21 g, 0.283 mol) in dry tetrahydrofuran (200 ml) at -20° C. and n-butyl lithium (114 ml of 2.5M solution in hexane, 0.285 mol)]. The resulting mixture was allowed to warm up to room temperture and stirred for an additional 12 hours. The solvent was evaporated off under reduced pressure and the residue was treated with water (500 ml) and extracted with chloroform (3×500 ml). The combined extracts were dried over sodium sulfate and the solvent was evaporated off under reduced pressure to yield crude 1,1-dimethylethyl 4-(4-pentenyl)benzoate as an oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([NH2:9])[CH2:5][CH2:6][O:7][CH3:8].Cl[C:11]1[CH:16]=[C:15]([CH3:17])[NH:14][C:13](=[O:18])[C:12]=1[N+:19]([O-:21])=[O:20].C(N(C(C)C)CC)(C)C>CC#N.C(Cl)Cl>[CH3:17][C:15]1[NH:14][C:13](=[O:18])[C:12]([N+:19]([O-:21])=[O:20])=[C:11]([NH:9][C@H:4]([CH2:3][O:2][CH3:1])[CH2:5][CH2:6][O:7][CH3:8])[CH:16]=1
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(=O)[nH]1
Reactant: COCCC(N)COC
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: ClCCl
Product: COCC[C@@H](COC)Nc1cc(C)[nH]c(=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-methoxymethyl-3-methoxypropylamine (4.19 g, 22.3 mmol), and 4-chloro-6-methyl-3-nitropyridone (3.87 g, 22.3 mmol) were mixed in CH3CN (70 mL) and diisopropyl-ethylamine (9.4 mL, 53.6 mmol) was added. The reaction was stirred at 25° C. for 16 h and at reflux for 2.5 h. The solvent was stripped off and the residue was dissolved in CH2Cl2 (150 mL) and the CH2Cl2 was washed with water (80 mL). The water was extracted with CH2Cl2 (50 mL) and the combined organic extracts were dried (MgSO4) and stripped in vacuo. The residue was crystallized from EtOAc and washed with 40% EtOAc/hexanes to give the product, (4.8 g, 75%). NMR(DMSO)d 9.13 (d, 1H, J=8.8 Hz), 5.9 (s, 1H), 3.92-4.02 (m, 1H), 3.20-3.25 (m, 2H), 3.28-3.4 (m, 2H), 3.25 (s, 3H), 3.18 (s, 3H), 2.09 (s, 3H), 1.65-1.90 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][N:17]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](=[S:14])[NH2:13])=[CH:8]2.[C:26]([O:31][CH2:32][CH3:33])(=[O:30])[C:27]#[C:28][CH3:29].C(P(CCCC)CCCC)CCC.O1CCCC1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][N:17]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:14][CH:28]([CH2:27][C:26]([O:31][CH2:32][CH3:33])=[O:30])[CH2:29][N:13]=1)=[CH:8]2
Reactant: CC#CC(=O)OCC
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)cn2)cc2cc(C(N)=S)[nH]c12
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cn4)cc(OC)c3[nH]2)S1
Temperature: 50 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
A mixture of 7-methoxy-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carbothioamide (2.06 g), ethyl 2-butynoate (0.95 mL), tributylphosphine (1.35 mL), tetrahydrofuran (50 mL) and toluene (100 mL) was stirred at 50° C. for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90 to 85/15, volume ratio) to give the title compound (1.36 g, 51%) as a pale yellow amorphous solid. MS 490 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[I:11]Cl>C(O)(=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[C:5]([OH:7])=[O:6]
Reactant: ClI
Reactant: O=C(O)c1cccc(O)c1
Solvent: CC(=O)O
Product: O=C(O)c1ccc(I)c(O)c1
Temperature: 45 °C
Reaction time: 15 h

Procedure:
30.0 g (217 mmol) of 3-hydroxybenzoic acid was dissolved in 200 ml of acetic acid. 53.0 g (326 mmol) of iodine monochloride was added to the obtained solution at room temperature. After stirring at 45° C. for 15 hours, the solvent was evaporated under reduced pressure, and the obtained residue was washed with 500 ml of 1% aqueous sodium thiosulfate solution twice and then with 500 ml of water twice, and dried to solid at 80° C. under reduced pressure to obtain the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:16][C:17]#[N:18])[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7]1)=O)C.CCN(CC)CC>N.CCO.C1(C)C=CC=CC=1.[Ni]>[O:13]1[C:9]2([CH2:14][CH2:15][C:6]3([CH2:16][CH2:17][NH:18][C:4]3=[O:3])[CH2:7][CH2:8]2)[O:10][CH2:11][CH2:12]1
Reactant: CCOC(=O)C1(CC#N)CCC2(CC1)OCCO2
Agent: [Ni]
Agent: N
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1NCCC12CCC1(CC2)OCCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.1 %

Procedure:
To a stirred solution of 8-cyanomethyl-1,4-dioxa-spiro[4.5]decane-8-carboxylic acid ethyl ester (12 g, 47.3 mmol) in a mixture of NH3-EtOH (200 ml, 7:93) was added Raney-Ni (4.16 g, 70.95 mmol) under nitrogen atmosphere at 25° C. The reaction mixture was then hydrogenated at 40° C. in an autoclave under 400 psi H2 pressure for 16 h. After the completion of reaction, the mixture was filtered through a bed of celite, and the filtrate was evaporated under reduced pressure. The crude material thus obtained (10 g, 38.9 mmol) was dissolved in dry toluene (100 ml) and to the stirred solution was added Et3N (10 ml, 71.14 mmol) under a nitrogen atmosphere at 25° C. The mixture was then heated under reflux for 24 h. After the completion of reaction, it was cooled to 25° C., the precipitated white solid was filtered, washed with hexane (3×50 ml), dried under vacuum to give the title compound (7.3 g) as a white solid. MS (m/e): 212.2 [MH+].
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([CH:14]2[S:19][CH2:18][C:17](=O)[CH2:16][S:15]2)[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].Cl.[NH2:27][OH:28]>CO.O.C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([CH:14]2[S:19][CH2:18][C:17](=[N:27][OH:28])[CH2:16][S:15]2)[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C2SCC(=O)CS2)ncn1Cc1ccccc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: Cc1c(C2SCC(=NO)CS2)ncn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.4 %

Procedure:
To a solution of 2-(1-benzyl-5-methyl-4-imidazolyl)-1,3-dithian-5-one (11.2 g., 0.0368 mole) in methanol (50 ml.) and water (20 ml.) is added sodium acetate (3.1 g.) and hydroxylamine hydrochloride (2.6 g., 0.037 mole). The reaction is stirred at ambient temperature for 5 hours. The mixture is diluted with chloroform, washed with water, dried and evaporated to give a solid crude product (11.1 g.), 2-(1-benzyl-5-methyl-4-imidazolyl)-1,3-dithian-5-one oxime, which is used as is in the following steps.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].C([Li])CCC.[Cl:10][C:11]1[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([C:19](F)(F)F)[C:12]=1[NH2:13].O>C(OCC)C>[Cl:10][C:11]1[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([C:19]2[NH:3][CH2:2][CH2:1][N:4]=2)[C:12]=1[NH2:13]
Reactant: Nc1c(Cl)cc(Cl)cc1C(F)(F)F
Reactant: NCCN
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: Nc1c(Cl)cc(Cl)cc1C1=NCCN1
Yield: 36.2 %

Procedure:
To a solution of ethylene diamine (1.2 mL, 18 mmol) in ethyl ether (50 mL) at −20° C. was added n-butyl lithium (6.4 mL, 2.5M in hexanes, 16 mmol). The mixture was stirred at 0° C. for 0.3 hour before the addition of 2,4-dichloro-6-trifluoromethyl aniline (0.92 g, 4.2 mmol). The mixture was stirred at 0° C. for an additional 1.5 hour, at which point water (0.36 mL, 20 mmol) was added and the solvent was removed under reduced pressure. Purification by flash column chromatography (silica gel, 1% to 10% methanol in dichloromethane) to give the title compound of Step A (0.35 g) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[CH2:13][CH2:14][N:15]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=[O:25])[CH:5]=[CH:6][CH:7]=1.[CH3:26][N:27]=[C:28]=[O:29].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:26][NH:27][C:28](=[O:29])[O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[CH2:13][CH2:14][N:15]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=[O:25])[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCN1CCCC1c1cccc(O)c1
Reactant: CN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNC(=O)Oc1cccc(C2CCCN2CCN2C(=O)c3ccccc3C2=O)c1
Reaction time: 0.75 h
Yield: 94 %

Procedure:
To a solution of 2-{2-[2-(3-hydroxyphenyl)-1-pyrrolidinyl]ethyl}-1H-isoindole-1,3(2H)dione (0.71 g) in dry tetrahydrofuran (35 ml) was added methyl isocyanate (0.13 ml) followed by milled potassium carbonate (0.38 g) at ambient temperature, under nitrogen. The reaction mixture was stirred for 45 mins, filtered through a pad of celite, and the filter cake was washed with ethyl acetate. The combined filtrates were concentrated, and the residue was triturated with petroleum ether. The residue was purified by flash column chromatography (silica gel, 1:1 ethyl acetate/heptane). The appropriate fractions were collected and concentrated to afford 0.78 g (94%) of product. Recrystallization from dichloromethane/petroleum ether gave the analytical sample, mp 96°-98° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@H:11]([CH2:42][CH2:43][NH2:44])[CH2:10]2)=[CH:5][CH:4]=1.[CH3:45][C:46]([CH3:48])=O.C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C.COC(C)(C)C>[CH:46]([NH:44][CH2:43][CH2:42][C@@H:11]1[CH2:10][C@H:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C@@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]3[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=3[CH:31]=2)[CH2:13][N:12]1[S:32]([C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=1)(=[O:33])=[O:34])([CH3:48])[CH3:45]
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CCN)C[C@@H]3c3ccc(OC)cc3)cc21
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CC(=O)O
Solvent: CCO
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CCNC(C)C)C[C@@H]3c3ccc(OC)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 100 mg of 2-[(2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-ethylamine in 3 ml of ethanol are added 0.006 ml of acetone, 0.009 ml of acetic acid and 0.032 g of sodium cyano borohydride. The reaction mixture is stirred overnight at room temperature, diluted with tert-butyl methyl ether, washed with 1N sodium hydroxide and the organic phases are combined and dried over sodium sulfate. The crude product is obtained as a turbid yellow oil, which is used in the next step without any further purification. Rf=0.23 (EtOAc-heptane 2:1); Rt=4.59.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]1[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:14]=[C:13]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:12]=1)[C:7]([CH3:25])=[CH:6][CH:5]=2.[Li:26]CCCC>CCCCC>[CH3:1][C:2]1[CH-:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]1[CH:12]=[C:13]([C:21]([CH3:22])([CH3:23])[CH3:24])[CH:14]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:16]=1)[C:7]([CH3:25])=[CH:6][CH:5]=2.[Li+:26]
Reactant: [Li]CCCC
Reactant: CC1=Cc2c(ccc(C)c2-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)C1
Solvent: CCCCC
Product: Cc1cc2c(-c3cc(C(C)(C)C)cc(C(C)(C)C)c3)c(C)ccc2[cH-]1
Product: [Li+]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2,5-Dimethyl-4-(3,5-di-t-butylphenyl)indene (3.4 g, 10 mmol), prepared as described above under (k), was dissolved in 200 ml of pentane. To the solution was added 4.1 ml of nBuLi (2.5 M in hexane), followed by stirring for four hours at room temperature. A white solid precipitated from solution and was collected by frit filtration and washed with additional pentane. Yield: 3.0 g (88%).