Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[C:7]([O:10][C:11](=[O:13])[CH3:12])(=O)[CH3:8].[CH3:14][C@H:15]([CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[CH2:16]/[CH:17]=[CH:18]/C(O)C>>[C:11]([O:10][CH:7](/[CH:18]=[CH:17]/[CH2:16][C@H:15]([CH3:14])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[CH3:8])(=[O:13])[CH3:12]
Reactant: CC(C)=CCC[C@@H](C)C/C=C/C(C)O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC(C)/C=C/C[C@H](C)CCC=C(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
A flame-dried, 250 mL, three-necked flask containing a magnetic stirring bar was charged under argon with 7.9 g (8.1 mL, 0.10 mol) of dry pyridine. After cooling in an ice-bath, 10.2 g (9.4 mL, 0.10 mol) of acetic anhydride and then 10.0 g (0.051 mol) of (2RS,3E,6R)-6,10-dimethyl-3,9-undecadien-2-ol were added dropwise, and the reaction was stirred for 2 hours at 0° C. and then overnight at 20° C.. The reaction mixture was poured onto 2N HCl/ice and extracted with 2×200 mL of ether. The combined extracts were washed with 2N HCl, sat. NaHCO3 solution, and brine, dried over Na2SO4, filtered and evaporated. Kugelrohr distillation at ca. 105°-130° C./0.1 mmHg afforded 12.05 g (99%) of (2RS,3E,6R)-6,10-dimethyl-3,9-undecadien-2-ol acetate as colorless liquid. Calcd. for C15H26O 2 (238.4): C, 75.58; H, 10.99; Found: C, 75.47; H, 11.04%. [α]D25 =2.16° (2.04% in CHCl3).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:15]([OH:19])[CH2:16][CH2:17][CH3:18])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CCOC(C)=O>C(Cl)Cl.O=[Mn]=O>[C:1]([C:5]1[CH:6]=[C:7]([C:15](=[O:19])[CH2:16][CH2:17][CH3:18])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC(O)c1cc(C(C)(C)C)cc(C(C)(C)C)c1
Agent: O=[Mn]=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCC(=O)c1cc(C(C)(C)C)cc(C(C)(C)C)c1
Reaction time: 3 h
Yield: 40 %

Procedure:
To 2.37 g (9.05 mmol) of alcohol 19 in 18 mL of CH2Cl2 was added 7.86 g (90.45 mmol) of MnO2. The reaction mixture was stirred for 3 h, then filtered (celite over silica gel pad) and the pad was washed repeatedly with 20 mL aliquots of CH2Cl2. After concentration, ketone 20 was purified by chromatography (SiO2, 3% EtOAc-hexanes) to give 941 mg (3.62 mmol) of 20 (40% yield 1 Hz TLC (10% EtOAc-90% hexanes) Rf 0.7; 1H-NMR (CDCl3) δ1.01 (t, 3H, CH2CH3), 1.34 (s, 18H, 6(CH3)), 1.78 (m, 2H, CH2CH3), 2.96 (t, J=7 Hz, 2H, CH2CH2CH3), 7.63 (t, J=1 Hz, 1H, Ar-H), 7.83 (d, J=1 Hz, 2H, Ar-H).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[C:13]([CH:14]([CH3:16])[CH3:15])=[CH:12][CH:11]=[CH:10][C:7]=1[CH2:8]O>C(Cl)(Cl)(Cl)Cl>[Cl:5][C:6]1[C:13]([CH:14]([CH3:16])[CH3:15])=[CH:12][CH:11]=[CH:10][C:7]=1[CH2:8][Cl:3]
Reactant: O=S(Cl)Cl
Reactant: CC(C)c1cccc(CO)c1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)c1cccc(CCl)c1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 85.7 %

Procedure:
At room temperature, 29.8 g of thionyl chloride is carefully dripped into 35 g of 2-chloro-3-isopropylbenzyl alcohol in 80 ml of carbon tetrachloride. The mixture is stirred for 15 hours at 25° C. and then evaporated down. Distillation (bp 0.3 :76°-78° C.) gives 33 g of 2-chloro-3-isopropylbenzyl chloride.
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[N:16]=[CH:17][C:10]=2[N:9]([CH3:33])[C:8]1=[O:34])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][C:14]2[C:11]3[C:12](=[O:13])[N:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:8](=[O:34])[N:9]([CH3:33])[C:10]=3[CH:17]=[N:16][C:15]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:31][CH:30]=1
Reactant: Cn1c(=O)n(CCCOC=O)c(=O)c2c(Cc3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)ncc21
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1c(=O)n(CCCO)c(=O)c2c(Cc3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)ncc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.9 %

Procedure:
To a solution of 3-(5-(4-chlorobenzyl)-6-(4-chlorophenyl)-1-methyl-2,4-dioxo-1,2-dihydropyrido[3,4-d]pyrimidin-3(4H)-yl)propyl formate (16 mg, 0.032 mmol) in THF (0.5 mL) and H2O (0.5 mL) was added LiOH.H2O (2.7 mg, 0.064 mmol). The reaction was stirred at RT for 0.5 h then diluted with EA (5 mL). The organic layer was washed with brine (5 mL), dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 5-(4-chlorobenzyl)-6-(4-chlorophenyl)-3-(3-hydroxypropyl)-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (6 mg, 80%) as a white solid. 1H NMR (CDCl3) δ: 8.79 (s, 1H), 7.42-7.33 (m, 2H), 7.28 (d, J=1.9 Hz, 1H), 7.26 (s, 1H), 7.17 (d, J=8.4 Hz, 2H), 6.80 (d, J=8.4 Hz, 2H), 4.64 (s, 2H), 4.17 (t, J=6.2 Hz, 2H), 3.74 (s, 3H), 3.46 (dd, J=11.5, 5.9 Hz, 2H), 2.70 (t, J=6.7 Hz, 1H), 1.96-1.71 (m, 2H). LCMS: MH+ 470 and TR=2.924 min.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[CH:8][C:9]([C:12](=[O:14])[CH3:13])=[N:10][CH:11]=2)=[CH:2]1.[BH4-].[Na+]>CO>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[CH:8][C:9]([CH:12]([OH:14])[CH3:13])=[N:10][CH:11]=2)=[CH:2]1
Reactant: CC(=O)c1ccc(-c2ccoc2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1ccc(-c2ccoc2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.7 %

Procedure:
To a solution of 1-(5-(furan-3-yl)pyridin-2-yl)ethanone (0.2 g, 1.0752 mmol) in MeOH (10 ml) was added sodium borohydride (0.0795 g, 2.150 mmol) at 0° C., the reaction mixture warmed to room temperature and was stirred for 2 h. The reaction mixture was evaporated under reduced pressure to remove the methanol, diluted with water (15 mL), extracted with ethyl acetate (200 mL), dried over sodium sulphate and concentrated under reduced pressure to obtain crude product. The crude product was purified by Biotage Isolera® One column (using 20% ethyl acetate and hexane to give 1-(5-(furan-3-yl)pyridin-2-yl)ethanol as a colorless liquid (0.150 g, 73% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.68 (s, 1H), 7.76 (t, 2H), 7.52 (s, 1H); 7.28 (t, 1H), 6.71 (s, 1H), 4.91 (d, 1H), 4.14-4.07 (m, 1H), 1.52 (d, 3H): LC-MS m/z calcd for [M+H]+ 189.08. found 190.0.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][C:7](=[S:17])[C:8]1[CH:13]=[C:12]([NH2:14])[C:11]([F:15])=[CH:10][C:9]=1[Cl:16])=[O:4].C(=O)([O-])[O-].[Ca+2].[C:23](Cl)(Cl)=[S:24].C(=O)=O>ClCCl.O>[CH3:1][O:2][C:3]([CH2:5][O:6][C:7](=[S:17])[C:8]1[CH:13]=[C:12]([N:14]=[C:23]=[S:24])[C:11]([F:15])=[CH:10][C:9]=1[Cl:16])=[O:4]
Reactant: S=C(Cl)Cl
Reactant: COC(=O)COC(=S)c1cc(N)c(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [Ca+2]
Solvent: ClCCl
Solvent: O
Product: COC(=O)COC(=S)c1cc(N=C=S)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 3.8 g of the resulting 5-amino-2-chloro-4-fluorothiobenzoic acid (methoxycarbonylmethyl) ester in 100 ml of dichloromethane is added dropwise at from 25° to 30° C. to a suspension of 6 g of calcium carbonate, 4 ml of thiophosgene, 20 ml of dichloromethane and 20 ml of water. When the evolution of carbon dioxide has ceased, the batch is stirred for a further 18 hours at room temperature. After filtering and washing with water, the organic phase is separated off, dried over sodium sulfate and then concentrated by evaporation to yield 4.8 g of 2-chloro-4-fluoro-5-isothiocyanatothiobenzoic acid (methoxycarbonylmethyl) ester in the form of an oil which is used without further purification in the next reaction step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:26]4[S:27][CH:28]=[CH:29][C:30]=4[Cl:31])([C:20]4[N:21]([CH3:25])[CH:22]=[N:23][CH:24]=4)[OH:19])[CH:16]=3)[N:11]=[C:10]([O:32]C)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:26]4[S:27][CH:28]=[CH:29][C:30]=4[Cl:31])([OH:19])[C:20]4[N:21]([CH3:25])[CH:22]=[N:23][CH:24]=4)[CH:16]=3)[NH:11][C:10](=[O:32])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(-c2cccc(Cl)c2)c2cc(C(O)(c3sccc3Cl)c3cncn3C)ccc2n1
Agent: Cl
Solvent: C1CCOC1
Product: Cn1cncc1C(O)(c1ccc2[nH]c(=O)cc(-c3cccc(Cl)c3)c2c1)c1sccc1Cl
Yield: 81.3 %

Procedure:
Following the same procedure as described in example 1F, [4-(3-chloro-phenyl)-2-methoxy-quinolin-6-yl]-(3-chloro-thiophen-2-yl)-(3-methyl-3H-imidazol-4-yl)-methanol (208 mg, 0.42 mmol) was treated with HCl in aqueous THF to yield the title compound of 21B as a yellow solid (164.7 mg, 81% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br.[Br:13][CH2:14][CH2:15][NH2:16].C(N(CC)CC)C>ClCCl.O>[Br:13][CH2:14][CH2:15][NH:16][S:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: NCCBr
Agent: Br
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(NCCBr)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Fluoro benzene sulfonyl chloride (8 g, 0.0411 mol) was added dropwise at 0° C. to a solution of 2-bromoethylamine hydrogen bromide (10.27 g, 0.0501 mol) and triethyl amine (14.3 ml, 0.1029 mol) in dry dichloromethane (100 ml) and stirred at room temperature for 1 h under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with ethyl acetate. Organic layer was washed with water and brine and dried over sodium sulfate. Solvent evaporation under reduced pressure afforded the sub-title product as a liquid. Yield: 11 g
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([N:29]2[CH2:41][CH2:40][N:32]3[C:33]4[CH2:34][CH2:35][CH2:36][CH2:37][C:38]=4[CH:39]=[C:31]3[C:30]2=[O:42])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:23]=C(C3CC3)N[N:20]=2)[C:15](=[O:27])[N:14]([CH3:28])[CH:13]=1)(=[O:3])[CH3:2].BrC1C=C(NC2C=[CH:57][C:56]([N:59]3[CH2:64][CH2:63][N:62]([CH2:65][C:66]([OH:69])([CH3:68])[CH3:67])[CH2:61][CH2:60]3)=[CH:55]N=2)C(=O)N(C)C=1.C(OCC1C(N2CCN3C4CCCCC=4C=C3C2=O)=NC=CC=1B1OC(C)(C)C(C)(C)O1)(=O)C>>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:29]2[CH2:41][CH2:40][N:32]3[C:33]4[CH2:34][CH2:35][CH2:36][CH2:37][C:38]=4[CH:39]=[C:31]3[C:30]2=[O:42])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:23]=[CH:55][C:56]([N:59]3[CH2:64][CH2:63][N:62]([CH2:65][C:66]([OH:69])([CH3:67])[CH3:68])[CH2:61][CH2:60]3)=[CH:57][N:20]=2)[C:15](=[O:27])[N:14]([CH3:28])[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc(C4CC4)[nH]n3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCN(CC(C)(C)O)CC3)cn2)c1=O
Agent: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(CC(C)(C)O)CC4)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Yield: 63 %

Procedure:
Following the procedures as described for preparation of 118c, reaction of 120a (435 mg, 1.0 mmol) and 3-(acetoxymethyl)-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)pyridin-4-ylboronic acid 113i (383 mg, 1 mmol) gave 120b (437 mg, 63%). LCMS: [M+H]+ 696.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[CH2:19][N:11]2[C:12]3[C:17]([CH:18]=[C:10]2[CH2:9][C@H:8]1[CH2:20]OS(C)(=O)=O)=[CH:16][CH:15]=[CH:14][CH:13]=3)(=O)=O.[CH3:26][C@H:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(O)C>[CH3:26][C@H:27]([N:34]1[CH2:6][C@@H:7]2[C@H:8]([CH2:9][C:10]3[N:11]([CH2:19]2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[CH:18]=3)[CH2:20]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CS(=O)(=O)OC[C@@H]1Cc2cc3ccccc3n2C[C@H]1COS(C)(=O)=O
Reactant: C[C@H](N)c1ccccc1
Solvent: CCO
Product: C[C@@H](c1ccccc1)N1C[C@H]2Cc3cc4ccccc4n3C[C@@H]2C1

Procedure:
A suspension of 11.0 g of trans-6,7,8,9-tetrahydro-7,8-bis[(methanesulphonyloxy)methyl]pyrido[1,2-a]indole [prepared as described in Example 14(iv)] in 60 ml of ethanol was treated with 26 ml of (S)-α-methylbenzylamine and heated to reflux for 18 hours. The cooled solution was concentrated and the precipitate was filtered off and purified by chromatography on silica gel using ethyl acetate/petroleum ether (2:1) for the elution. There were obtained 2.1 g of trans-2,3,3a,4,11,11a-hexahydro-2-[alpha(S)-methylbenzyl]-1H-pyrrolo[3',4':4,5]pyrido[1,2-a]indole, diastereomer A, of melting point 153° C., [α]D20 =+17.7° (CHCl3, c=0.51), and 1.6 g of trans-2,3,3a,4,11,11a-hexahydro-2-[alpha(S)-methylbenzyl]-1H-pyrrolo[3',4':4,5]pyrido[1,2-a]indole, diastereomer B, of melting point 154°-156° C.; [α]D20 =-54.2° (CHCl3, c=0.49).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.[CH3:14][CH:15]1[CH2:20][CH:19]([CH3:21])[CH2:18][NH:17][CH2:16]1>C1COCC1>[CH3:14][CH:15]1[CH2:20][CH:19]([CH3:21])[CH2:18][N:17]([C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=2)[CH2:16]1
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: CC1CNCC(C)C1
Solvent: C1CCOC1
Product: CC1CC(C)CN(c2ncc([N+](=O)[O-])cc2[N+](=O)[O-])C1
Temperature: 60 °C
Yield: 92.6 %

Procedure:
2 g (9.82 mmol) of 2-chloro-3,5-dinitropyridine, 10 ml of THF and 20 mmol of 3,5-dimethylpiperidine were placed in a round-bottomed flask. he mixture was maintained at 60° C. for 15 hours with stirring and was then poured into a mixture of ice-water with stirring. The precipitate formed was filtered off by suction and dried under vacuum to constant weight. 2.55 g of yellow powder were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[Br:22]Br.CO>C(O)(=O)C>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:9])=[CH:6][C:5]([Br:22])=[CH:4][N:3]=1
Reactant: Nc1ncccc1C(=O)c1cccnc1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ncc(Br)cc1C(=O)c1cccnc1
Reaction time: 2 h

Procedure:
(2-Amino-pyridin-3-yl)-pyridin-3-yl-methanone (0.13 g, 0.65 mmol) is dissolved in glacial acetic acid (6 ml). Na2CO3 (0.075 g, 0.72 mmol) is added. After evolution of gas has finished, a solution of bromine (0.025 ml, 0.49 mmol) in acetic acid (3 ml) is added dropwise. Na2CO3 (0.075 g, 0.72 mmol) is added, followed by a second solution of bromine (0.025 ml, 0.49 mmol) in acetic acid (3 ml). The resulting yellow suspension is left to stir for 2 hour. The reaction is quenched by pouring onto ice water (150 ml), and neutralised using NaHCO3. The product is extracted with EtOAc and dried (MgSO4). Concentration in vacuo affords an oil, which is trituatuted with methanol to yield the title compound [M+H]+ 277.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][N:9]=[CH:10][C:11]1[CH:35]=[CH:34][C:14]([CH2:15][N:16]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:17](=[O:25])[NH:18][CH2:19][C:20]([O:22]CC)=[O:21])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+:37].O>C(O)C>[C:1]([O:5][C:6]([NH:8][N:9]=[CH:10][C:11]1[CH:35]=[CH:34][C:14]([CH2:15][N:16]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:17](=[O:25])[NH:18][CH2:19][C:20]([O-:22])=[O:21])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3].[Na+:37]
Reactant: CCOC(=O)CNC(=O)N(Cc1ccc(C=NNC(=O)OC(C)(C)C)cc1)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NN=Cc1ccc(CN(OCc2ccccc2)C(=O)NCC(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2.78 g (5.74 mmol) of ethyl (3-(4-(tert-butyloxycarbonylaminoiminomethyl)benzyl)-3-benzyloxyureido)acetate in 50 ml of ethanol are treated with 0.23 g (5.74 mmol) of NaOH and 1.2 ml of water and the mixture is stirred at room temperature for 18 h. The solvent is removed in vacuo and the residue is freeze-dried.
Reaction SMILES: N1C=CC=CC=1C1NC2C=CC=CC=2N=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1.[Br:27][C:28]1[CH:33]=[CH:32][C:31](I)=[CH:30][C:29]=1[O:35][CH3:36]>[Cu]I.CN(C=O)C>[Br:27][C:28]1[CH:33]=[CH:32][C:31]([N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)=[CH:30][C:29]=1[O:35][CH3:36]
Reactant: COc1cc(I)ccc1Br
Reactant: c1c[nH]cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(-n2ccnc2)ccc1Br
Temperature: 60 °C
Yield: 67.3 %

Procedure:
A mixture of 2-(2-pyridyl)benzimidazole (287 mg, 1.469 mmol), cesium carbonate (5.98 g, 18.36 mmol), copper(I) iodide (280 mg, 1.469 mmol) and DMF (5 mL) were combined in a microwave vial fitted with an N2 inlet and magnetic stir bar. The slurry was heated at 60° C. for 1 h, followed by addition of imidazole (500 mg, 7.34 mmol) and 1-bromo-4-iodo-2-methoxybenzene (2.3 g, 7.34 mmol). The reaction mixture was heated at 90° C. for 2 days. The reaction mixture was filtered through celite, washed with EtOAc, and concentrated in vacuo. The crude material was purified by silica gel chromotography (10% to 40% EtOAc in heptanes) to give 1-(4-bromo-3-methoxyphenyl)-1H-imidazole (1.25 g, MS: 255.2 [M+H+])
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[N+:11]([O-])([OH:13])=[O:12].O>C(Cl)Cl>[OH:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(O)cc1C#N
Solvent: O
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])c(O)cc1C#N
Yield: 29.2 %

Procedure:
5-Hydroxy-2-methylbenzonitrile (D90, 475 mg, 3.57 mmol) was dissolved in DCM (5 mL) and 70% nitric acid (1 mL, 22 mmol) was added dropwise to the reaction. The mixture was stirred for 45 min before the addition of H2O (15 mL). The two phases were separated and the aqueous phase was extracted with DCM (2×). The combined organics were dried (Na2SO4) and concentrated by rotary evaporation to give a yellow solid. The crude residues were purified by flash column chromatography (silica, 10% EtOAc/90% iso-hexane to 50% EtOAc/50% iso-hexane) to give 5-hydroxy-2-methyl-4-nitrobenzonitrile (D91, 186 mg, 26%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:12]([N:15]2[CH2:20][CH2:19][N:18]3[CH2:21][C@H:22]([O:24][C:25]4[CH:30]=[N:29][C:28]([CH:31]5[CH2:33][CH2:32]5)=[CH:27][N:26]=4)[CH2:23][C@H:17]3[CH2:16]2)(=[O:14])=[O:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Cu][C:35]#[N:36]>CN(C)C=O>[CH:31]1([C:28]2[N:29]=[CH:30][C:25]([O:24][C@H:22]3[CH2:21][N:18]4[CH2:19][CH2:20][N:15]([S:12]([C:4]5[CH:3]=[C:2]([CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=5)[C:35]#[N:36])(=[O:13])=[O:14])[CH2:16][C@@H:17]4[CH2:23]3)=[N:26][CH:27]=2)[CH2:32][CH2:33]1
Reactant: O=S(=O)(c1cc(Br)cc(C(F)(F)F)c1)N1CCN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: N#Cc1cc(C(F)(F)F)cc(S(=O)(=O)N2CCN3C[C@H](Oc4cnc(C5CC5)cn4)C[C@H]3C2)c1
Temperature: 130 °C
Reaction time: 16 h

Procedure:
To a solution of the product from Example 64A (30 mg, 0.055 mmol) in N,N-dimethylformamide (0.3 mL) was added copper(I) cyanide (10 mg, 0.11 mmol), and the resulting mixture was stirred at 130° C. for 16 hours. The cooled mixture was partitioned between water and ethyl acetate (3×), and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-60% ethyl acetate in hexanes to give the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 0.87-1.00 (m, 4H), 1.74-1.90 (m, 1H), 1.91-2.07 (m, 2H), 2.19 (t, J=10.34 Hz, 1H), 2.34 (dd, J=10.17, 5.09 Hz, 1H), 2.39-2.63 (m, 3H), 2.98-3.10 (m, 1H), 3.66 (dd, J=10.17, 6.78 Hz, 1H), 3.80 (dd, J=10.17, 1.70 Hz, 1H), 3.88-3.99 (m, 1H), 5.24-5.36 (m, 1H), 7.92 (d, J=1.36 Hz, 1H), 8.03 (d, J=1.36 Hz, 1H), 8.11-8.14 (m, J=1.02 Hz, 1H), 8.17-8.26 (m, J=4.07, 1.02 Hz, 2H); MS (ESI) m/z 494.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:15][CH2:16][CH2:17][NH:18][C:19](=[O:21])[CH3:20])[CH:3]=1>C(N)CN>[NH2:15][CH2:16][CH2:17][NH:18][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:15][CH2:16][CH2:17][NH:18][C:19](=[O:21])[CH3:20])[CH:3]=1
Reactant: CC(=O)NCCNc1cc(Cl)nc(-c2ccc(Cl)cc2)n1
Solvent: NCCN
Product: CC(=O)NCCNc1cc(NCCN)nc(-c2ccc(Cl)cc2)n1
Temperature: 25 °C
Yield: 138.8 %

Procedure:
N-(2-{[6-Chloro-2-(4-chlorophenyl)pyrimidin-4-yl]amino}ethyl)acetamide (0.90 g) was dissolved in ethylenediamine (20 ml) and heated with stirring to reflux for 18 hrs. After cooling to ambient temperature the solution was evaporated onto silica gel. Purification via flash chromatography on silica gel eluting with increasingly polar solvent systems from ethyl acetate to methanol furnished the title compound (0.67 g).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.[NH2:14][C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][C:16]=1[CH2:26]Cl>C(O)(C)C>[NH2:14][C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][C:16]=1[CH2:26][S:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:4]=2[N:3]=1
Reactant: COc1ccc2nc(S)[nH]c2c1
Reactant: CCOC(=O)c1ccc(N)c(CCl)c1
Agent: Cl
Solvent: CC(C)O
Product: CCOC(=O)c1ccc(N)c(CSc2nc3cc(OC)ccc3[nH]2)c1
Yield: 25.3 %

Procedure:
The title compound was prepared by the method of Example 1 using 1.30 g of 2-mercapto-5-methoxybenzimidazole instead of 2-mercaptobenzimidazole and 1.80 g of ethyl 4-amino-3-(chloromethyl)benzoate hydrochloride (prepared as for Example 70) instead of 2-(chloromethyl)-N,N-dimethylaniline in isopropyl alcohol. The basic extraction used 10% sodium hydroxide instead of sodium carbonate and 1,2-dichloroethane instead of dichloromethane. The 1,2-dichloroethane extract was dried over sodium sulfate, filtered, and concentrated in vacuo to a gum. Recrystallization from diethyl ether-hexane gave 650 mg of the title compound: m.p. 140-146° C. Analysis. Calc'd. for C18H19N3O3S: C, 60.49; H, 5.36; N, 11.76; S, 8.90. Found: C, 60.27; H, 5.44; N, 11.39; S, 8.70.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2.[H-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.C(OCC)(=O)C>CN(C=O)C>[C:14]1([S:20]([N:10]2[C:11]3[C:7](=[CH:6][CH:5]=[CH:4][C:3]=3[O:2][CH3:1])[CH:8]=[CH:9]2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc2cc[nH]c12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc2ccn(S(=O)(=O)c3ccccc3)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7-methoxyindole (1 eq) in DMF cooled in an ice bath was added NaH (60% dispersion in oil, 1.2 eq). The reaction was stirred for 1 hr at room temperature then recooled in an ice bath. Benzenesulfonyl chloride (1.1 eq) was added then the reaction was stirred for 2 hrs at room temperature. Water/ethyl acetate were added and the ethyl acetate layer was washed repeatedly (3×) with water. The ethyl acetate layer was concentrated and evaporated to dryness.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[S:9])[NH:8][C:4]=2[CH:3]=1.Cl.[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16]Cl.C(=O)([O-])O.[Na+]>C(O)C>[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][S:9][C:7]1[NH:8][C:4]2[CH:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:5]=2[N:6]=1
Reactant: CN(C)CCCl
Reactant: Cc1ccc2[nH]c(=S)[nH]c2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc2nc(SCCN(C)C)[nH]c2c1
Yield: 64.8 %

Procedure:
4.11 g (25 mmoles) of 5-methyl-benzimidazoline-2-thione, 4.32 g (30 mmoles) of 2-(dimethylamino)-ethylchloride hydrochloride and 2.55 g of sodium hydrogencarbonate are refluxed in 50 ml of ethanol for 6 hours. The reaction mixture is filtered off, concentrated and the residue is worked up according to the method of Example 2. The dichloromethane extracts are concentrated and the residue is crystallized from petrolether. 3.81 g of 2-(2-dimethylamino-ethylthio)-5-methyl-benzimidazole are obtained, which melting point does not change after recrystallizaton from acetonitrile. M.p.: 103° C.