Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N:11]([O-])=O.[Na+].[Cl:15][Sn]Cl.O>O.Cl>[ClH:15].[N+:1]([C:4]1[CH:5]=[C:6]([NH:10][NH2:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Cl[Sn]Cl
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.8 %

Procedure:
3-Nitro-phenylamine (27.6 g, 0.2 mol) was dissolved in the mixture of H2O (40 mL) and 37% HCl (40 mL). A solution of NaNO2 (13.8 g, 0.2 mol) in H2O (60 mL) was added to the mixture at 0° C., and then a solution of SnCl2.H2O (135.5 g, 0.6 mol) in 37% HCl (100 mL) was added at that temperature. After stirring at 0° C. for 0.5 h, the insoluble material was isolated by filtration and was washed with water to give (3-nitrophenyl)hydrazine hydrochloride (27.6 g, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([OH:8])[CH:7]=1.Br[CH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][C:30]=1[F:37]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([CH:7]=1)[O:8][CH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][C:30]=1[F:37]
Reactant: N#Cc1ccc(CBr)c(F)c1
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1
Product: N#Cc1ccc(COc2cc(Cl)ccc2-c2nc3cc(F)c(F)cc3n2CC2CCCCC2)c(F)c1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from 5-chloro-2-(1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazol-2-yl)-phenol (Example 19, intermediate a) and 4-bromomethyl-3-fluoro-benzonitrile (CAS Reg. No. 105942-09-4). Light brown powder (78%). MS (Turbo Spray): m/z=510.2 (M+H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:26])[C:13](=[O:25])[N:14]([C:15]4[C:16]([CH3:24])=[N:17][N:18]([CH2:20][C:21]([OH:23])=[O:22])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][N:30]=1>CN(C=O)C.C([O-])([O-])=O.[K+].[K+].CO.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>[CH3:27][O:28][C:29]1[N:30]=[CH:31][C:32]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:26])[C:13](=[O:25])[N:14]([C:15]5[C:16]([CH3:24])=[N:17][N:18]([CH2:20][C:21]([OH:23])=[O:22])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)=[CH:33][CH:34]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: Cc1nn(CC(=O)O)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc3ncc4c(c3c2)n(-c2cn(CC(=O)O)nc2C)c(=O)n4C)cn1
Temperature: 105 °C
Reaction time: 1.25 h

Procedure:
A mixture of [4-(8-bromo-3-methyl-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-3-methyl-pyrazol-1-yl]-acetic acid (Stage 101.1.1b, 161 mg, 0.387 mmol), 2-methoxypyridine-5-boronic acid (Aldrich, Buchs, Switzerland, 77 mg, 0.503 mmol), and PdCl2(PPh3)2 (17 mg, 0.024 mmol) in DMF (4.0 ml) and 1 M aqueous K2CO3 (1.16 ml) was stirred under argon at 105° C. for 1.25 h. The RM was cooled to rt. The mixture was diluted with MeOH+3 drops TFA and purified directly by Prep.HPLC (H2O (0.1% TFA)/CH3CN 95:5 to 65:35). The fractions containing products were collected together concentrated, before being lyophilized to give the title compound as a TFA-salt and white powder. (HPLC: tR 2.38 min (Method A); M+H=446 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.22 (s, 1H), 8.46 (s, 1H), 8.23-8.14 (m, 3H), 7.87-7.79 (m, 1H), 7.74-7.68 (m, 1H), 6.94-6.88 (m, 1H), 5.15-4.98 (m, 2H), 3.89 (s, 3H), 3.60 (s, 3H), 1.97 (s, 3H))
Reaction SMILES: [OH:1][C@:2]1([C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C:25](=[CH:26][CH2:27]2)[C@:23]2([CH3:24])[C:18](=[CH:19][C:20](=[O:30])[CH2:21][CH2:22]2)[CH2:17][CH2:16]3)[CH2:13][CH2:12]1)[C:3](=[O:11])[CH2:4][O:5][C:6]([CH2:8][CH:9]=[CH2:10])=[O:7]>C(OCC(F)(F)F)(=O)CCCCCCCCCCCCCCCCC.O1CCCC1>[C:2]([O:1][C@:2]1([C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C:25](=[CH:26][CH2:27]2)[C@:23]2([CH3:24])[C:18](=[CH:19][C:20](=[O:30])[CH2:21][CH2:22]2)[CH2:17][CH2:16]3)[CH2:13][CH2:12]1)[C:3](=[O:11])[CH2:4][O:5][C:6]([CH2:8][CH:9]=[CH2:10])=[O:7])(=[O:1])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: C=CCC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@@]21C
Agent: CCCCCCCCCCCCCCCCCC(=O)OCC(F)(F)F
Solvent: C1CCOC1
Product: C=CCC(=O)OCC(=O)[C@@]1(OC(=O)CCCCCCCCCCCCCCCCC)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@@]21C
Temperature: 45 °C
Reaction time: 48 h

Procedure:
Crude 17α-hydroxy-21 -allylcarbonyloxy-pregna-4,9(11)-diene-3,20-dione was dissolved in 15 g of trifluoroethyl octadecanoate and 150 ml of tetrahydrofuran, the resulting solution was added with 4 g of Bacillus subtilis protease and the suspension was stirred for 2 days at 45° C., adding further protease at regular time intervals to 3 g total. The protease was filtered off, the filtrate was removed under vacuum and the residue was chromatographed on a silica gel column with a dichloromethane/methanol 99:1 mixture. The less polar fraction was evaporated off to obtain a residue of 17α-octadecanoyloxy-21-allylcarbonyloxy-pregna-4,9(11)-diene-3,20-dione.
Reaction SMILES: C(N[C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])=O.[H-].[Na+].IC.[CH3:17][N:18]([CH:20]=[O:21])C>>[CH:20]([N:18]([C:5]1[CH:4]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])[CH3:17])=[O:21]
Reactant: CN(C)C=O
Reactant: O=CNc1cccc(C(=O)O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CN(C=O)c1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
3-Formylamino benzoic acid (2.28 g, 13.8 mmol) was taken up in DMF (25 ml) and added dropwise to a suspension of sodium hydride (1.05 g, 80% disp. in oil) in DMF (15 ml) at 0° C. The mixture was allowed to warm to r.t. over 1 h and then iodomethane (0.95 ml) added. A second portion of iodomethane (0.95 ml) was added after 1 h and the mixture stirred at r.t. overnight. The solvent was removed by evaporation and the product partitioned between ethyl acetate and 1M HCl. The organic layer was washed with brine, then filtered (Whatman® 1 PS phase separator) and evaporated. The residue was chromatographed on silica (eluant 60% ethyl acetate in hexanes) to provide the title compound as a colourless solid (2.30 g, 86%). A portion of the ester (900 mg, 4.66 mmol) was taken up in dioxan/water (2/1, v/v, 30 ml) and treated with LiOH.H2O (378 mg, 9 mmol) at r.t. with stirring overnight. The mixture was acidified with 1M HCl and extracted twice with EtOAc. The combined extracts were washed with brine, filtered (Whatman® 1 PS phase separator) and evaporated. The acid (420 mg, 50%) was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:17]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[F:28])=[CH:18][N:19]=1)[C:5]([NH:7][O:8][CH2:9][C@H:10]1[CH2:14]OC(C)(C)[O:11]1)=[O:6].FC(F)(F)[C:31](O)=[O:32].CCOC(C)=O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C:17]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[F:28])=[CH:18][N:19]=1)[C:5]([NH:7][O:8][CH2:9][CH:10]([OH:11])[CH2:14][CH2:31][OH:32])=[O:6]
Reactant: O=C(O)C(F)(F)F
Reactant: CC1(C)OC[C@H](CONC(=O)c2cc(Br)ncc2Nc2ccc(I)cc2F)O1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(NOCC(O)CCO)c1cc(Br)ncc1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
2-Bromo-N-(2,4-dihydroxy-butoxy)-5-(2-fluoro-4-iodo-phenylamino)-isonicotinamide was synthesized as described in General method 3: To a solution of 2-bromo-N-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-5-[(2-fluoro-4-iodophenyl)amino]-isonicotinamide (100.0 mg, 0.18 mmol) in dichloromethane (1 ml) was added trifluoroacetic acid (1 ml) at RT. The reaction mixture was stirred at RT for 30 min, and monitored by TLC (Hex:EtOAc=1:1 and contain TEA). Upon completion, the volatiles were evaporated, and the residue was dissolved in dichloromethane, washed with 5% aq. NaHCO3 to get a precipitate. The residue was filtered, washed with water, and dried to get 53 mg (56%) of 2-Bromo-N-(2,4-dihydroxy-butoxy)-5-(2-fluoro-4-iodo-phenylamino)-isonicotinamide. LC/MS: [8.76 min, 541 (M+1)]
Reaction SMILES: [H-].[Li+].[NH2:3][C:4]1[N:12]=[C:11]2[C:7]([NH:8][CH:9]=[N:10]2)=[C:6]([O:13][CH2:14][CH2:15][O:16][CH3:17])[N:5]=1.[CH2:18]([O:20][P:21]([CH2:26][O:27][CH2:28][CH2:29][CH2:30]Br)([O:23][CH2:24][CH3:25])=[O:22])[CH3:19].O>CN(C)C=O>[NH2:3][C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[CH2:30][CH2:29][CH2:28][O:27][CH2:26][P:21]([O:23][CH2:24][CH3:25])([O:20][CH2:18][CH3:19])=[O:22])=[C:6]([O:13][CH2:14][CH2:15][O:16][CH3:17])[N:5]=1
Reactant: CCOP(=O)(COCCCBr)OCC
Reactant: COCCOc1nc(N)nc2nc[nH]c12
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(COCCCn1cnc2c(OCCOC)nc(N)nc21)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of lithium hydride (560 mg, 60 mmol) in dry dimethylformamide (DMF, 200 ml) was added 2-amino-6-methoxyethoxy purine (8.0 g, 40 mmol) (prepared according to the literature procedure: J. Kjellberg, M. Liljenberg and N. G. Johansson, Tetrahedron Lett. 877, 1986]and stirred for 60 min at 25° C. To this solution was added over 3 min a solution of 3-(diethylphosphonomethoxy)-1-bromopropane (12.0 g, 41.5 mmol) in DMF (5 mL) and the solution was heated at 55° C. for 4 h. The reaction mixture was then cooled to room temperature and water (50 mL) was added dropwise. Insoluble material was removed by filtration. The filtrate was concentrated in vacuo to give a viscous oil which was purified by column chromatography on silica gel (5% methanol in CH2Cl2) to afford 2-amino-9-(3-(diethylphosphonomethoxy)propyl]-6-methoxyethoxy purine as a white crystalline solid: yield 3.45 g (21%); mp 78°-79° C.
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[O:5][CH2:4][C:2]1=[O:3].[C:8]([C:11]1[S:15][C:14]([CH:16]=O)=[CH:13][CH:12]=1)([OH:10])=[O:9]>C1COCC1>[C:8]([C:11]1[S:15][C:14]([CH:16]=[C:1]2[C:2](=[O:3])[CH2:4][O:5][C:6]2=[O:7])=[CH:13][CH:12]=1)([OH:10])=[O:9]
Reactant: O=Cc1ccc(C(=O)O)s1
Reactant: O=C1COC(=O)C1
Solvent: C1CCOC1
Product: O=C1COC(=O)C1=Cc1ccc(C(=O)O)s1
Reaction time: 0.17 h
Yield: 67 %

Procedure:
As before, 0.571 gm of tetronic acid (FW=100, 5.7 mmole) was reacted with 2.2 equiv. or 1.96 gm of 5-carboxy-2-thiophenecarboxaldehyde with 6 mL of THF and 10.5 mL of conc. HC1 and applied heat. A greenish precipitate formed immediately. Stirring was continued for 10 minutes. Workup and recrystallization from methanol gave 0.91 gm (67%) of the product having a M. p. of approximately 255°-268° C. and a molecular formula of C10H6O5S: calculated %C 50.42; %H 2.54; found %c 50.22; %H 2.75.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].[CH:18]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][N:22]=1)([CH3:20])[CH3:19]>CN1CCCC1=O.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:28][CH2:27][C:24]3[CH:23]=[N:22][C:21]([CH:18]([CH3:19])[CH3:20])=[CH:26][CH:25]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccc(C(C)C)nc1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)c1ccc(CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 16.3 %

Procedure:
To a solution of 8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g. 0.00045 mol) in N-methyl 2-pyrolidone (1.0 mL) was added powdered potassium hydroxide (0.140 g, 0.0025 mol) and allowed to stir for 10 min at RT. 2-Isopropyl-5-vinyl-pyridine (0.185 g, 0.00125 mol) was added and stirred for further 4 h. at 100 deg C. After completion (TLC), reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure using rotary evaporator. The crude was purified through column chromatography (7% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch), Then further purified by preparative TLC, to give the desired compound as yellow oil (0.027 g, 15% yield). 8-Chloro-5-[2-(6-isopropyl-pyridin-3-yl)-ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.027 g, 0.00007 mol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.009 g, 0.00007 mol) in THF (0.5 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.027 g, 81% yield).
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[C:14]([C:17](=[O:21])[CH2:18][CH2:19][CH3:20])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1([C:9]([OH:11])=[O:10])[CH2:8][CH2:7][CH2:6]1.Cl.[CH3:23]NC.C=O.C(O)(=O)C>CN(C)C=O>[Cl:1][C:2]1[C:15]([Cl:16])=[C:14]([C:17](=[O:21])[C:18](=[CH2:23])[CH2:19][CH3:20])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1([C:9]([OH:11])=[O:10])[CH2:8][CH2:7][CH2:6]1
Reactant: CNC
Reactant: CCCC(=O)c1ccc(OC2(C(=O)O)CCC2)c(Cl)c1Cl
Agent: C=O
Agent: Cl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: C=C(CC)C(=O)c1ccc(OC2(C(=O)O)CCC2)c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(2,3-dichloro-4-butyrylphenoxy)cyclobutane-1-carboxylic acid (4 g, 0.012 mole), dimethylamine hydrochloride (5.5 g, 0.067 mole), paraformaldehyde (1.2 g, 0.04 equiv.) and acetic acid (0.3 ml) were stirred and heated on a steam bath for 2.25 hours. N,N-dimethylformamide (30 ml) was added and stirring and heating was continued for another 2 hours. The mixture was poured into ice water and extracted with ether. The ether layer was washed with water and then with brine and finally dried over MgSO4. The solution was treated with p-xylene and the solvents were removed in vacuo. The resulting residue was recrystallized from hexane to give 1-[2,3-dichloro-4-(2-methylenebutyryl)phenoxy]cyclobutane-1-carboxylic acid, m.p. 120° C.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([N+:18]([O-])=O)[CH:12]=3)[S:7][C:6]=2[CH:5]=1)([O-])=O.NN>C(O)C>[NH2:18][C:11]1[CH:10]=[CH:9][C:8]2[S:7][C:6]3[C:15](=[CH:16][CH:17]=[C:4]([NH2:1])[CH:5]=3)[S:14][C:13]=2[CH:12]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)Sc1ccc([N+](=O)[O-])cc1S2
Agent: NN
Solvent: CCO
Product: Nc1ccc2c(c1)Sc1ccc(N)cc1S2
Temperature: 25 °C

Procedure:
To a solution of 2,7-dinitrothianthrene (550 mg, 1.8 mmole) in 100 mL of ethanol was added graphite (1.72 g, 144 mmole) and hydrazine (0.56 mL, 18 mmole) with continued stirring and the mixture was refluxed for over night. The reaction mixture was cooled to room temperature and filter through a short column of celite 545. The solvent was then removed and the resulting white solid was dried in vacuo. It was then recrystallized from CHCl3 or used without further purification. mp 185˜186° C. 1H NMR (300 MHz, CDCl3) δ: 7.15 (d, 2H, J=8.1 Hz), 6.81 (d, 2H, J=2.7 Hz), 6.52 (dd, 2H, J=8.1, 2.7 Hz), 3.68 (bs, 4H). 13C NMR (75 MHz, d6-acetone) δ: 149.5, 139.1, 130.0, 121.9, 114.8, 114.6. HR-MS (ESI): calcd. for C12H10N2S2+Na 269.0178 [(M+Na)+]. Found 269.0176.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:47][N:48]([CH3:68])[CH:49]([CH2:66][CH3:67])[CH:50]([C:56]1[CH:65]=[CH:64][C:59]2[N:60]=[C:61]([NH2:63])[S:62][C:58]=2[CH:57]=1)[N:51]1[CH:55]=[CH:54][N:53]=[CH:52]1>CN(C=O)C>[CH3:47][N:48]([CH3:68])[CH:49]([CH2:66][CH3:67])[CH:50]([C:56]1[CH:65]=[CH:64][C:59]2[N:60]=[C:61]([NH:63][C:9]([C:8]3[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:13][CH:12]=3)=[O:11])[S:62][C:58]=2[CH:57]=1)[N:51]1[CH:55]=[CH:54][N:53]=[CH:52]1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: CCC(C(c1ccc2nc(N)sc2c1)n1ccnc1)N(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(C(c1ccc2nc(NC(=O)c3ccc(C(=O)OC)cc3)sc2c1)n1ccnc1)N(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 4-(methoxycarbonyl)benzoic acid (18 mg, 0.1 mmol), HATU (41.8 mg, 0.11 mmol), and diisopropylethylamine (39 mg) in DMF was stirred at RT for 5 min. A syn and anti mixture of 6-(2-(dimethylamino)-1-(1H-Imidazol-1-yl)butyl)benzo[d]thiazol-2-amine (31.5 mg, 0.1 mmol) in DMF was added and stirred at RT. DMF was evaporated and the residue was purified by PTLC using 10% methanol in DCM as eluent to afford the syn and anti isomers of methyl 4-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)carbamoyl)benzoate. ESI: m/z 478.2 [M+1+].
Reaction SMILES: C(N=CC)(C)(C)C.C([N-]C(C)C)(C)C.[Li+].P(Cl)(OCC)([O:18][CH2:19][CH3:20])=O.O=[C:26]1[CH2:31][CH2:30][CH:29]([C:32]([O:34][CH3:35])=[O:33])[CH2:28][CH2:27]1>>[O:18]=[CH:19][CH:20]=[C:26]1[CH2:31][CH2:30][CH:29]([C:32]([O:34][CH3:35])=[O:33])[CH2:28][CH2:27]1
Reactant: COC(=O)C1CCC(=O)CC1
Reactant: CCOP(=O)(Cl)OCC
Agent: CC(C)[N-]C(C)C
Agent: CC=NC(C)(C)C
Agent: [Li+]
Product: COC(=O)C1CCC(=CC=O)CC1

Procedure:
The epoxides used as the starting materials in the general process described above can be obtained from available starting materials using an appropriate series of reactions. Thus, methyl 4-hydroxybenzoate is hydrogenated using 5% rhodium on alumina as catalyst to give methyl 4-hydroxycyclohexanecarboxylate. This is then oxidized with pyridinium chlorochromate resulting in methyl 4-oxocyclohexanecarboxylate. The 2-carbon homologation of methyl 4-oxocyclohexanecarboxylate to give methyl 4-(oxoethylidene)cyclohexanecarboxylate is carried out using the method developed by A. I. Meyers. Acetaldehyde t-butylimine is metalated with lithium diisopropylamide and then treated with diethyl chlorophosphate to provide the lithioeneaminephosphonate. Addition of methyl 4-oxocyclohexanecarboxylate and subsequent acid hydrolysis gives methyl 4-(oxoethylidene)cyclohexanecarboxylate. The reduction of this oxoethylidene compound with sodium borohydride gives methyl 4-(2-hydroxyethylidene)cyclohexanecarboxylate.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[Cl:28])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:30][CH3:31].C(N(CC)C(C)C)(C)C>C1COCC1>[CH2:30]([N:13]1[CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[Cl:28])=[CH:17][CH:16]=2)[CH2:9][C@@H:8]1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:31]
Reactant: Cc1ccc(Cl)c(-c2ccc(CN3CCN[C@@H](Cc4ccccc4)C3)cc2)c1
Reactant: CCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCN1CCN(Cc2ccc(-c3cc(C)ccc3Cl)cc2)C[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
This compound was made in the following manner: 50 mg of 3-(S)-benzyl-1-(2′-chloro-5′-methyl-biphenyl-4-ylmethyl)-piperazine was dissolved in THF, 2 equ. of bromoethane and 2 equ. of N,N-diisopropylethylamine were added. The reaction was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was diluted with DCM, washed with saturated aqueous sodium bicarbonate solution, then dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography to afford the title compound as the free base. Treatment with 1 equ. 1M HCl in dioxane and concentration in vacuo afforded 29.5 mg of the corresponding hydrochloride salt. Yield 51%, ES MS m/z 419/421.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:17])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=O)[CH2:10][CH2:9]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1.C(=O)([O-])O.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:17])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[S:27])[NH2:16])[CH2:10][CH2:9]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)C1CCN(c2c(Cl)cncc2Cl)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: NC(=S)C1CCN(c2c(Cl)cncc2Cl)CC1
Temperature: 25 °C
Yield: 48.2 %

Procedure:
To a solution of 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide 23 (40 mg, 0.15 mmol) in THF (2 mL) was added Lawesson's reagent (71 mg, 0.18 mmol) and the mixture was heated at reflux for 2.5 h. After cooling to r.t. the mixture was poured into a saturated solution of sodium hydrogen carbonate (20 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (20 mL), brine (20 mL), dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (CH2Cl2, MeOH, 99:1) to furnish the title compound as a white solid (21 mg, 40%), m/z (ESI) C11H14Cl2N2S requires 290.0280 found [M+H]+ 290.0280.
Reaction SMILES: [C-:1]#[N:2].[Na+].[NH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[CH2:10]([S:13]([N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)(=[O:15])=[O:14])[CH2:11][CH3:12].[OH-].[Na+]>Cl.CO>[CH2:10]([S:13]([N:16]1[CH2:21][CH2:20][C:19]([C:1]#[N:2])([N:4]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)[CH2:18][CH2:17]1)(=[O:15])=[O:14])[CH2:11][CH3:12]
Reactant: CCCS(=O)(=O)N1CCC(=O)CC1
Reactant: C1CCNCC1
Reactant: [C-]#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCS(=O)(=O)N1CCC(C#N)(N2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sodium cyanide (0.98 g, 20.0 mmol) was added to a solution of piperidine (1.98 ml, 20.0 mmol) in 1 N hydrochloric acid (20 mL). A solution of 1-(propylsulfonyl)piperidin-4-one (4.11 g, 20.0 mmol) in methanol (40 mL) was added dropwise to the mixture over 30 min. On complete addition the mixture was allowed to warm to ambient temperature and stirred for 18 h. The precipitate was filtered and washed with water (10 mL) and dried under high vacuum at 60° C. which gave a white solid. The volume of the filtrate was reduced to approx 20 mL and the pH of the aqueous residue was adjusted to 7 by the addition of 4 N sodium hydroxide solution. The aqueous phase was extracted with ethyl acetate (2×100 mL) and dichloromethane (2×100 mL). The combined organics were dried over anhydrous sodium sulfate, filtered and evaporated to give 1′-(propylsulfonyl)-1,4′-bipiperidine-4′-carbonitrile as a colourless oil. 1H NMR (400 MHz, CDCl3): δ 3.70-3.64 (m, 2 H); 3.09-3.03 (m, 2 H); 2.85-2.81 (m, 2 H); 2.51 (t, J=5.0 Hz, 4 H); 2.15 (d, J=13.6 Hz, 2 H); 1.83-1.75 (m, 4 H); 1.58-1.54 (m, 4 H); 1.45-1.39 (m, 2 H); 1.00 (t, J=7.5 Hz, 3 H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]([CH3:33])=[C:27]2[CH3:34].Cl>C(O)(C)C>[ClH:1].[CH3:33][C:28]1[NH:29][C:30]2[C:26]([C:27]=1[CH3:34])=[CH:25][C:24]([NH:23][C:2]1[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=1)=[CH:32][CH:31]=2
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Reactant: Cc1[nH]c2ccc(N)cc2c1C
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2c(Nc3ccc4[nH]c(C)c(C)c4c3)ncnc2cc1OCC1CCN(C)CC1
Temperature: 70 °C
Yield: 79 %

Procedure:
A suspension of 4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (100 mg, 0.31 mmol), (prepared as described for the starting material in Example 10), and 5-amino-2,3-dimethylindole (55 mg, 0.34 mmol) in isopropanol (6 ml) containing 5.5M hydrogen choride in isopropanol (60 μL) was heated for 30 minutes at 70° C. After cooling, the solid was collected by filtration, washed with isopropanol, followed by ether and dried under vacuum to give 4-(2,3-dimethylindol-5-ylamino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline hydrochloride (118 mg, 74%).