Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(=O)[CH2:4][NH:5][CH2:6][C@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12]([O:14]C(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:6]1[NH:5][CH2:4][C:12](=[O:14])[N:8]2[CH2:9][CH2:10][CH2:11][C@H:7]12
Reactant: COC(=O)CNC[C@H]1CCCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CNC[C@H]2CCCN12
Yield: 99 %

Procedure:
1,1-Dimethylethyl (2R)-2-({[2-(methyloxy)-2-oxoethyl]amino}methyl)-1-pyrrolidinecarboxylate (D3; 800 mg, 2.94 mmol) was dissolved in methylene chloride (10 ml) and treated with trifluoroacetic acid (2.5 ml) for 2 h. The reaction mixture was loaded as such on a SCX column and the non-basic compounds were washed away with methanol. The ninhydrine-positive fractions eluted with 1M methanolic ammonia were concentrated under vacuum at 40° C. for 30 min, isolating the title compound as a pale yellow oil: 410 mg, 2.92 mmol, 99% yield.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:14]([O:18][C:19]([N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[C:30]1[CH:35]=[C:34]([CH:36]=O)[C:33]([O:38][CH3:39])=[CH:32][C:31]=1[O:40][CH3:41])=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[C:30]1[CH:35]=[C:34](/[CH:36]=[CH:2]/[C:1](=[O:3])[C:4]2[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:8][CH:9]=2)[C:33]([O:38][CH3:39])=[CH:32][C:31]=1[O:40][CH3:41])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(=O)c1ccc(S(N)(=O)=O)cc1
Reactant: COc1cc(OC)c(-c2cc3ccccc3n2C(=O)OC(C)(C)C)cc1C=O
Product: COc1cc(OC)c(-c2cc3ccccc3n2C(=O)OC(C)(C)C)cc1/C=C/C(=O)c1ccc(S(N)(=O)=O)cc1
Yield: 40 %

Procedure:
The title compound was prepared by condensing 4-acetyl-benzenesulfonamide (Ex-26A) and 2-(5-formyl-2,4-dimethoxy-phenyl)-indole-1-carboxylic acid tert-butyl ester (Ex-36A) in a similar manner as described in Ex-22. Yellow solid, 40% yield, mp 120–122° C. 1H-NMR (CDCl3) δ 8.01–8.19 (m, 6H), 7.68 (s, 1H), 7.56 (d, J=8 Hz, 1H), 7.46 (d, J=16 Hz, 1H), 7.21–7.35 (m, 2H), 6.53 (d, J=14 Hz, 2H), 5.01 (s, 2H), 4.00 (s, 3H), 3.85 (s, 3H), 1.42 (s, 9H), MS m/z=563 ([M+H]+). HRMS (ES+) Calcd. for C30H30N2O7S: 563.1852. Found: 563.1862.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:27])=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH:15]([CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:14]3)[CH:11]=2)[C:6](=[O:28])[C:5]([C:29]([OH:31])=[O:30])=[CH:4]1)[CH3:2].[CH2:32]=O>C(O)=O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:27])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH3:32])[CH:15]([CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:14]3)[CH:11]=2)[C:6](=[O:28])[C:5]([C:29]([OH:31])=[O:30])=[CH:4]1)[CH3:2]
Reactant: C=O
Reactant: CCCCCCOCC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3CC)CCN1
Solvent: O=CO
Product: CCCCCCOCC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3CC)CCN1C

Procedure:
A 400 mg portion of 1-ethyl-6-fluoro-7-[3-[(hexyloxy)methyl]-1-piperazinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was added to a mixture of 1.2 ml of 37% formaldehyde and 1.5 ml of 90% formic acid. The mixture was heated on a steam bath for one hour, evaporated to an oil, diluted with 5 ml of water and neutralized with 1N sodium hydroxide. The solid was collected and dried, giving 360 mg of the desired product, mp 172°-174° C.
Reaction SMILES: [2H][C:2]1[C:7]([2H])=[C:6]([NH2:9])[C:5]([NH2:10])=[C:4]([2H])[C:3]=1[2H].C(O)(=O)C(O)=O.[Br:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=O>C(O)C.O>[Br:19][C:20]1[CH:21]=[C:22]([C:23]2[NH:10][C:5]3[CH:4]=[CH:3][CH:2]=[CH:7][C:6]=3[N:9]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: [2H]c1c([2H])c([2H])c(N)c(N)c1[2H]
Reactant: O=Cc1cccc(Br)c1
Agent: O=C(O)C(=O)O
Solvent: CCO
Solvent: O
Product: Brc1cccc(-c2nc3ccccc3[nH]2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 26.6 %

Procedure:
Method 1—Step a O-phenylenediamine (81.8 g, 756.6 mmol) and oxalic acid (3.40 g, 37.8 mmol) were completely dissolved in EtOH—H2O/1:1 (2 L) previously warmed at 80° C. 3-Bromobenzaldehyde (44.10 mL, 378.30 mmol) was then added dropwise to the solution. The reaction mixture was stirred overnight at 70° C. to the open air. The day after solid was filtered off and triturated with MeOH (150 mL) to give the product as a pale yellow solid (27.50 g). 3.8 g were recovered from the mother liquors. Total yield 31.30 g (30%).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH3:20])[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:5])C.[OH-].[Na+]>CCO.O>[C:12]([N:7]1[CH2:8][CH2:9][CH2:10][CH2:11][C:6]1([CH3:20])[C:4]([OH:5])=[O:3])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C1(C)CCCCN1C(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1(C(=O)O)CCCCN1C(=O)c1ccccc1
Temperature: 40 °C
Yield: 12.9 %

Procedure:
Ethyl-1-benzoyl-2-methyl-piperidine-2-carboxylate (6.49 g, 23.51 mmol) was dissolved in EtOH (54 mL) and H2O (16 mL). NaOH (2.75 g, 68.6 mmol) was added and the reaction was heated to 40° C. for 1 h. An additional portion of NaOH (2.75 g, 68.6 mmol) was added and the reaction was heated to 65° C. for 1 h. The ethanol was removed and the residue was diluted with 50 mL of H2O. The pH was adjusted to ~2 with HCl (c). The aqueous layer was extracted 3× with ether and ethyl acetate. Removal of solvent provided 0.75 g, 22% yield of 1-benzoyl-2-methyl-piperidine-2-carboxylic acid. 1H NMR (200 MHz, DMSO) δ1.4 (s, 3H), 1.5-1.9 (comp m, 4H), 3.0 (m, 2H), 3.4 (m, 2H), 7.4 (m, 5H).
Reaction SMILES: COC(=O)[NH:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][N:13]([CH3:16])[C:14]=2[Br:15])[N:7]=[CH:6]1.[OH-].[Na+]>>[Br:15][C:14]1[N:13]([CH3:16])[N:12]=[CH:11][C:10]=1[C:8]1[N:7]=[CH:6][N:5]([NH2:4])[CH:9]=1
Reactant: COC(=O)Nn1cnc(-c2cnn(C)c2Br)c1
Agent: [Na+]
Agent: [OH-]
Product: Cn1ncc(-c2cn(N)cn2)c1Br
Temperature: 100 °C

Procedure:
A mixture of methyl[4-(5-bromo-1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]carbamate (400 mg, 1.33 mmol) and aqueous sodium hydroxide solution (1 M, 1.33 mL, 1.33 mmol) was heated at 100° C. for 18 hours. After cooling, the aqueous mixture was extracted five times with 2-butanol, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to provide the product as a beige solid. Yield: 310 mg, 1.28 mmol, 96%. 1H NMR (400 MHz, CD3OD) δ 3.89 (s, 3H), 7.46 (d, J=1.2 Hz, 1H), 7.61 (d, J=1.3 Hz, 1H), 7.82 (s, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:22]4[C:23]5[CH:35]=[CH:34][CH:33]=[N:32][C:24]=5[NH:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[C:21]4=[N:20][C:19]=3[C:36]3[CH:41]=[CH:40][C:39]([CH2:42][N:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[CH:38][CH:37]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.[ClH:50].O1CCOCC1>CO>[ClH:50].[ClH:50].[ClH:50].[ClH:50].[N:43]1([CH2:42][C:39]2[CH:40]=[CH:41][C:36]([C:19]3[N:20]=[C:21]4[C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[NH:25][C:24]5[N:32]=[CH:33][CH:34]=[CH:35][C:23]=5[N:22]4[C:18]=3[C:15]3[CH:14]=[CH:13][C:12]([C:8]4([NH2:7])[CH2:11][CH2:10][CH2:9]4)=[CH:17][CH:16]=3)=[CH:37][CH:38]=2)[CH2:44][CH2:45][O:46][CH2:47][CH2:48]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(CN5CCOCC5)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NC1(c2ccc(-c3c(-c4ccc(CN5CCOCC5)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Reaction time: 15 h

Procedure:
tert-butyl[1-(4-{2-[4-(morpholin-4-ylmethyl)phenyl]-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl}phenyl)cyclobutyl]carbamate (28 mg, 0.043 mmol) in MeOH (0.5 mL) was added 4N HCl-dioxane (2 mL) and stirred at r.t for 15 hours. The mixture was concentrated to afford the desired product (31 mg, quant) as a yellow solid. 1HNMR (DMSO-d6) 400 MHz δ: 8.74 (br s, 2H), 8.61 (s, 1H), 8.10 (dd, J=4.9 Hz and 1.4 Hz, 1H), 7.96 (dd, J=7.7 Hz and 1.4 Hz, 1H), 7.59 (dd, J=15.5 Hz and 8.6 Hz, 4H), 7.53 (d, J=8.6 Hz, 2H), 7.36 (d, J=7.4 Hz, 3H), 7.30 (dd, J=7.4 Hz and 1.1 Hz, 1H), 7.13 (td, J=7.4 Hz and 1.1 Hz, 1H), 6.88 (dd, J=8.0 Hz and 1.1 Hz, 1H), 6.73 (dd, J=7.4 Hz and 4.9 Hz, 1H), 5.76 (s, 2H), 4.30 (d, J=5.2 Hz, 2H), 3.94 (dd, J=12.0 Hz and 2.3 Hz, 2H), 3.22 (d, J=11.5 Hz, 2H), 3.11-3.04 (m, 2H), 2.59-2.55 (m, 4H), 2.24-2.16 (m, 1H), 1.87-1.78 (m, 1H). LCMS: 555 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=3)[N:11]=2)[N:8]=1.[Br:22]N1C(=O)CCC1=O>C(#N)C.O.C([O-])(O)=O.[Na+]>[Br:22][C:9]1[N:7]2[N:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]2=[N:11][C:10]=1[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2nc(-c3ccc(C)c([N+](=O)[O-])c3)cn2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1ccc2nc(-c3ccc(C)c([N+](=O)[O-])c3)c(Br)n2n1
Temperature: 60 °C
Yield: 94 %

Procedure:
To a stirred solution of 6-methoxy-2-(4-methyl-3-nitrophenyl)imidazo[1,2-b]pyridazine (0.250 g, 0.879 mmol) in acetonitrile (20 mL) is added N-bromosuccinimide (0.879 mmol) and the mixture is heated at 60° C. for 8 hours. The reaction mixture is diluted with water (50 mL) and sat. aqueous NaHCO3 (50 mL). The precipitate that forms is collected by filtration, washed with water (3×25 mL) and dried under vacuum to give the title product (0.300 g, 94% yield) as a yellow solid: Rf 0.51 (1:1 EtOAc:hexanes); LCMS (m/z)=363.2, 365.2 [M+H]+, tR=3.02 min.
Reaction SMILES: O[CH2:2][C:3]1([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:6][CH2:5][CH2:4]1.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:23]=2)[CH:18]=[C:17]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:11]([O:10][C:9]([NH:8][CH2:7][C:3]1([CH2:2][N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:23]=3)[CH:18]=[C:17]2[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:6][CH2:5][CH2:4]1)=[O:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)NCC1(CO)CCC1
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)[nH]c2c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC3(CNC(=O)OC(C)(C)C)CCC3)c2c1
Reaction time: 60 h

Procedure:
To a solution of tert-butyl {[1-(hydroxymethyl)cyclobutyl]methyl}carbamate (12 g, 55.76 mmol), diethyl 1H-indole-2,6-dicarboxylate (14.56 g, 55.76 mmol) and triphenylphosphine (29.2 g, 111.5 mmol.) in THF (110 mL) is added diisopropyl azodicarboxylate (22.41 mL, 111.5 mmol) at room temperature and the reaction mixture is stirred for 60 h. The solvent is evaporated and the residue is purified by flash column chromatography using 12% EtOAc in petroleum ether to afford diethyl 1-[(1-{[(tert-butoxycarbonyl)amino]methyl}cyclobutyl)methyl]-1H-indole-2,6-dicarboxylate contaminated with un-reacted diethyl 1H-indole-2,6-dicarboxylate. The mixture is used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:18]([O:19][CH3:20])=[C:17]([O:21][CH3:22])[CH:16]=[CH:15][C:3]=1[CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][N:6]=1.[Cl:23][CH2:24][C:25](Cl)=[O:26]>C(OCC)(=O)C>[Cl:23][CH2:24][C:25]([NH:1][C:2]1[C:18]([O:19][CH3:20])=[C:17]([O:21][CH3:22])[CH:16]=[CH:15][C:3]=1[CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:26]
Reactant: COc1ccc(Cc2nccc3ccccc23)c(N)c1OC
Reactant: O=C(Cl)CCl
Solvent: CCOC(C)=O
Product: COc1ccc(Cc2nccc3ccccc23)c(NC(=O)CCl)c1OC

Procedure:
1-(2-[2-chloro-acetyl]amino-3,4-dimethoxybenzyl)isoquinoline was prepared from 5.9g (0.02 mol) of 1-(2-amino-3,4-dimethoxybenzyl) isoquinoline dissolved in 400 ml. of ethyl acetate, and stirred for 2 hours with 15 ml. of chloro-acetyl chloride. The precipitate which formed was filtered and dried to yield 7.1g (87%) of the hydrochloride salt, mp 193°-194°, which was suspended in 200 ml. of water and stirred for 10 min. with 10% Na2CO3 solution. The free base was extracted with chloroform, and the organic layer was washed with water, dried (sodium sulfate) and concentrated to yield a residue which was crystallized from methanol to give the pure base; mp 166°-167°; maxKBR 1650 cm-1 (aminde C=0); δtmsCDCl3 3.75 (s, 3, OCH3), 3.90 (s, 3, OCH3), 4.20 (s, 2, CH2Cl), 4.55 (s, 2, CH2), 6.63-7.00 (m, 2, aromatic), 7.23-7.85 (m, 4, aromatic), 8.20-8.45 (m, 2 aromatic) and 9.80 (broad s, 1, NH).
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19](=[O:27])(=[O:26])[NH:18]2)=[C:9]1[CH3:28])(C)(C)C.Br[CH2:31][CH2:32][OH:33]>>[OH:33][CH2:32][CH2:31][N:18]1[CH:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([CH2:7][C:6]([OH:29])=[O:5])[C:9]=2[CH3:28])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[S:19]1(=[O:27])=[O:26]
Reactant: Cc1c(C2NS(=O)(=O)c3ccccc32)c2ccccc2n1CC(=O)OC(C)(C)C
Reactant: OCCBr
Product: Cc1c(C2c3ccccc3S(=O)(=O)N2CCO)c2ccccc2n1CC(=O)O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 3, step c) and 2-bromoethanol. 1H NMR (DMSO-d6) δ 7.98-7.95 (m, 1H), 7.62-7.58 (m, 3H), 7.36 (d, J=8.4 Hz, 1H), 7.04-7.01 (m, 2H), 6.80-6.78 (m, 1H), 6.14 (s, 1H), 5.00 (s, 2H), 4.75 (bs, 1H), 3.59-3.53 (m, 1H), 3.26-3.17 (m, 2H), 3.02-2.92 (m, 1H), 2.39 (s, 3H); MS: ESI (negative): 399 (M−H).
Reaction SMILES: [C:1]([C:3]1[C:7]([CH:8]=O)=[CH:6][N:5]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=2[Cl:21])[N:4]=1)#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:42](Br)([F:44])[F:43]>ClCCl>[C:1]([C:3]1[C:7]([CH:8]=[C:42]([F:44])[F:43])=[CH:6][N:5]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=2[Cl:21])[N:4]=1)#[N:2]
Reactant: FC(F)(Br)Br
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C=C(F)F
Temperature: 70 °C
Reaction time: 3 h

Procedure:
3-Cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-formylpyrazole (1.3 g), triphenylphosphine (5.1 g), dibromodifluoromethane (2 g) and dichloromethane (50 ml) were placed in a stainless steel bomb and heated and stirred at 70° C. for 3 hours. The reaction mixtiure was evaporated and the residue was purified by column chromatography on silica gel eluting with dichloromethane: hexane (9:1). Combination and evaporation of suitable fractions gave the title compound as a white solid, m.p. 75-77° C.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)(O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:24])=[CH:4][CH:3]=1.S(Cl)([Cl:29])=O>>[Cl:29][C:15]1([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:24])[N:7]1[CH2:6][C:5]1[CH:25]=[CH:26][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=C1c2ccccc2C(O)(c2ccc(Cl)cc2)N1Cc1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Product: O=C1c2ccccc2C(Cl)(c2ccc(Cl)cc2)N1Cc1ccc(Cl)cc1
Yield: 100 %

Procedure:
2-(4-Chlorobenzyl)-3-(4-chlorophenyl)-3-hydroxyisoindolinone (150 mg, 0.390 mmol.) was reacted with thionyl chloride (0.031 mL, 0.429 mmol.) and a catalytic amount of DMF as for general procedure B, and the solvent removed to give a colourless oil of the crude 3-chloro-2-(4-chlorobenzyl)-3-(4-chlorophenyl)isoindolin-1-one (157 mg, 0.390 mmol., 100%).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]1([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=2[O:18][CH2:19][CH:20]2[CH2:22][O:21]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCCC1>[CH3:1][N:2]([CH2:22][CH:20]([OH:21])[CH2:19][O:18][C:17]1[CH:23]=[CH:24][CH:25]=[CH:26][C:16]=1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:3]
Reactant: c1ccc(CCCCCCc2ccccc2OCC2CO2)cc1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)CC(O)COc1ccccc1CCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
0.7 ml of 50% by volume aqueous dimethylamine were added to a solution of 0.200 g of 2-[2-(6-phenylhexyl)phenoxymethyl]oxirane [prepared as described in step (a) above] in 7 ml of tetrahydrofuran, and the mixture was stirred at room temperature for one day. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 15:1 by volume mixture of methylene chloride and methanol as the eluent, to give 0.227 g (yield 99%) of the title compound as a colorless oil.
Reaction SMILES: [CH:1]1([C:7](=[S:9])[NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:11][C:12](=O)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(O)C>[CH:1]1([C:7]2[S:9][CH:11]=[C:12]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=S)C1CCCCC1
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CCO
Product: CCOC(=O)Cc1csc(C2CCCCC2)n1
Yield: 71.3 %

Procedure:
A mixture of cyclohexanethiocarboxamide (5.0 g), ethyl 4-chloroacetoacetate (5.74 g), ethanol (50 ml) was heated under reflux for 1 hour. After dilution with water, mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium bicarbonate solution and water, dried (MgSO4), and concentrated. The residue was purified by chromatography on silica gel with ethyl acetate-hexane (1:4) to yield ethyl 2-cyclohexyl-4-thiazoleacetate as an oil (6.3 g, 70.9%). IR (Neat): 1735, 1255 cm-1. NMR (CDCl3)δ: 1.28 (3H, t, J=7 Hz), 1.2-2.3 (10H, m), 2.97 (1H, m), 3.77 (2H, s), 4.17 (2H, q, J=7 Hz), 7.0 (1H, s).
Reaction SMILES: C1C2C(COC(=O)[NH:17][C@H:18]3[CH2:23][CH2:22][CH2:21][C:20]([F:25])([F:24])[C@@H:19]3[NH:26][C:27]([C:29]3[S:30][C:31]([CH2:43][CH3:44])=[C:32]([C:34]4[N:38]5[N:39]=[CH:40][CH:41]=[CH:42][C:37]5=[N:36][CH:35]=4)[CH:33]=3)=[O:28])C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C=O)C>[NH2:17][C@@H:18]1[C@@H:19]([NH:26][C:27]([C:29]2[S:30][C:31]([CH2:43][CH3:44])=[C:32]([C:34]3[N:38]4[N:39]=[CH:40][CH:41]=[CH:42][C:37]4=[N:36][CH:35]=3)[CH:33]=2)=[O:28])[C:20]([F:25])([F:24])[CH2:21][CH2:22][CH2:23]1
Reactant: CCc1sc(C(=O)N[C@@H]2[C@@H](NC(=O)OCC3c4ccccc4-c4ccccc43)CCCC2(F)F)cc1-c1cnc2cccnn12
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CCc1sc(C(=O)N[C@@H]2[C@@H](N)CCCC2(F)F)cc1-c1cnc2cccnn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
9H-Fluoren-9-ylmethyl[(1S,2R)-2-({[5-ethyl-4-(imidazo[1,2-b]pyridazin-3-yl)thiophen-2-yl]carbonyl}amino)-3,3-difluorocyclohexyl]carbamate (168 mg, 0.268 mmol) was dissolved in DMF (2.68 mL) and piperidine added (0.265 mL, 2.68 mmol). The solution was stirred at room temperature for 2 h. The solution was then subjected to prep HPLC for purification. The compound was neutralized by taking the fractions and adding an aqueous saturated sodium bicarbonate solution and extracting three times with dichloromethane. The combined organics were dried with magnesium sulfate, filtered, and concentrated to afford the title compound as a yellow solid. 1H NMR (500 MHz, CD3SOCD3) δ 8.61 (d, 1H); 8.41 (d, 1H); 8.21 (d, 1H); 8.19 (s, 1H); 7.95 (s, 1H); 7.29 (dd, 1H); 4.07 (m, 1H); 2.86 (m, 1H); 2.85 (q, 2H); 2.07 (m, 1H); 1.88 (m, 1H); 1.86 (m, 1H); 1.70 (m, 1H); 1.36 (m, 2H); 1.21 (t, 3H). LRMS (APCI) calc'd for (C19H21F2N5OS) [MA-1]+, 406.1. found 406.1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:17])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][CH:7]=1.[CH:18](=O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C([BH3-])#N.[Na+].[ClH:30]>O.CO>[ClH:30].[CH2:18]([NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:17])[C:6]1[CH:7]=[CH:8][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:10][CH:11]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CS(=O)(=O)Nc1ccc(C(=O)NCCN)cc1
Reactant: CCCCCCC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCCCCNCCNC(=O)c1ccc(NS(C)(=O)=O)cc1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
To 1 l. of methanol is added 10.0 g (0.0389 mole) of N-(2-aminoethyl)-4-[(methylsulfonyl)amino]benzamide. The suspension is refluxed for 1 hour, then cooled. To the suspension is added 4.66 g (0.0408 mole) heptaldehyde, the mixture is then stirred over ice for 30 minutes. To the chilled mixture is added 10.26 g (0.1632 mole) of sodium cyanoborohydride. The reaction is stirred at room temperature for 24 hours, conc. HCl is added to keep the pH at about 6.0. After about 24 hours the pH of of the reaction is adjusted to pH=1.0 and reduced to 1/3 volume. 100 ml of water is added and the solid is filtered. The resultant solid is suspended in 100 ml DMF, heated to 120° C. and filtered hot. The solution is cooled and the resultant solid is filtered and dried to yield the title compound.
Reaction SMILES: [H-].[Na+].Br[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1.O.[F:13][C:14]([F:19])([F:18])[C@H:15]([OH:17])[CH3:16]>CN(C)C=O>[F:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([CH2:4][O:17][C@H:15]([CH3:16])[C:14]([F:19])([F:18])[F:13])[CH:6]=1
Reactant: C[C@@H](O)C(F)(F)F
Reactant: Fc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](OCc1cccc(F)c1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 69.3 %

Procedure:
Under argon atmosphere, a suspension of sodium hydride (76 mg, 60 wt % oil dispersion) in N,N-dimethylformamide (2.0 ml) was cooled to 0° C., a solution of N,N-dimethylformamide (2.0 ml) in (R)-1,1,1-trifluoropropan-2-ol (219 mg) was added thereto, and the mixture was stirred for 25 minutes. Then, a solution of 1-bromomethyl-3-fluorobenzene (297 mg) in N,N-dimethylformamide (2.0 ml) was added thereto, and then the mixture was stirred for 2 hours. To this reaction mixture was added water, and the mixture was extracted with ethyl acetate. This organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (eluent: n-hexane/ethyl acetate=9/1) to give the titled compound (242 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17](O)=[O:18])=[CH:14][CH:15]=3)[C:10](=[O:20])[O:9]2)=[CH:4][CH:3]=1.[NH3:21]>S(Cl)(Cl)=O.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([NH2:21])=[O:18])=[CH:14][CH:15]=3)[C:10](=[O:20])[O:9]2)=[CH:4][CH:3]=1
Reactant: N
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2c1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: NC(=O)c1ccc2c(c1)C(=O)OC2c1ccc(F)cc1
Reaction time: 8 h
Yield: 80 %

Procedure:
A stirred suspension of 1-(4-fluoro-phenyl)-3-oxo-1,3-dihydro-isobenzofuran-5-carboxylic acid (1 g, 3.7 mmol) in thionyl chloride (25 mL) was heated at reflux for 25 min, during which time the solid dissolved. The thionyl chloride was then evaporated, and the residue was dissolved in toluene, and again evaporated. The residue was dissolved in toluene (15 mL) and was treated with a solution of ammonia in ether and a heavy precipitate formed. The mixture was stirred overnight, diluted with toluene and aqueous ammonia solution, and filtered. The residue was dried to give the title compound as a white solid (0.80 g, 80%). 1H NMR (d6-DMSO): δ 6.81 (s, 1H), 7.25 (t, 2H), 7.40 (dd, 2H), 7.54 (d, 1H), 7.59 (bs, 1H), 8.24 (bs, 1H), 8.24 (dd, 1H), 8.42 (s, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][CH:5]=1.[I-:12].[Na+]>CC(C)=O>[I:12][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][CH:5]=1
Reactant: [I-]
Reactant: OCc1ccc(CCCl)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: OCc1ccc(CCI)cc1
Temperature: 25 °C

Procedure:
To 60.0 g (352 mmol) [4-(2-chloro-ethyl)-phenyl]-MeOH (preparation 1a) in 280 mL of acetone is added 105 g (703 mmol) sodium iodide. The reaction mixture is refluxed overnight and cooled to RT. After filtration, the residue is elutriated in DCM, filtered and dried.