Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C@H:3]([CH3:7])[C:4]([OH:6])=O.[Cl:8][C:9]1[CH:10]=[C:11]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][C:32]=3[O:34][C@H:35]([CH3:39])[CH2:36][NH:37][CH3:38])[N:27]=[CH:26][N:25]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>>[Cl:8][C:9]1[CH:10]=[C:11]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][C:32]=3[O:34][C@H:35]([CH3:39])[CH2:36][N:37]([CH3:38])[C:4](=[O:6])[C@H:3]([O:2][CH3:1])[CH3:7])[N:27]=[CH:26][N:25]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: CNC[C@@H](C)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: CO[C@H](C)C(=O)O
Product: CO[C@H](C)C(=O)N(C)C[C@@H](C)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 44 %

Procedure:
The procedure described in Example 1 was repeated using (R)-(+)-2-methoxypropionic acid and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(1R)-1-methyl-2-(methylamino)ethoxy]quinazolin-4-amine (obtained as described in Example 2.3, preparation of starting materials) to give the title compound as a brown gum in 44% yield; NMR spectrum (DMSO-d6 373K) 1.11 (d, 3H), 1.37 (d, 3H), 2.97 (s, 3H), 3.09 (s, 3H), 3.38 (m, 1H), 4.17 (q, 1H), 4.26 (dd, 1H), 5.16 (m, 1H), 5.28 (s, 2H), 7.24 (m, 2H), 7.33 (d, 1H), 7.37 (dd, 1H), 7.56 (d, 1H), 7.64 (dd, 1H), 7.69 (t, 1H), 7.86 (dt, 1H), 8.13 (d, 1H), 8.44 (s, 1H), 8.59 (d, 1H), 9.89 (s, 1H); Mass spectrum MH+ 536.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][NH:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=1[N+:14]([O-])=O)C>[Pd].C(O)C>[CH3:13][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:7]=1[NH:6][CH2:5][C:4](=[O:3])[NH:14]2
Reactant: CCOC(=O)CNc1c(C)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1cccc2c1NCC(=O)N2

Procedure:
A mixture of N-(6-methyl-2-nitrophenyl)glycine ethyl ester (XV, EXAMPLE 17, 675 rag), ethanol (60.0 ml) and palladium on carbon (10%, 150 mg) is hydrogenated (48 psi) at 20°-25° for 3.5 hr. The mixture is filtered, the residue washed with ethanol, and the combined filtrates are concentrated to give the title compound, mp 168°-171°; IR (mineral oil) 3382, 2955, 2925, 1671, 1490, 1444, 1393, 1295 and 770 cm-1 ; NMR (CDCl3) 8.68, 6.79, 6.6-6.75, 4.04, 3.76 and 2.17 δ; MS (m/z) 162 and 133.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:22][C:21]([C:23]([NH:25][CH:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])=[O:24])=[N:20][CH:19]=2)=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:10])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:22][C:21]([C:23]([NH:25][CH:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])=[O:24])=[N:20][CH:19]=2)=[CH:14][CH:13]=1
Reactant: O=C=Nc1ccccc1Cl
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc(N)cc2)o1)C(C)C
Product: COC(=O)C(NC(=O)c1ncc(-c2ccc(NC(=O)Nc3ccccc3Cl)cc2)o1)C(C)C
Yield: 79 %

Procedure:
The title compound was synthesized analogous to Example 1, using 1-chloro-2-isocyanatobenzene and intermediate 1. Yield: 79%; 1HNMR (DMSO-d6, 300 MHz): δ 9.68 (s, 1H), 8.98 (d, 1H), 8.39 (s, 1H), 8.15 (dd, 1H), 7.82 (s, 1H), 7.78 (d, 2H), 7.63 (d, 2H), 7.48 (dd, 1H), 7.34 (m, 1H), 7.05 (m, 1H), 4.3, (m, 1H), 3.68 (s, 3H), 2.26 (m, 1H), 0.95 (d, 6H); MS (ES+) m/z 471 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13](=[O:16])[N:12]([CH2:17][C:18]3[CH:19]=[C:20]([C:24]4[N:29]=[CH:28][C:27]([O:30][CH2:31][CH:32]5[CH2:37][CH2:36][N:35]([C:38](OC(C)(C)C)=O)[CH2:34][CH2:33]5)=[CH:26][N:25]=4)[CH:21]=[CH:22][CH:23]=3)[N:11]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[NH2:2].C=O>C(O)=O.O>[CH3:38][N:35]1[CH2:34][CH2:33][CH:32]([CH2:31][O:30][C:27]2[CH:26]=[N:25][C:24]([C:20]3[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=3)[CH2:17][N:12]3[C:13](=[O:16])[CH:14]=[CH:15][C:10]([C:6]4[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=4)[C:1]([NH2:2])=[O:3])=[N:11]3)=[N:29][CH:28]=2)[CH2:37][CH2:36]1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cnc(-c3cccc(Cn4nc(-c5cccc(C(N)=O)c5)ccc4=O)c3)nc2)CC1
Agent: C=O
Solvent: O
Solvent: O=CO
Product: CN1CCC(COc2cnc(-c3cccc(Cn4nc(-c5cccc(C(N)=O)c5)ccc4=O)c3)nc2)CC1
Temperature: 110 °C
Reaction time: 48 h

Procedure:
1.25 g (2.1 mmol) of tert-butyl 4-(2-{3-[3-(3-carbamoylphenyl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yloxymethyl)piperidine-1-carboxyl-ate are dissolved in 6 ml of formic acid, and 500 μl (6.3 mmol) of 35% formaldehyde solution in water are added. The reaction mixture is stirred at 110° C. for 48 h. The reaction mixture is evaporated, taken up in dichloro-methane, washed with saturated sodium hydrogencarbonate solution, dried over sodium sulfate and purified by means of column chromatography on silica gel. ESI: 511 (M+H);
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])[CH3:2].C([O-])=O.[NH4+]>CO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:15]2[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=2)[C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2ccc([N+](=O)[O-])cc2)c1C(F)(F)F
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCOC(=O)c1cnn(-c2ccc(N)cc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1-(4-nitrophenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.5 g, 1.5 mmol) dissolved in methanol (4 mL) was added palladium on carbon and ammonium formate (0.428 g, 6.8 mmol). This mixture was stirred at room temperature overnight. The solvent was removed under vacuum, then the material was resuspended in chloroform, and washed with water (twice) and saturated sodium bicarbonate (once), and the organic layer dried over magnesium sulfate (MgSO4). The solid was filtered and the solvents removed under vacuum. The reaction product was purified over silica gel to yield the named product (m.p. 102° C.–103° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][C@H:6]1[CH2:11][C@@H:10]([C:12](=[O:19])[CH2:13][C:14](OCC)=[O:15])[CH2:9][CH2:8][N:7]1[C:20]([O:22][CH3:23])=[O:21].[OH-].[Na+].[NH2:30]O.Cl>CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][C@H:6]1[CH2:11][C@@H:10]([C:12]2[O:19][NH:30][C:14](=[O:15])[CH:13]=2)[CH2:9][CH2:8][N:7]1[C:20]([O:22][CH3:23])=[O:21]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](Cc2ccc(F)c(F)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(F)c(F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 66.4 %

Procedure:
Cis-methyl 2-(3,4-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (2.233 g, 5.82 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.233 g, 5.82 mmol) dissolved in water (2.000 mL) was added during 10 min and the yellow solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.357 mL, 5.82 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (30 mL, 180.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a yellow semi-solid. The compound was purified by preparative HPLC in 3 injections on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-25% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Cis-methyl 2-(3,4-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.361 g, 66%) was isolated as a white solid. 1H NMR (400 MHz, cdcl3) δ 1.84-2.14 (m, 4H), 2.52-2.62 (m, 1H), 2.71-2.80 (m, 1H), 2.95-3.05 (m, 1H), 3.09-3.20 (m, 1H), 3.64 (s, 3H), 3.95-4.06 (m, 1H), 4.20-4.30 (m, 1H), 5.74 (s, 1H), 6.77-6.83 (m, 1H), 6.90-6.98 (m, 1H), 6.98-7.09 (m, 1H). MS m/z 353 (M+H)+
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH2:12][CH2:13][O:14][CH3:15])[CH:3]=1.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1.C(OCC)(=O)C.O>CS(C)=O>[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:23][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH2:12][CH2:13][O:14][CH3:15])[CH:3]=2)=[CH:20][CH:19]=1
Reactant: COc1ccc(CN)cc1
Reactant: COCCOc1cc(F)ccc1[N+](=O)[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COCCOc1cc(NCc2ccc(OC)cc2)ccc1[N+](=O)[O-]

Procedure:
To a solution of 2-methoxy-ethanol in 4 ml dry THF, was added tert-butoxide (378 mg, 3.37 mmol) at 0° C. The resulting mixture was added dropwise to the solution of 2,4-difluoro-1-nitro-benzene (536 mg, 3.37 mmol) in 5 ml dry THF at 0° C. The mixture was stirred at 0° C. for 30 minutes, then diluted with ethyl acetate and washed with brine. The organic layers were combined and concentrated in vacuo to give 4-Fluoro-2-(2-methoxy-ethoxy)-1-nitro-benzene. 4-Fluoro-2-(2-methoxy-ethoxy)-1-nitro-benzene (1.35 g, 6.3 mmol) was treated with p-methoxybenzylamine (1.64 mL, 12.6 mmol) in dimethyl sulfoxide at 80° C. in a sealed tube for 4 hr. After work up with ethyl acetate and water isolated N-(4-methoxybenzyl)3-(2-methoxyethoxy)-4-nitrobenzenamine intermediate. RP-HPLC: 2.13 min; ES-MS (M+H)+=346; To this intermediate added trifluoroacetic acid and heated the reaction mixture at 80° C. for 1 hr to deprotect the p-methoxybenzyl functionality to give final product 3-(2-methoxyethoxy)-4-nitobenzenamine. RP-HPLC: 1.14 min; ES-MS (M+H)+=213; 1H-NMR (MeOH-d4) δ (ppm): 3.4 (s, 3 H), 3.8 (t, 2 H), 4.10 (t, 2 H), 6.2 (dd, 1 H), 6.26 (d, 1 H), 7.76 (d, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:19]3[C:14](=[CH:15][C:16]([CH2:21][OH:22])=[CH:17][CH:18]=3)[NH:13][C:12]=2[C:11]([C:23]([NH2:25])=[O:24])=[CH:10][CH:9]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>C(Cl)Cl.C(#N)C.C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:19]3[C:14](=[CH:15][C:16]([CH:21]=[O:22])=[CH:17][CH:18]=3)[NH:13][C:12]=2[C:11]([C:23]([NH2:25])=[O:24])=[CH:10][CH:9]=1
Reactant: NC(=O)c1ccc(-c2ccccc2F)c2c1[nH]c1cc(CO)ccc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: NC(=O)c1ccc(-c2ccccc2F)c2c1[nH]c1cc(C=O)ccc12
Reaction time: 0.5 h

Procedure:
Step 1 A solution of 4-(2-fluorophenyl)-7-(hydroxymethyl)-9H-carbazole-1-carboxamide (Example 30-1, 147 mg, 0.440 mmol) in DCM (3 mL), acetonitrile (5 mL) and THF (3 mL) was treated with 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1 H)-one (Dess-Martin periodinane, 373 mg, 0.879 mmol). After 30 min at rt, the mixture was diluted with EtOAc (30 mL), washed twice with 1 M aqueous sodium sulfite and brine, dried and concentrated to give 4-(2-fluorophenyl)-7-formyl-9H-carbazole-1-carboxamide as a tan solid (ca. 80% purity, 163 mg, 87%), used without purification. Mass spectrum m/z 333.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:9]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH2:16][N:17]4[CH2:20][CH:19]([C:21]5[N:25]=[C:24]([C:26]6[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=6)[NH:23][N:22]=5)[CH2:18]4)=[CH:12][CH:11]=3)[C:7]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:6][N:5]2[CH:39]=1.[Br:40]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:40][C:39]1[N:5]2[CH:6]=[C:7]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH2:16][N:17]4[CH2:20][CH:19]([C:21]5[N:25]=[C:24]([C:26]6[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=6)[NH:23][N:22]=5)[CH2:18]4)=[CH:12][CH:11]=3)=[N:9][C:4]2=[N:3][C:2]=1[CH3:1]
Reactant: Cc1cccc(-c2nc(C3CN(Cc4ccc(-c5nc6nc(C)cn6cc5-c5ccccc5)cc4)C3)n[nH]2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: Cc1cccc(-c2nc(C3CN(Cc4ccc(-c5nc6nc(C)c(Br)n6cc5-c5ccccc5)cc4)C3)n[nH]2)n1
Yield: 32.9 %

Procedure:
50 mg (0.098 mmol) 2-Methyl-7-{4-{3-[5-(6-methylpyridine-2-yl)-1H-[1,2,4]triazole-3-yl)-azetidine-1-ylmethyl]-phenyl}-6-phenyl-imidazo[1,2-a]pyrimidine are dissolved in 3.9 mL chloroform. 19.1 mg (0.11 mmol) N-bromosuccinimide are added and the reaction mixture is heated for one hour at reflux. The solvent is evaporated and the residue is purified by chromatography (silicagel, eluents: dichloromethane/methanol). 19.1 mg (31.5%) of the desired compound are obtained.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.Cl>C(OCC)(=O)C.CC(O)C>[F:1][C:2]1[C:3]([CH2:24][NH:25][CH3:26])=[CH:4][N:5]([S:14]([C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1cccnc1S(=O)(=O)n1cc(CN(C)C(=O)OC(C)(C)C)c(F)c1-c1cccnc1F
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2ncccc2C)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.2 %

Procedure:
To a solution of tert-butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(3-methylpyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (107 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) were added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent:hexane-ethyl acetate=4:1→1:1) to give 1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(3-methylpyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine as a pale-yellow oil (yield 45 mg, 54%). A solution of the obtained 1-{4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(3-methylpyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine in ethyl acetate (2 mL) was added dropwise to a solution of fumaric acid (14 mg) in ethanol (2 mL) and the mixture was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-ethanol to give the title compound as a white solid (yield 51 mg, 88%).
Reaction SMILES: [Br-].N[CH2:3][CH2:4][N+:5]([CH2:8][CH2:9][NH:10][C:11]([C:13]1[C:18]([NH2:19])=[N:17][C:16]([NH2:20])=[C:15]([Cl:21])[N:14]=1)=[O:12])([CH3:7])[CH3:6].[Br:22]CC[CH2:25][CH2:26][N:27]1C(=O)C2=CC=CC=C2C1=O>>[Br-:22].[NH2:27][CH2:26][CH2:25][CH2:3][CH2:4][N+:5]([CH2:8][CH2:9][NH:10][C:11]([C:13]1[C:18]([NH2:19])=[N:17][C:16]([NH2:20])=[C:15]([Cl:21])[N:14]=1)=[O:12])([CH3:6])[CH3:7]
Reactant: C[N+](C)(CCN)CCNC(=O)c1nc(Cl)c(N)nc1N
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: [Br-]
Product: C[N+](C)(CCCCN)CCNC(=O)c1nc(Cl)c(N)nc1N

Procedure:
The title compound is prepared by an analogous procedure to (2-amino-ethyl)-{2-[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-ethyl}-dimethyl-ammonium bromide (Intermediate K) by replacing N-(4-bromoethyl)-phthalimide with N-(4-bromobutyl)-phthalimide. M+ 330.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH2:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.Cl.[O:13](C(OC(C)(C)C)=O)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:11][C:14](=[O:13])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:9])[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(C)(N)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C)(C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a solution of 2-(4-bromophenyl)propan-2-amine, hydrochloric acid (1.0 g, 4.0 mmol, AKOS) in DCM (30 mL) at about 0° C. was added TEA (1.11 mL, 7.98 mmol). A solution of BOC2O (1.623 ml, 7.01 mmol) in DCM (10 mL) was added dropwise over about 10 min. After about 30 min, the ice bath was removed and the mixture was stirred overnight at rt. The mixture was diluted with water (30 mL) and extracted with DCM (2×30 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by flash chromatograph (40 g silica gel column, 0-40% EtOAc/Heptane) to give tert-butyl 2-(4-bromophenyl)propan-2-ylcarbamate the title compound (1.13 g, 90%): LC/MS (Table 2, Method b) Rt=2.66 min.; MS m/z: 315 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:10])[C:8]=1[Cl:9])[NH2:5].[F:11][C:12]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:13]=1[C:14]([N:16]=[C:17]=[O:18])=[O:15]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:17]([NH:16][C:14](=[O:15])[C:13]2[C:19]([F:23])=[CH:20][CH:21]=[CH:22][C:12]=2[F:11])=[O:18])[CH:6]=[C:7]([Cl:10])[C:8]=1[Cl:9]
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: Nc1cc(Cl)c(Cl)c(Cl)c1
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1cc(Cl)c(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3,4,5-trichloro-aniline (19.7 g) and 2,6-difluorobenzoyl isocyanate (18.3 g) were dissolved in toluene (200 ml) at 50° C., and the solution was allowed to stand at this temperature for five hours. After cooling the solution to room temperature, the title compound was isolated by suction filtration and dried.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH:11]([N:16]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1)[CH3:17])[CH2:10]2>N1C=CC=CC=1>[CH3:1][S:2]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH:11]([N:16]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([NH:25][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:23][CH:24]=1)[CH3:17])[CH2:10]2)(=[O:4])=[O:3]
Reactant: CN(Cc1ccc(N)cc1)C1Cc2ccc(N)cc2C1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CN(Cc1ccc(NS(C)(=O)=O)cc1)C1Cc2ccc(NS(C)(=O)=O)cc2C1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Methanesulphonyl chloride (0.53 ml) was added to 5-amino-2-[N-(4-aminobenzyl)-N-methylamino]indane (1.1 g) in pyridine and the reaction mixture was stirred at room temperature for 17 hours. The solvent was then removed by evaportion in vacuo and the residue taken up in methylene chloride, washed with aqueous sodium bicarbonate, dried (MgSO4) and evaporated in vacuo. The resulting gum was purified by column chromatography on silica eluting with methylene chloride containing methanol (0% up to 2%). The product-containing fractions were combined and evaporated to dryness in vacuo to give the title compound as a colourless foam. This foam was dissolved in chloroform and the solution was evaporated to dryness in vacuo to give the title compound as a colourless foam, yield 0.2 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](N)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.N([O-])=O.[Na+].[CH2:18]([O:20][C:21]([SH:23])=[S:22])[CH3:19].[K]>O.C(O)C>[CH2:18]([O:20][C:21](=[S:22])[S:23][C:4]1[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=[C:2]([Br:1])[CH:3]=1)[CH3:19]
Reactant: CCOC(=S)S
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Agent: Cl
Agent: O=N[O-]
Agent: [K]
Solvent: O
Solvent: CCO
Product: CCOC(=S)Sc1cc(Br)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 51 %

Procedure:
3-Bromo-5-trifluoromethyl-phenylamine (4.0 mL, 28.3 mmoles) was dissolved into concentrated HCl (70 mL). This solution was chilled to 0° C. and to it was slowly added a solution of sodium nitrite (2.5 g, 36.2 mmoles) in 50 mL of water. After completion of the addition enough ethanol (90%) was added (25 mL) to affect nearly complete dissolution of the resultant mixture. The mixture was stirred at 0° C. for an additional 20 minutes. After this period the heterogeneous mixture was quickly transferred (cold) to an addition funnel. The diazonium mixture was added to a solution of O-ethylxanthic acid, potassium salt (5.7 g, 35.6 mmoles) in 50 mL of water at 60° C. The mixture was next heated to 90° C. and was stirred at this temperature for 2 hours. After this period the mixture was allowed to cool to ambient temperature, and the crude xanthate (a red liquid) was removed from the bottom of the aqueous mixture via pipette. The crude product taken up in 100 mL of diethyl ether and was washed with water (2×25 mL) and brine (20 mL). The ether layer was evaporated in vacuo to yield crude xanthate. The crude product was purified using flash silica chromatography (0-1% EtOAc/Hexane) to yield 4.7 g (51% yield) of dithiocarbonic acid S-(3-bromo-5-trifluoromethyl-phenyl) ester O-ethyl ester as a red liquid. 1H-NMR (CDCl3): δ 7.83 (d, J=5.8 Hz, 2H), 7.71 (s, 1H), 4.63 (q, J=7.1 Hz, 2H), 1.36 (t, J=7.1 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[N:4][CH:5]=[C:6]([CH2:16][OH:17])[C:7]=1[CH:8]1[NH:12][CH:11]([C:13]([OH:15])=[O:14])[CH2:10][S:9]1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>O>[C:19]([N:12]1[CH:11]([C:13]([OH:15])=[O:14])[CH2:10][S:9][CH:8]1[C:7]1[C:6]([CH2:16][OH:17])=[CH:5][N:4]=[C:3]([CH3:18])[C:2]=1[OH:1])(=[O:21])[CH3:20]
Reactant: Cc1ncc(CO)c(C2NC(C(=O)O)CS2)c1O
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)N1C(C(=O)O)CSC1c1c(CO)cnc(C)c1O
Temperature: 80 °C
Yield: 110.8 %

Procedure:
To water (1.06 ml) were added 2-[3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-4-yl]thiazolidine-4-carboxylic acid (500 mg, 1.85 mmol) and acetic anhydride (1.06 ml, 11.1 mmol), and the mixture was heated at 80° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, to the residue was added toluene (5 ml×3), and the mixture was concentrated under reduced pressure to give N-acetyl-2-[3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-4-yl]thiazolidine-4-carboxylic acid as an amorphous solid (0.64 g).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[NH2:15][C:16]1[C:24]2[O:23][C:22]([CH3:26])([CH3:25])[CH2:21][C:20]=2[CH:19]=[CH:18][CH:17]=1>>[CH3:25][C:22]1([CH3:26])[CH2:21][C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:15][C:8]3[CH:7]=[CH:6][C:5]4[C:4]([NH2:1])=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]=3)[C:24]=2[O:23]1
Reactant: CC1(C)Cc2cccc(N)c2O1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Product: CC1(C)Cc2cccc(Nc3ccc4c(N)cccc4n3)c2O1

Procedure:
The title compound, MS: m/e=306.1 (M+H+), was prepared in accordance with the general method of example 1 from 5-nitro-2-chloroquinoline and 7-amino-2,3-dihydro-2,2-dimethylbenzofuran (CAS 68298-46-4).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:5]([C:7](Cl)=[O:8])[N:6]=1.[Br:17][C:18]1[C:26]2[N:25]=[C:24]([CH2:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]3)[NH:23][C:22]=2[CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>ClCCl>[Br:17][C:18]1[C:26]2[N:25]=[C:24]([CH2:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][N:29]3[C:7]([C:5]3[N:6]=[C:2]([CH3:1])[S:3][C:4]=3[C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[O:8])[NH:23][C:22]=2[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc(C(=O)Cl)c(-c2ccc(F)cc2)s1
Reactant: Brc1cccc2[nH]c(CC3CCCCN3)nc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(C(=O)N2CCCCC2Cc2nc3c(Br)cccc3[nH]2)c(-c2ccc(F)cc2)s1
Yield: 89 %

Procedure:
2-Methyl-5-(4-fluorophenyl)thiazole-4-carbonyl chloride (383 mg, 1.5 mmol) was added portionwise over 5 min. to a stirred solution of (RS)-4-bromo-2-piperidin-2-ylmethyl-1H-benzoimidazole, D39 (400 mg, 1.4 mmol) and triethylamine (0.57 ml, 5.0 mmol) in dichloromethane (20 ml) at room temperature. After 20 h the mixture was washed with saturated sodium hydrogen carbonate. The organic layer was dried (Na2SO4) and the solvent removed in vacuo. Chromatography (silica gel, 10-100% ethyl acetate-hexane then 1-10% methanol-ethyl acetate) afforded the title compound as a pale brown amorphous solid (620 mg, 89%).