Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[I:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([C:21]([OH:23])=O)[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([Cl:33])[CH:32]=1)[CH2:28][NH2:29].CC(C)N=C=NC(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([Cl:33])[CH:32]=1)[CH2:28][NH:29][C:21]([C:14]1([C:11]2[CH:10]=[CH:9][C:8]([I:7])=[CH:13][CH:12]=2)[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]1)=[O:23]
Reactant: NCc1cc(Cl)cc(Cl)c1
Reactant: CN1CCC(C(=O)O)(c2ccc(I)cc2)CC1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CN1CCC(C(=O)NCc2cc(Cl)cc(Cl)c2)(c2ccc(I)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.5 %

Procedure:
To a solution of 4-(4-iodo-phenyl)-1-methyl-piperidine-4-carboxylic acid pyridine salt (0.44 g, 1.04 mmol, see Example 6) and 3,5-dichlorobenzylamine (0.22 g, 1.24 mmol, 1.2 eq) in anhydrous DMF (5 mL) was added DIC (0.326 mL, 2.08 mmol, 2 eq) followed by DMAP (0.006 g, 0.052 mmol, 5%). The mixture was stirred at room temperature for 16 h and then it was partitioned between EtOAc (50 mL) and saturated aqueous NaHCO3 (50 mL). The organic layer was separated, washed with H2O (3×40 mL) and saturated brine (50 mL), dried over Na2SO4, filtered and concentrated by rotary evaporation. The crude material was purified by silica gel chromatography by eluting with 10% MeOH/EtOAc to give 60 mg (11%) of 4-(4-iodo-phenyl)-1-methyl-piperidine-4-carboxylic acid 3,5-dichloro-benzylamide as a white solid. MS(ESI): 503.1/505.1. To a flask containing 4-(4-iodo-phenyl)-1-methyl-piperidine-4-carboxylic acid 3,5-dichloro-benzylamide (60 mg, 0.12 mmol) was added Pd(PPh3)4 (3.2 mg, 0.012 mmol, 10 mol %), 3-cyanophenylboronic acid (26.4 mg, 0.18 mmol, 1.5 eq.) and Na2CO3 (0.21 g, 2 mmol). The mixture was suspended in toluene (2 mL), EtOH (1 mL) and H2O (1 mL) and heated at 90° C. for 18 h. The reaction mixture was cooled to room temperature and partitioned between EtOAc (10 mL) and saturated Na2CO3 (5 mL). The organic layer was washed with saturated Na2CO3 (3×5 mL), dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation. The crude product was purified by HPLC to give 4-(3′-cyano-biphenyl-4-yl)-1-methyl-piperidine-4-carboxylic acid 3,5-dichloro-benzylamide as a white solid (0.05 g, 0.0105 mmol, 10%). 1H NMR (300 MHz, CDCl3): δ 7.88 (m, 2H), 7.71 (m, 3H), 7.52 (d, 2H), 7.31 (t, 1H), 7.00 (dd, 2H), 6.55 (t, 1H), 4.55 (br, 1H), 4.44 (d, 2H), 3.76 (m, 2H). 3.32 (m, 2H), 2.94 (s, 3H), 2.86 (m, 2H). 2.52 (t, 2H). MS (ESI): 478.1/480.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:10][C:11]2[CH:25]=[CH:24][C:14]([O:15][C:16]([CH3:23])([CH3:22])[C:17]([O:19]CC)=[O:18])=[CH:13][CH:12]=2)[CH3:9])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]([CH3:22])([CH3:23])[C:17]([OH:19])=[O:18])=[CH:24][CH:25]=2)[CH3:9])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CN(C)c2ccc(Cl)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(Cc1ccc(OC(C)(C)C(=O)O)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.9 %

Procedure:
In 20 ml of ethanol is dissolved 1.2 g of ethyl 2-[4-{N-(4-chlorophenyl)-N-methylaminomethyl}phenoxy]-2-methylpropionate. Subsequently, 15 ml of 1 N aqueous solution of sodium hydroxide is added to the solution, and the mixture is stirred at room temperature for 4 hours. After distilling off the ethanol from the reaction mixture under reduced pressure, the residue is dissolved in water. The solution is adjusted to pH 4 with 10% hydrochloric acid, and the precipitated crystals are collected by filtration and dried to give 0.94 g of 2-[4-{N-(4-chlorophenyl)-N-methylaminomethyl}phenoxy]-2-methylpropionic acid, mp 63° to 65° C.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:22]=[CH:23][C:24]=1[Cl:25])[O:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][NH2:21])[CH2:15][CH2:14]1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH2:50]([O:52][C:53]1[CH:54]=[C:55]([CH:59]=[CH:60][CH:61]=1)[C:56](O)=[O:57])[CH3:51].C(N(CC)C(C)C)(C)C.C([O-])(O)=O.[Na+].Cl>CN(C=O)C.C(Cl)(Cl)Cl>[ClH:8].[Cl:8][C:9]1[CH:10]=[C:11]([CH:22]=[CH:23][C:24]=1[Cl:25])[O:12][CH:13]1[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][NH:21][C:56](=[O:57])[C:55]2[CH:59]=[CH:60][CH:61]=[C:53]([O:52][CH2:50][CH3:51])[CH:54]=2)[CH2:17][CH2:18]1
Reactant: NCCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Reactant: CCOc1cccc(C(=O)O)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cccc(C(=O)NCCN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)c1
Yield: 59.6 %

Procedure:
The product of Example 1 step (iv) (0.4 g) was dissolved in DMF (10 ml), PyBrop (0.541 g), 3-ethoxybenzoic acid (0.167 g ) and N,N-di-isopropylethylamine (0.5 g) were added. After 18 hours at room temperature chloroform and aqueous NaHCO3 solution were added. The organic phase was separated, dried and concentrated to leave a gum which was purified by chromatography (ethyl acetate:methonol 97:3) to give an oil. Addition of 1.0M ethereal hydrogen chloride solution gave the titled product as a solid (0.14 g).
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([CH3:18])[CH:16]=2)[C:11](=[O:19])[C:10]([C:20]([O:22]CC)=[O:21])=[CH:9]1.O.[OH-].[Li+]>CO.O.C(#N)C>[C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([CH3:18])[CH:16]=2)[C:11](=[O:19])[C:10]([C:20]([OH:22])=[O:21])=[CH:9]1
Reactant: CCOC(=O)c1cn(Cc2ccccc2-c2ccccc2)c2cc(C)cnc2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC#N
Product: Cc1cnc2c(=O)c(C(=O)O)cn(Cc3ccccc3-c3ccccc3)c2c1
Reaction time: 15 h
Yield: 20.2 %

Procedure:
To a solution of ethyl 1-(biphenyl-2-ylmethyl)-7-methyl-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate (20) (80 mg, 0.2 mmol) in methanol (10 mL) was added the solid lithium hydroxide monohydrate (168 mg, 4.02 mmol) at room temperature under nitrogen atmosphere. It gave a clear solution within 30 minutes and this light yellow solution was stirred for 15 h at which time LCMS analysis indicated the absence of starting material. Then, it was diluted with water and the methanol was removed under vacuum. The basic aqueous layer was diluted with water and then extracted with ethyl acetate (50 mL) to remove any neutral impurities. Then, the basic aqueous layer was neutralized with 1.0N HCl. Then, the acid was extracted with ethyl acetate (2×30 mL) and the combined extracts were washed with brine solution and dried over anhydrous MgSO4. Filtration and concentration gave the yellow solids which were dissolved in acetonitrile and water. The mixture was frozen and then lyophilized under high vacuum to obtain 1-(biphenyl-2-ylmethyl)-7-methyl-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylic acid (21) (15 mg, 20% yield) as a light yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=O)=[CH:7][C:6]=1[Cl:16])([CH3:4])([CH3:3])[CH3:2].[Cl-].ClC1N(C)CC[NH+]1C.Cl.[NH2:27][C@@H:28]([C:30]1[CH:35]=[CH:34][C:33]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[CH:32][CH:31]=1)[CH3:29]>C(N(CC)CC)C>[C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([NH:27][C@@H:28]([C:30]2[CH:31]=[CH:32][C:33]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[CH:34][CH:35]=2)[CH3:29])=[O:13])=[CH:7][C:6]=1[Cl:16])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](N)c1ccc(NS(C)(=O)=O)cc1
Reactant: CC(C)(C)c1ccc(OCC(=O)O)cc1Cl
Agent: CN1CC[NH+](C)C1Cl
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)COc1ccc(C(C)(C)C)c(Cl)c1)c1ccc(NS(C)(=O)=O)cc1
Yield: 41.5 %

Procedure:
(4-tert-Butyl-3-chlorophenoxy)acetic acid (121 mg, 0.50 mmol), 2-chloro-1,3-dimethylimidazolinium chloride (CDI) (86 mg, 0.53 mmol), triethylamine (0.5 ml) and N-{4-[(1R)-1-aminoethyl]phenyl}methanesulfonamide hydrochloride (125 mg, 0.50 mmol, Bioorganic & Medicinal Chemistry Letters, 2004, 14, 1751–1755) were treated in the same procedure described in Example 2(b) to give 91 mg (40% yield) of the titled compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:9]=[N:10][C:11]3[CH:12]([NH:17][C:18]([C:20]4([NH2:23])[CH2:22][CH2:21]4)=[O:19])[CH2:13][CH2:14][C:15]=3[CH:16]=2)[CH:7]=1.[N:31]1[CH:36]=[CH:35][C:34]([C:37](O)=[O:38])=[CH:33][N:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[C:6]([C:8]2[CH:9]=[N:10][C:11]3[CH:12]([NH:17][C:18]([C:20]4([NH:23][C:37]([C:34]5[CH:35]=[CH:36][N:31]=[N:32][CH:33]=5)=[O:38])[CH2:22][CH2:21]4)=[O:19])[CH2:13][CH2:14][C:15]=3[CH:16]=2)[CH:7]=1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2cnc3c(c2)CCC3NC(=O)C2(N)CC2)no1
Reactant: O=C(O)c1ccnnc1
Product: Cc1nc(-c2c(F)cc(Cl)cc2-c2cnc3c(c2)CCC3NC(=O)C2(NC(=O)c3ccnnc3)CC2)no1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-1 [B], 1-amino-cyclopropanecarboxylic acid{(rac)-3-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-6,7-dihydro-5H-[1]pyrindin-7-yl}-amide (example 37) has been coupled with pyridazine-4-carboxylic acid to yield the title compound as light brown amorphous solid. MS: 534.1 (MH+, 1Cl).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:39].[NH2:40][CH2:41][CH2:42][N:43]([CH3:51])[C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:40][CH2:41][CH2:42][N:43]([CH3:51])[C:44](=[O:50])[O:45][C:46]([CH3:47])([CH3:48])[CH3:49])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)=[O:23])[CH:32]=[CH:33][C:34]=3[CH3:35])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:39]
Reactant: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(S(C)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CN(CCN)C(=O)OC(C)(C)C
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(NCCN(C)C(=O)OC(C)(C)C)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 102.9 %

Procedure:
To a solution of 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide (50 mg, 0.09 mmol) in DCM (5 mL) was added 1,1-dimethylethyl (2-aminoethyl)-methylcarbamate (0.09 mL, 0.5 mmol). The resultant mixture was stirred at room temperature overnight. The mixture was concentrated under vacuo. Flash chromatography (90% CH2Cl2/7% MeOH/3% NH4OH) then provide the title compound (61 mg, 100%). LC-MS (ES) m/z 659 (M+H)+; 1H-NMR(CDCl3) δ 1.39 (s, 9H), 1.70 (br, 1H), 2.32 (s, 3H), 2.65 (s, 2H), 2.82 (s, 2H), 3.22 (s, 3H), 3.60 (br, 1H), 6.34 (d, 1H), 7.03 (m, 4H), 7.34 (m, 1H), 7.48 (m, 2H), 7.64 (m, 1H), 7.84 (m, 2H), 8.14 (d, 1H).
Reaction SMILES: [C:1]([NH2:4])(=[S:3])[CH3:2].Br[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=O>O>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2[N:4]=[C:1]([CH3:2])[S:3][CH:6]=2)=[CH:10][CH:11]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: CC(N)=S
Solvent: O
Product: COc1ccc(-c2csc(C)n2)cc1
Temperature: 140 °C
Yield: 69.6 %

Procedure:
The mixture of thioacetamide (16.0 g, 213 mmol) and 2-bromo-1-(4-methoxy-phenyl)-ethanone (4.0 g, 17.5 mmol) was heated at 140° C. for 24 h under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (100 mL) was added and extracted with ethyl acetate (3×100 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified over silica gel (230-400 M, 1% EtOAc-Hexane) to get the desired product (2.5 g, 69%).
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH:5][C:6]([NH:8][CH2:9][C:10]1[C:15]([CH2:16][OH:17])=[CH:14][N:13]=[C:12]([CH3:18])[C:11]=1[OH:19])=[O:7].Cl.[N:21]([O-])=[O:22].[Na+]>>[ClH:2].[Cl:2][CH2:3][CH2:4][N:5]([N:21]=[O:22])[C:6]([NH:8][CH2:9][C:10]1[C:15]([CH2:16][OH:17])=[CH:14][N:13]=[C:12]([CH3:18])[C:11]=1[OH:19])=[O:7]
Reactant: O=N[O-]
Reactant: Cc1ncc(CO)c(CNC(=O)NCCCl)c1O
Agent: Cl
Agent: [Na+]
Product: Cc1ncc(CO)c(CNC(=O)N(CCCl)N=O)c1O
Reaction time: 1.5 h

Procedure:
To a solution of 1 g. of 1-(2-chloroethyl)-3-[(2-methyl-3-hydroxy-5-hydroxymethylpyridine-4-yl)methyl] urea.hydrochloride in 10 ml. of 5% hydrochloric acid was added gradually 0.4 g. of sodium nitrite at 0° - 5° C. while stirring. After completion of the addition, the reaction mixture was stirred at 0° - 5° C. for additional 1.5 hours. The crystalline substances separated in situ during the stirring were recovered by filtration and recrystallized from 8 ml. of ethanol to give 0.1 g. of the pure desired product having pale yellow color and a decomposition point of 171° C.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[O:17])=[CH:11][CH:10]=1.[CH2:18]1[O:20][CH:19]1[CH2:21][OH:22]>ClCCl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:19]([CH2:21][OH:22])[CH2:18][O:20][C:16]2=[O:17])=[CH:11][CH:10]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: OCC1CO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1OCC(CO)N1c1ccc(Cl)cc1
Reaction time: 20 h
Yield: 143 %

Procedure:
A 8.5 ml quantity of triethylamine was added dropwise to a dichloromethane (25 ml) solution of 2.5 g of 4-chlorophenyl isocyanate and 2.5 g of glycidol at 40° C., and the mixture was stirred at the same temperature for 20 hours. The reaction mixture was washed with 5% hydrochloric acid, dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and purified by dichloromethane-ethanol gradient elution to give 5.30 g of the title compound as an oil (yield 69%).
Reaction SMILES: [CH3:1][C@H:2]1[C@H:30]([CH3:31])[C@@H:29]2[C@@:5]([C:33]([O:35][CH3:36])=[O:34])([CH2:6][CH2:7][C@@:8]3([CH3:32])[C@:13]4([CH3:28])[CH2:14][CH2:15][C@H:16]5[C@@:21]([CH2:23][OH:24])([CH3:22])[C@@H:20]([OH:25])[C@H:19]([OH:26])[CH2:18][C@:17]5([CH3:27])[C@H:12]4[CH2:11][CH:10]=[C:9]32)[CH2:4][CH2:3]1.[C:37]1(C)[CH:42]=CC(S(O)(=O)=O)=C[CH:38]=1.O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C@H:2]1[C@H:30]([CH3:31])[C@@H:29]2[C@@:5]([C:33]([O:35][CH3:36])=[O:34])([CH2:6][CH2:7][C@@:8]3([CH3:32])[C@:13]4([CH3:28])[CH2:14][CH2:15][C@H:16]5[C@:21]6([CH3:22])[CH2:23][O:24][C:37]([CH3:42])([CH3:38])[O:25][C@H:20]6[C@H:19]([OH:26])[CH2:18][C@:17]5([CH3:27])[C@H:12]4[CH2:11][CH:10]=[C:9]32)[CH2:4][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(=O)[C@]12CC[C@@H](C)[C@H](C)[C@H]1C1=CC[C@@H]3[C@@]4(C)C[C@@H](O)[C@H](O)[C@@](C)(CO)[C@@H]4CC[C@@]3(C)[C@]1(C)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)[C@]12CC[C@@H](C)[C@H](C)[C@H]1C1=CC[C@@H]3[C@@]4(C)C[C@@H](O)[C@@H]5OC(C)(C)OC[C@@]5(C)[C@@H]4CC[C@@]3(C)[C@]1(C)CC2
Yield: 60.3 %

Procedure:
Methyl asiatate 2 (27.7 mg, 0.055 mmole) was dissolved in anhydrous acetone (3 ml), added with p-toluenesulfonic acid (27.7 mg) and then refluxed. Water was added to the reaction mixture, and the solution was neutralized with 5% potassium carbonate and then extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The was chromatographed with benzene and ethyl acetate (3:2) to give pure desired compound (18 mg, 60%).
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]2[N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]3[CH:24]=[CH:25][C:26]([C:28]#[N:29])=[CH:27][C:16]=3[N:15]=2)[C:5]1=[O:30])([CH3:3])[CH3:2].ClCC1N(CCC(C)C)C2C=CC(C#N)=CC=2N=1.C(N1C2C=CC=CC=2NC1=O)(C)=C.[H-].[Na+]>>[C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]2[N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]3[CH:24]=[CH:25][C:26]([C:28]#[N:29])=[CH:27][C:16]=3[N:15]=2)[C:5]1=[O:30])([CH3:3])=[CH2:2]
Reactant: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(C#N)ccc21
Agent: C=C(C)n1c(=O)[nH]c2ccccc21
Agent: CC(C)CCn1c(CCl)nc2cc(C#N)ccc21
Agent: [H-]
Product: C=C(C)n1c(=O)n(Cc2nc3cc(C#N)ccc3n2CCC(C)C)c2ccccc21

Procedure:
2-(3-Isopropenyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazole-5-carbonitrile was prepared as described for 2-(3-Isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazole-5-carbonitrile using 2-chloromethyl-1-(3-methyl-butyl)-1H-benzoimidazole-5-carbonitrile and 1-Isopropenyl-1,3-dihydro-benzoimidazol-2-one with NaH as base.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[C:12]([CH2:13][O:14][C:15]2[C:20]([F:21])=[CH:19][C:18]([CH2:22][CH2:23][C:24](OCC)=[O:25])=[C:17]([F:29])[C:16]=2[F:30])=[C:11]([C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH3:38])=[CH:33][CH:32]=2)[S:10][N:9]=1>>[Cl:7][C:8]1[C:12]([CH2:13][O:14][C:15]2[C:20]([F:21])=[CH:19][C:18]([CH2:22][CH2:23][CH2:24][OH:25])=[C:17]([F:29])[C:16]=2[F:30])=[C:11]([C:31]2[CH:32]=[CH:33][C:34]([CH2:37][CH3:38])=[CH:35][CH:36]=2)[S:10][N:9]=1
Reactant: CCOC(=O)CCc1cc(F)c(OCc2c(Cl)nsc2-c2ccc(CC)cc2)c(F)c1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCc1ccc(-c2snc(Cl)c2COc2c(F)cc(CCCO)c(F)c2F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 156 following Step 2 by LAH reduction of ethyl 3-(4-((3-chloro-5-(4-ethylphenyl)isothiazol-4-yl)methoxy)-2,3,5-trifluorophenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) 7.65 (d, J=7.5 Hz, 2H), 7.32 (d, J=7.5 Hz, 2H), 6.74 (m, J=5.5 Hz, 1H), 5.10 (s, 2H), 3.72 (t, J=7.0 Hz, 2H), 2.78 (m, J=5.8 Hz, 2H), 1.88 (m, 2H), 1.55 (br, s, 2H), 1.28 (t, J=7.6 Hz, 2H). LCMS (ESI, M/Z) for C21H19ClF3NO2S: 441.1, 443.1.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12](N)=[CH:11][C:10]=2[CH3:16])[CH2:5][CH2:4]1)[CH3:2].[BrH:17].N([O-])=O.[Na+]>O.[Cu]Br>[Br:17][C:12]1[CH:13]=[CH:14][C:9]([N:6]2[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]2)=[C:10]([CH3:16])[CH:11]=1
Reactant: CCN1CCN(c2ccc(N)cc2C)CC1
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCN1CCN(c2ccc(Br)cc2C)CC1
Temperature: 60 °C

Procedure:
4-(4-Ethyl-piperazin-1-yl)-3-methyl-phenylamine (1.3 g, 6 mmol) in hydrobromic acid (61% in H2O, 9.2 ml, 70 mmol) is diazotized at 0° C. with sodium nitrite (443 mg, 6.42 mmol) in 2.3 ml H2O and the mixture is poured into a solution of copper(I) bromide (1.84 g, 12.5 mmol) in hydrobromic acid (61% in H2O, 7.7 ml, 58.8 mmol) at 0° C. The cooling bath is then removed and the mixture is heated at 60° C. for 5 h. After cooling, the mixture is basified with a 2M NaOH solution and diluted with CH2Cl2. After separation, the aqueous phase is extracted with CH2Cl2 several times. The combined organic layers are washed with brine, dried over Na2SO4, filtered and the filtrate is concentrated in vacuo. The residue is purified by chromatography on a 120 g silica gel column on a Combiflash Companion™ (Isco Inc.) apparatus (gradient CH2Cl2/CH2Cl2:EtOH:NH3 90:9:1 from 1:0=>4:6) to afford the title compound as a pale brown solid, Rt=0.878 min (Acquity HPLC BEH C18, 2.1×50 mm, 1.7 micron, detection 215 nM, 0.1 min 2% CH3CN in H2O, 2% to 100% CH3CN in H2O in 1.5 min, 0.4 min 100% CH3CN+0.1% TFA, flow rate 1.0 ml/min); MS: 283 (M+1, 79Br)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([Cl:16])[CH:9]=2)[CH:5]=[N:6][CH:7]=1.[CH:17]1([S:20](Cl)(=[O:22])=[O:21])[CH2:19][CH2:18]1>N1C=CC=CC=1>[Cl:16][C:10]1[CH:9]=[C:8]([C:4]2[CH:3]=[C:2]([NH:1][S:20]([CH:17]3[CH2:19][CH2:18]3)(=[O:22])=[O:21])[CH:7]=[N:6][CH:5]=2)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: N#Cc1ccc(-c2cncc(N)c2)cc1Cl
Reactant: O=S(=O)(Cl)C1CC1
Solvent: c1ccncc1
Product: N#Cc1ccc(-c2cncc(NS(=O)(=O)C3CC3)c2)cc1Cl
Yield: 29.3 %

Procedure:
According to General Sulfonylation Procedure 2 in Example 1, to a solution of 4-(5-amino-pyridin-3-yl)-2-chloro-benzonitrile (20 mg, 87 μmol, 1 eq) in anhydrous pyridine (500 μl) was added cyclopropanesulfonyl chloride (9.8 μl, 96 mmol, 1.1 eq). The crude product was purified by Isco Cornbiflash® Companion™ flash chromatography system on normal phase (4 g SiO2, flow rate 18 mL/min), eluting with mixtures of dichloromethane/methanol, to give cyclopropanesulfonic acid [5-(3-chloro-4-cyano-phenyl)-pyridin-3-yl]-amide (8.5 mg, >95% purity, yield: 29.2%). The isolated product was lyophilized and identified by LC-MS (system 1) and NMR (system 2): ESI-MS m/z: 334 [M+H]+, retention time=1.90 min, 1H NMR (400 MHz, DMSO-d6) δ ppm 0.93-0.99 (m, 4H) 2.80-2.85 (m, 1H) 7.84 (dd, J=8.08, 1.64 Hz, 1H) 7.89 (t, J=2.21 Hz, 1H) 8.08 (d, J=8.08 Hz, 1H) 8.10 (s, 1H) 8.48 (d, J=2.40 Hz, 1H) 8.70 (d, J=1.89 Hz, 1H) 10.15 (br. s., 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[C:3]=1[Cl:12].[C:13]([NH:17][C:18](=[O:32])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:20]=1)([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl.C(OCC)(=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:29]2[CH2:28][CH2:27][N:26]([CH2:25][C:21]3[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=3)[C:18]([NH:17][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:32])[CH2:31][CH2:30]2)=[O:8])=[C:4]([F:11])[C:3]=1[Cl:12]
Reactant: Nc1ccc(C(=O)O)c(F)c1Cl
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCNCC2)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)c(Cl)c3F)CC2)c1
Reaction time: 2 h
Yield: 46 %

Procedure:
To 4-amino-3-chloro-2-fluorobenzoic acid (0.754 mmol, 143 mg), N-tert-butyl-3-(piperazin-1-ylmethyl)benzamide (0.754 mmol, 208 mg) and triethylamine (3.02 mmol, 0.421 ml, 305 mg) in dichloromethane (8 mL) was added 1-propanephosphonic acid cyclic anhydride (1.886 mmol, 1.117 mL, 1200 mg, 50% solution in ethyl acetate). After 2 hours stirring, ethyl acetate was added. The organic solution was washed with saturated sodium hydrogen carbonate, water, and saturated sodium chloride. The organic phase was dried with sodium sulfate, filtered and concentrated. The residue was purified by silica chromatography to yield the title compound (155 mg).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([C:14]1[C:18]2[CH2:19][CH2:20][C:21]3[CH:22]=[N:23][C:24]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([CH2:34][OH:35])=[CH:30][C:29]=4[O:36][CH3:37])=[N:25][C:26]=3[C:17]=2[N:16]([CH3:38])[N:15]=1)=[O:13])[CH3:2]>C(Cl)Cl.O=[Mn]=O>[CH2:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[NH:11][C:12]([C:14]1[C:18]2[CH2:19][CH2:20][C:21]3[CH:22]=[N:23][C:24]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([CH:34]=[O:35])=[CH:30][C:29]=4[O:36][CH3:37])=[N:25][C:26]=3[C:17]=2[N:16]([CH3:38])[N:15]=1)=[O:13])[CH3:10]
Reactant: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(Nc3ccc(CO)cc3OC)nc1-2
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(Nc3ccc(C=O)cc3OC)nc1-2
Temperature: 25 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
To a solution of N-(2,6-diethylphenyl)-8-{[4-(hydroxymethyl)-2-methoxyphenyl]amino}-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (50 mg, 0.097 mmol) in 1 ml of dry DCM, MnO2 (68 mg, 0.78 mmol) was added. The mixture was stirred at room temperature for 5 h, MnO2 filtered off and the solvent removed in vacuo affording the title compound in 80% yield.