Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9]1[N:10]=[CH:11][CH:12]=[C:13]2[CH:17]=[C:16]([C:18]([OH:20])=O)[NH:15][C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:28][CH2:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O>[CH2:21]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[N:10]=[CH:11][CH:12]=[C:13]2[CH:17]=[C:16]([C:18]([NH:28][CH2:29][C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)=[O:20])[NH:15][C:14]=12)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)c1cc2ccnc(N(Cc3ccccc3)Cc3ccccc3)c2[nH]1
Reactant: NCc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccncc1)c1cc2ccnc(N(Cc3ccccc3)Cc3ccccc3)c2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.3 %

Procedure:
A mixture of 7-(dibenzylamino)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Reference Example 4) (398 mg, 1.11 mmol), 4-(aminomethyl)pyridine (169 mg, 1.56 mmol), 1-ethyl-3-dimethylaminopropylcarbodiimide (EDCI) (299 mg, 1.56 mmol), 1-hydroxybenzotriazole (HOBt) (211 mg, 1.56 mol) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 18 h. The mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with aqueous sodium hydrogen carbonate, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0:10 to 1:10 methanol/ethyl acetate). Recrystallization from hexanes/ethyl acetate gave 7-(dibenzylamino)-N-(4-pyridinylmethyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (419 mg, 84%) as colorless crystals: Rf 0.20 (silica gel, ethyl acetate); mp 119-120° C.; 1H NMR (300 MHz, CDCl3) δ4.62 (2H, d, J=6.0 Hz), 4.90 (4H, s), 6.40-6.52 (1H, m), 6.75 (1H, s), 7.01 (1H, d, J=5.6 Hz), 7.21 (2H, d, J=5.9 Hz), 7.25-7.38 (10H, m), 7.91 (1H, d, J=5.6 Hz), 8.57 (2H, d, J=5.9 Hz), 8.98 (1H, br s); ESI MS m/z 448 [C28H25N5O+H]+; HPLC (Method A) >99% (AUC), tR=15.7 min.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([OH:9])=[CH:4][CH:3]=1.CI.[C:12](=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:12])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1nc(Br)ccc1O
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COc1ccc(Br)nc1C
Temperature: 25 °C
Yield: 72.9 %

Procedure:
A mixture of 6-bromo-2-methyl-pyridin-3-ol (4.06 g, 21.59 mmol), methyl iodide (1.61 mL, 25.91 mmol), potassium carbonate (5.97 g, 43.18 mmol) and acetonitrile (183.0 mL) was heated at reflux for 17 hours. The mixture was cooled to room temperature, filtered through a plug of celite and the solvent was evaporated under reduced pressure. Water (50 mL) and ethyl acetate (100 mL) were added. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel chromatography utilizing a gradient of 0-20% ethyl acetate in hexane to yield 6-bromo-3-methoxy-2-methyl-pyridine (3.18 g, 73%) as a white solid. 1H NMR (400 MHz, DMSO) δ 7.42 (d, J=8.6 Hz, 1H), 7.33 (d, J=8.6 Hz, 1H), 3.82 (s, 3H), 2.32 (s, 3H). ESI-MS m/z calc. 201.0, found 202.1 (M+1)+; Retention time: 1.19 minutes (3 min run).
Reaction SMILES: [C:1]([C:3]([C:21]#[N:22])=[C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N:16]([CH2:18][CH2:19][OH:20])[CH3:17])[CH:12]=2)[CH:7]=1)[CH3:5])#[N:2].Cl[CH2:24][CH2:25][OH:26]>C(#N)C>[C:1]([C:3]([C:21]#[N:22])=[C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N:16]([CH2:18][CH2:19][O:20][CH2:24][CH2:25][OH:26])[CH3:17])[CH:12]=2)[CH:7]=1)[CH3:5])#[N:2]
Reactant: OCCCl
Reactant: CC(=C(C#N)C#N)c1ccc2cc(N(C)CCO)ccc2c1
Solvent: CC#N
Product: CC(=C(C#N)C#N)c1ccc2cc(N(C)CCOCCO)ccc2c1
Temperature: 80 °C
Reaction time: 17 h
Yield: 60 %

Procedure:
0.40 g (1.4 mmol) of the fourth compound 4 is obtained to be dissolved in 8 mL of anhydrous acetonitrile. 0.35 g (4.3 mmol) of 2-chloro-ethanol is added to be heated with stirring at 80° C. for 17 hrs. After cooling, extraction is processed with dichloromethane. After being dried with anhydrous sodium sulfate, an organic phase is concentrated under reduced pressure to be separated and purified by liquid chromatography (SiO2, CHCl3:EtOAc=1:1). Thus, a product, 2-(1,1-dicyanopropen-2-yl)-6-{[2-(2-hydroxy-ethoxy)-ethyl]methylamino}naphthalene 5 (hereinafter referred to as fifth compound 5), is obtained, which has a weight of 0.29 g and a yield of 60.0%.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([O:13]C)=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[Cl:23].[Li+].[OH-].Cl>C1COCC1.CO>[F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([OH:13])=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[Cl:23]
Reactant: COC(=O)c1cc2scnc2c(F)c1Nc1ccc(Br)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2scnc2c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
To a solution of methyl 4-fluoro-5-((4-bromo-2-chlorophenyl)amino)benzo[d]thiazole-6-carboxylate (8.74 g, 21.02 mmol) in THF and MeOH (20 mL, 4:1, v/v) was added 5.0 M LiOH (aq., 9.5 mL). After stirring at ambient temperature for 2 h, the reaction was treated with 10% HCl (aq.) till the solution was acidic. The aqueous layer was extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with water (100 mL) and brine (100 mL) sequentially, dried over Na2SO4, filtered and concentrated to give the desired product (8.08 g, 95.7% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.09 (s, 1H), 9.18 (s, 1H), 8.71 (s, 1H), 8.47 (s, 1H), 7.44 (m, 1H), 7.31 (m, 1H), 6.65 (m, 1H).
Reaction SMILES: Cl.[CH2:2]([C:4]1[S:8][C:7](=[NH:9])[N:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[N:5]=1)[CH3:3].[C:28]12[C:36](=[O:37])[O:35][C:33](=[O:34])[C:29]=1[CH2:30][CH2:31][CH2:32]2.O>CN(C)C=O>[CH2:2]([C:4]1[S:8][C:7](=[N:9][C:36]([C:28]2[CH2:32][CH2:31][CH2:30][C:29]=2[C:33]([OH:35])=[O:34])=[O:37])[N:6]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:24][N:25]=[N:26][N:27]=3)=[CH:15][CH:16]=2)[N:5]=1)[CH3:3]
Reactant: CCc1nn(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=N)s1
Reactant: O=C1OC(=O)C2=C1CCC2
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nn(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=NC(=O)C2=C(C(=O)O)CCC2)s1
Temperature: 25 °C
Reaction time: 72 h
Yield: 63.8 %

Procedure:
To a solution of 5-ethyl-2-imino-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3,4-thiadiazoline hydrochloride (200 mg) in N,N-dimethylformamide (3 ml) was added 1-cyclopentene-1,2-dicarboxylic anhydride (100 mg), and they were stirred at room temperature for 3 days. To the reaction mixture was added water (20 ml), and powders so precipitated were collected by filtration. The powders were washed successively with water, ethanol and diethyl ether and then dried, whereby 160 mg of the title compound was obtained.
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][CH:6]([CH2:11][C:12]([OH:14])=O)[C:7]([O:9][CH3:10])=[O:8]>ClCCl.CN(C)C=O>[Br:5][CH:6]([CH2:11][C:12]([Cl:3])=[O:14])[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)C(Br)CC(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)C(Br)CC(=O)Cl
Temperature: 25 °C
Yield: 100 %

Procedure:
Thionyl chloride (6.54 g, 54.9 mmol) in dichloromethane (7 mL) was added dropwise over 30 minutes to a mixture of 1-methyl hydrogen bromobutanedioate (i.e. the product of Step A) (10 g, 47.4 mmol) and N,N-dimethylformamide (5 drops) in dichloromethane (20 mL) heated at reflux. The mixture was heated at reflux for an additional 60 minutes and then allowed to cool to room temperature. The solvent was removed under reduced pressure to leave the title product as an oil (11 g, about 100% yield).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:14])([F:13])[C@@H:10]([OH:12])[CH3:11].Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:17]>CN(C)C1C=CN=CC=1.ClCCl>[F:8][C:9]([F:14])([F:13])[C@@H:10]([O:12][C:16](=[O:17])[O:18][C:19]1[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=1)[CH3:11]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: C[C@H](O)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reaction time: 0.5 h

Procedure:
Triethylamine (2.3 mL) is added to a solution of 4-dimethylaminopyridine (13 mg), (S)-1,1,1-trifluoro-propan-2-ol (75% in tert-butyl methyl ether; 2.00 g), and 4-nitrophenyl chloroformate (2.90 g) in dichloromethane (80 mL) chilled in an ice bath. The solution is stirred in the cooling bath for 30 min and then at room temperature overnight. The solution is washed with 10% aqueous K2CO3 solution and water and dried (MgSO4). The solvent is evaporated and the residue is chromatographed on silica gel (dichloromethane) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[CH:6]=O.Cl.NO.C[N:16](C=O)C>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[C:6]#[N:16]
Reactant: COc1cc(C=O)ccc1O
Reactant: CN(C)C=O
Agent: Cl
Agent: NO
Solvent: O
Product: COc1cc(C#N)ccc1O
Temperature: 140 °C

Procedure:
To a 3-necked 500 mL round bottom flask equipped with a mechanical stirrer and a condenser, 3-methoxy-4-hydroxy benzoaldehyde (50.2 g, 0.33 mole), hydroxylamine hydrochloride (25.5 g, 0.37 mole), and N,N′-dimethylformamide (40 mL) were successively added at 25° C., followed by heating in an oil bath at 140° C. for 1 hour. The reaction mixture was allowed to cool to 85° C., and water (250 mL) was added to yield 3-methoxy-4-hydroxybenzonitrile. The reaction mixture was further cooled to 10° C. for a complete precipitation, and the resulting solid was then isolated by filtration and dried under reduced pressure to yield a product as an off-white solid with a yield of 95% and a purity of higher than 99% as indicated by HPLC analysis.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])=[CH:3]\[CH2:4]O.N1C(C)=CC(C)=CC=1C.[Cl-].[Li+].CS([Cl:27])(=O)=O>CN(C=O)C>[Cl:27][CH2:4]/[CH:3]=[C:2](\[CH3:1])/[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10]
Reactant: CC(C)=CCC/C(C)=C/CO
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Product: CC(C)=CCC/C(C)=C/CCl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 89.4 %

Procedure:
To a stirred solution of 30.0 g (0.194 mol) of (E)-3,7-dimethyl-2,6-octadien-1-ol and 28.27 mL (0.213 mol) of 2,4,6-collidine under argon at room temperature was added dropwise 8.23 g (0.194 mol) of lithium chloride in 100 mL of DMF. The mixture was cooled to 0° C. and treated with 16.56 mL (0.213 mol) of methanesulfonyl chloride dropwise over 10 minutes. The reaction was stirred at 0° C. for 1.5 hours (solid present), then was poured into 500 mL of ice/water. The aqueous solution was washed three times with 200 mL portions of hexane, the organic layers were combined and washed with 5% KHSO4, water, NaHCO3, brine, dried (MgSO4) and evaporated to provide 29.95 g of a pale yellow oil. Rapid flash chromatography was performed on 400 g of silica gel, eluting with 3:9 EtOAc/hexane. Pure product fractions were combined and evaporated to provide 25.20 g (75%) of title compound as a pale yellow oil.
Reaction SMILES: [N:1]1([C@H:13]2[CH2:17][CH2:16][C@H:15]([NH2:18])[CH2:14]2)[C:12]2[C:4](=[CH:5][N:6]=[C:7]3[C:11]=2[CH:10]=[CH:9][NH:8]3)[N:3]=[N:2]1.[F:19][C:20]([F:26])([F:25])[CH2:21][C:22](O)=[O:23].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[F:19][C:20]([F:26])([F:25])[CH2:21][C:22]([NH:18][C@H:15]1[CH2:16][CH2:17][C@H:13]([N:1]2[C:12]3[C:4](=[CH:5][N:6]=[C:7]4[C:11]=3[CH:10]=[CH:9][NH:8]4)[N:3]=[N:2]2)[CH2:14]1)=[O:23]
Reactant: O=C(O)CC(F)(F)F
Reactant: N[C@H]1CC[C@H](n2nnc3cnc4[nH]ccc4c32)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CC(F)(F)F)N[C@H]1CC[C@H](n2nnc3cnc4[nH]ccc4c32)C1
Reaction time: 18 h
Yield: 46.2 %

Procedure:
To a stirred solution of racemic trans 3-(6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclopentylamine (120 mg, 0.49 mmol) in DMF (3 mL), 3,3,3-trifluoropropionic acid (53.0 μL, 0.60 mmol), DMAP (103 mg, 0.84 mmol), HOBt (100 mg, 0.74 mmol) and EDCI (161 mg, 0.84 mmol) were added. Stirring was continued for 18 hours at ambient temperature. The mixture was diluted with water and purified by column chromatography (SCX-2, gradient: methanol to 2M NH3 in methanol). The isolated product was triturated (DCM), washed with water and dried in vacuo at 40° C. for 18 hours affording 79.8 mg (45%) of racemic trans 3,3,3-trifluoro-N-[3-(6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclopentyl]-propionamide as a grey powder. LCMS (Method A, ESI): RT=3.14 min, m+H=353.3; 1H NMR (400 MHz, DMSO) δ: 12.37 (s, 1H), 9.00 (s, 1H), 8.53 (d, 1H), 7.61 (t, 1H), 7.00 (dd, 1H), 5.67 (m, 1H), 4.48 (m, 1H), 3.26 (q, 2H), 2.55 (m, 2H), 2.33-2.18 (m, 3H), 1.71 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:13][CH2:12][CH2:11][NH:10][CH2:9][C:8]=2[CH:14]=1)([O-])=O.O.NN>C(O)C.[Pd]>[CH:14]1[C:8]2[CH2:9][NH:10][CH2:11][CH2:12][S:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:1]
Reactant: O=[N+]([O-])c1ccc2c(c1)CNCCS2
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(c1)CNCCS2
Yield: 89.7 %

Procedure:
To a mixture of 2-nitro 6,7,8,9-tetrahydro-5-thia-8-aza-benzocycloheptene (1.0 g, 0.0047 mol), hydrazine hydrate (10 mL) in ethanol (40 mL) was added 10% palladium on carbon (0.2 g) and refluxed 3 days, filtered and concentrated to give 6,7,8,9-tetrahydro-5-thia-8-aza-benzocyclohepten-2-ylamine (0.76 g, 90%) as a yellow solid. MP: 110-111° C.; 1H-NMR (DMSO-d6) δ 7.08-15 (d, 1H), 6.45 (s, 1H), 6.25-33 (d, 1H), 5.15 (s, 2H), 3.78 (s, 2H), 3.10-20 (m, 2H), 2.50-60 (m, 2H), 2.00-22 (br, 1H); LC/MS (ESI+): 181 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:13])=[N:7]2.[Br:14][C:15]1[C:25]([Br:26])=[C:24]([Br:27])[C:23]([Br:28])=[C:17]2[C:18]([O:20][C:21](=O)[C:16]=12)=[O:19]>ClC1C(Cl)=C(Cl)C=CC=1>[CH3:12][C:9]1[CH:10]=[CH:11][C:2]([N:1]2[C:21](=[O:20])[C:16]3=[C:15]([Br:14])[C:25]([Br:26])=[C:24]([Br:27])[C:23]([Br:28])=[C:17]3[C:18]2=[O:19])=[C:3]2[C:8]=1[N:7]=[C:6]([CH3:13])[CH:5]=[CH:4]2
Reactant: Cc1ccc2c(N)ccc(C)c2n1
Reactant: O=C1OC(=O)c2c(Br)c(Br)c(Br)c(Br)c21
Agent: Clc1cccc(Cl)c1Cl
Product: Cc1ccc2c(N3C(=O)c4c(Br)c(Br)c(Br)c(Br)c4C3=O)ccc(C)c2n1
Yield: 86 %

Procedure:
172 g (1.0 mole) of 5-amino-8-methylquinaldine and 464 g (1.0 mole) of 3,4,5,6-tetrabromophthalic anhydride were reacted in 2,000 g of trichlorobenzene for 2 hours under reflux to afford 532 g (0.86 mole) of 8-methyl-5-(3,4,5,6-tetrabromophthalimido)-quinaldine. 369 g (1.29 moles) of tetrachlorophthalic anhydride and 2,000 g of α-chloronaphthalene were added, and the mixture was reacted for 2 hours under reflux. The product was collected by hot filtration at 120° C., and dispersed in 1,000 g of α-chloronaphthalene, and the mixture was heated with stirring to wash the product. After hot filtration, the product was washed with ethanol and dried to afford 671 g (0.75 mole) of a yellow compound.
Reaction SMILES: C1(COC2C(C3N(CC4C=CC(CCC(O)=O)=CC=4)C4C=C(F)C(F)=CC=4N=3)=CC=CN=2)CC1.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[N:46]([CH2:47][CH:48]3[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]3)[C:45]3[CH:54]=[C:55]([F:59])[C:56]([F:58])=[CH:57][C:44]=3[N:43]=2)=[C:38]([O:60][CH2:61]C2C=CC=CC=2Cl)[CH:37]=1.BrCC1C=CC=C([Cl:77])C=1>>[Cl:77][C:50]1[CH:49]=[C:48]([CH:53]=[CH:52][CH:51]=1)[CH2:47][N:46]1[C:45]2[CH:54]=[C:55]([F:59])[C:56]([F:58])=[CH:57][C:44]=2[N:43]=[C:42]1[C:39]1[CH:40]=[CH:41][C:36]([Cl:35])=[CH:37][C:38]=1[O:60][CH3:61]
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3OCc3ccccc3Cl)n(CC3CCCCC3)c2cc1F
Reactant: Clc1cccc(CBr)c1
Agent: O=C(O)CCc1ccc(Cn2c(-c3cccnc3OCC3CC3)nc3cc(F)c(F)cc32)cc1
Product: COc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1Cc1cccc(Cl)c1

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 2-(4-chloro-2-methoxy-phenyl)-5,6-difluoro-1H-benzoimidazole (Example 19, intermediate c) and 1-bromomethyl-3-chloro-benzene (CAS Reg. No. 766-80-3). Brown sticky solid (95%). MS (Turbo Spray): m/z=419.2 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[NH:9][C:10]1[C:15]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][N:17]=2)=[CH:14][CH:13]=[CH:12][N:11]=1.N1C=CC=CC=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>C(Cl)Cl>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([NH:9][C:10]3[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][N:17]=4)=[CH:14][CH:13]=[CH:12][N:11]=3)[CH:4]=2)(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: Cc1ccc(N)cc1Nc1ncccc1-c1ccncn1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(NS(=O)(=O)c2ccc(Cl)cc2)cc1Nc1ncccc1-c1ccncn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-methyl-N3-(3-pyrimidin-4-yl-pyridin-2-yl)-benzene-1,3-diamine (40 mg, 0.14 mmol) in CH2Cl2 (2.5 mL) was added pyridine (0.012 mL, 0.14 mmol) and 4-chlorobenzenesulfonyl chloride (30 mg, 0.14 mmol). The mixture was stirred overnight at RT, concentrated and purified by flash chromatography (0→50% EtOAc/n-Hexanes) to yield 4-chloro-N-(4-methyl-3-((3-(4-pyrimidinyl)-2-pyridinyl)amino)phenyl)benzenesulfonamide. MS m/z=452 [M+1]+. Calc'd for C22H18ClN5O2S: 451.94.
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:14])[CH:11]=2)[C:6]1=[O:15]>CN(C)C=O.O>[C:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:14])[CH:11]=2)[C:6]1=[O:15])#[N:2]
Reactant: O=C1c2ccc(Cl)cc2CC1Cl
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC1Cc2cc(Cl)ccc2C1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
10.4 g of sodium cyanide were dissolved in a mixture of 100 ml of dimethylformamide and 6 ml of water and initially charged. This solution was heated with stirring to 50° C., and 20.4 g of 2,5-dichloroindan-1-one, dissolved in 100 ml of dimethylformamide, were then added dropwise over a period of 60 minutes. After the addition had ended, stirring was continued at 50° C. for 1 hour. The mixture was then allowed to cool to room temperature and the solvent was stripped off using a rotary evaporator. The resulting crystal slurry was mixed with 200 ml of water and acidified to pH 4.5 using 10% by weight strength aqueous hydrochloric acid. The precipitated solid was filtered off with suction, washed with water, recrystallized from toluene and dried in a vacuum drying cabinet. This gave 18.5 g of 2-cyano-5-chloroindan-1-one (yield: 97% of theory).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].CO.Cl[C:8]1[N:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=3)[CH2:16][CH2:15]2)=[CH:12][CH:13]=1>O>[CH3:1][O:2][C:8]1[N:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=3)[CH2:16][CH2:15]2)=[CH:12][CH:13]=1
Reactant: C[O-]
Reactant: Cc1cccc(N2CCN(c3ccc(Cl)nn3)CC2)c1
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CO
Product: COc1ccc(N2CCN(c3cccc(C)c3)CC2)nn1
Yield: 50 %

Procedure:
To a stirred sodium methoxide solution, previously prepared starting from 1.6 parts of sodium in 24 parts of methanol, were added 4 parts of 3-chloro-6-[4-(3-methylphenyl)-1-piperazinyl]pyridazine. The whole was stirred and refluxed for 40 hours. After cooling 25 parts of water were added. The product was filtered off, washed with water and dissolved in trichloromethane. The organic layer was dried, filtered and evaporated. The residue was crystallized from a mixture of 2-propanol and 2,2'-oxybispropane. The product was filtered off and dried, yielding 2 parts (50%) of 3-methoxy-6-[4-(3-methylphenyl)-1-piperazinyl]pyridazine; mp. 137.1° C. (compound 258).
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[CH2:6]([N:16]1[C:22]([CH3:24])([CH3:23])[C:20](=[O:21])[NH:19][C:17]1=[O:18])[N:7]1[C:13]([CH3:15])([CH3:14])[C:11](=[O:12])[NH:10][C:8]1=[O:9].C=O.[CH3:27][C:28]1(C)NC(=O)N[C:29]1=[O:34]>>[CH2:6]([N:7]1[C:13]([CH3:15])([CH3:14])[C:11](=[O:12])[N:10]([CH2:27][CH:28]2[O:34][CH2:29]2)[C:8]1=[O:9])[N:16]1[C:22]([CH3:24])([CH3:23])[C:20](=[O:21])[N:19]([CH2:1][CH:3]2[O:5][CH2:4]2)[C:17]1=[O:18].[CH2:6]([N:7]1[C:13]([CH3:15])([CH3:14])[C:11](=[O:12])[NH:10][C:8]1=[O:9])[N:16]1[C:22]([CH3:24])([CH3:23])[C:20](=[O:21])[NH:19][C:17]1=[O:18]
Reactant: ClCC1CO1
Reactant: CC1(C)NC(=O)NC1=O
Agent: C=O
Agent: CC1(C)C(=O)NC(=O)N1CN1C(=O)NC(=O)C1(C)C
Product: CC1(C)C(=O)N(CC2CO2)C(=O)N1CN1C(=O)N(CC2CO2)C(=O)C1(C)C

Procedure:
1,1'-Methylene-bis[3-glycidyl-5,5-dimethylhydantoin] is prepared by the reaction of epichlorohydrin and 1,1'-methylene-bis[5,5-dimethylhydantoin] according to Example 1 of U.S. Pat. No. 3,592,923. 1,1'-Methylene-bis[5,5-dimethylhydantoin] is prepared by the general procedure of Example I of U.S. Pat. No. 3,793,248 using paraformaldehyde and 5,5-dimethylhydantoin.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[OH:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([NH:25][NH2:26])=[O:24].ClC1C(C)=C(N[C@H]([C@@H](O)C)C(NNC(=O)C2C=CC=CC=2)=O)C=CC=1C#N>CO.CCOC(C)=O>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([NH:26][NH:25][C:23](=[O:24])[C:22]2[CH:27]=[CH:28][CH:29]=[C:20]([OH:19])[CH:21]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: NNC(=O)c1cccc(O)c1
Reactant: Cc1c(N[C@@H](C(=O)O)[C@@H](C)O)ccc(C#N)c1Cl
Agent: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccccc2)[C@H](C)O)ccc(C#N)c1Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2cccc(O)c2)[C@@H](C)O)ccc(C#N)c1Cl

Procedure:
(2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (663 mg, 2.5 mmol) (intermediate 3a) and 3-hydroxy-benzohydrazide (376 mg, 2.5 mmol) were coupled similarly to the procedure used for intermediate 1b. After column chromatography (5% methanol/EtOAc) the title compound was isolated as a white solid (615 mg, 62%). 1H NMR (500 MHz, acetone-d6, δ in ppm) 9.79 (br s, 1H), 8.81 (br s, 1H), 7.45 (ad, J=8.7 Hz, 1H), 7.38 (m, 2H), 7.27 (t, J=7.87 Hz, 1H), 7.02 (m, 1H), 6.71 (d, J=8.7 Hz, 1H), 5.61 (m, 1H), 4.23 (m, 1H), 4.14 (m, 1H), 2.29 (s, 3H), 1.37 (d, J=6.5 Hz, 3H).