Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])/[C:16]/3=[CH:23]\[C:24]2[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=2[CH3:33])(=[O:12])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[N:34]1([CH2:39][C@@H:40]2[CH2:44][CH2:43][CH2:42][NH:41]2)[CH2:38][CH2:37][CH2:36][CH2:35]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>>[Cl:8][C:6]1[CH:5]=[C:4]([CH2:9][S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])/[C:16]/3=[CH:23]\[C:24]2[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:41]3[CH2:42][CH2:43][CH2:44][C@H:40]3[CH2:39][N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:32])[C:25]=2[CH3:33])(=[O:11])=[O:12])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cc(Cl)cc(Cl)c4)cc32)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cc(Cl)cc(Cl)c4)cc32)c(C)c1C(=O)N1CCC[C@H]1CN1CCCC1

Procedure:
5-[5-(3,5-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (120 mg, 0.24 mmol) was coupled with (S)-2-pyrrolidin-1-ylmethyl-pyrrolidine (40 mg, 1.2 eq.) using HOBt (1.2 eq.), EDAC.HCl (1.2 eq.) and TEA (3 eq.) at rt for 2 days to give the titled compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]([CH3:29])[C:26]([CH2:30][O:31][CH:32]2[CH2:35][N:34]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:33]2)=[CH:25][CH:24]=1>>[NH2:9][C:7]([C:6]1[CH:5]=[C:4]([C:10]2[C:11]([F:21])=[CH:12][C:13]([C:17]([OH:20])([CH3:18])[CH3:19])=[CH:14][C:15]=2[F:16])[S:3][C:2]=1[NH:1][C:23]1[N:28]=[C:27]([CH3:29])[C:26]([CH2:30][O:31][CH:32]2[CH2:35][N:34]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:33]2)=[CH:25][CH:24]=1)=[O:8]
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: Cc1nc(Cl)ccc1COC1CN(C(=O)OC(C)(C)C)C1
Product: Cc1nc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)ccc1COC1CN(C(=O)OC(C)(C)C)C1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.48 mmol) and tert-butyl 3-[(6-chloro-2-methylpyridin-3-yl)methoxy]azetidine-1-carboxylate (150 mg, 0.48 mmol) as starting materials.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[C:3]=1[CH3:19].[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:32]=[CH:31][C:30]([C:33]3[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=3)=[CH:29][C:27]=2[NH2:28])[CH2:22][CH2:21]1.Cl.O1CCOCC1>CN1C(=O)CCC1>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:4]1[C:3]([CH3:19])=[C:2]([NH:28][C:27]2[CH:29]=[C:30]([C:33]3[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=3)[CH:31]=[CH:32][C:26]=2[N:23]2[CH2:24][CH2:25][O:20][CH2:21][CH2:22]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1c(-c2ccccc2F)nc2ccccc2c1Cl
Reactant: Nc1cc(-c2cccnc2)ccc1N1CCOCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1c(-c2ccccc2F)nc2ccccc2c1Nc1cc(-c2cccnc2)ccc1N1CCOCC1

Procedure:
Prepared according to general Procedure K using 4-chloro-2-(2-fluorophenyl)-3-methylquinoline (64 mg, 0.23 mmol), 2-morpholino-5-(pyridin-3-yl)aniline (60 mg, 0.23 mmol) and a 4.0M solution of HCl in dioxane (0.06 mL, 0.23 mmol) in NMP (1.0 mL) and heating in the microwave for 2 h at 150° C. After purification 2-(2-fluorophenyl)-3-methyl-N-(2-(4-morpholinyl)-5-(3-pyridinyl)phenyl)-4-quinolinamine was obtained. 1H NMR (400 MHz, chloroform-d) δ ppm 8.49 (1H, dd, J=4.7, 1.6 Hz), 8.19 (1H, d, J=8.2 Hz), 7.92 (1H, d, J=8.2 Hz), 7.59-7.76 (4H, m), 7.54 (1H, d, J=7.4 Hz), 7.47 (1H, d, J=8.2 Hz), 7.31-7.36 (1H, m), 7.10-7.24 (4H, m), 6.65 (1H, br. s.), 3.97 (4H, t, J=4.7 Hz), 3.09-3.30 (4H, m), 2.26 (3H, d, J=2.3 Hz). Mass Spectrum (ESI) m/e=491.0 (M+1).
Reaction SMILES: [C:1]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([F:24])[CH:13]=1)([O:3][CH2:4][C:5]1C=CC=CC=1)=[O:2].C([Li])(C)(C)C.ClC[C@@H](O)[CH2:33][N:34]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[Cl-].[NH4+]>C(OCC)(=O)C.CO>[CH2:42]([N:34]([CH2:33][C@@H:4]1[O:3][C:1](=[O:2])[N:11]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[C:14]([F:24])[CH:13]=2)[CH2:5]1)[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O[C@H](CCl)CN(Cc1ccccc1)Cc1ccccc1
Reactant: O=C(Nc1ccc(N2CCOCC2)c(F)c1)OCc1ccccc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1O[C@@H](CN(Cc2ccccc2)Cc2ccccc2)CN1c1ccc(N2CCOCC2)c(F)c1
Temperature: -30 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
N-carbobenzoxy-3-fluoro-4-morpholinylaniline (0.33 g, 1 mmol) was added to 8 mL of methanol. The solution was cooled to −30° C. under the protection of nitrogen flow and then the methanol solution containing 1 mmol of tert-butyl lithium was added. The mixture was stirred at −78° C.˜−20° C. for 2 hours. (S)-1-chloro-3-(dibenzylamino)propan-2-ol (0.29 g, 1 mmol) was added and then the mixture was heated slowly to 100° C. and stirred for 2 hours. After the solution was cooled down, saturated ammonium chloride solution and ethyl acetate were added to separate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness to provide 0.31 g of white solid in 65% yield. HPLC: 99.2%.
Reaction SMILES: S(Cl)([Cl:3])=O.[O:5]=[C:6]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[O:9][C:8]2[CH:16]=[CH:17][C:18]([C:20]([O-:22])=O)=[CH:19][C:7]1=2.[Na+]>C(Cl)(Cl)(Cl)Cl>[O:5]=[C:6]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[O:9][C:8]2[CH:16]=[CH:17][C:18]([C:20]([Cl:3])=[O:22])=[CH:19][C:7]1=2
Reactant: O=S(Cl)Cl
Reactant: O=C([O-])c1ccc2oc3ncccc3c(=O)c2c1
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(Cl)c1ccc2oc3ncccc3c(=O)c2c1

Procedure:
2.5 g of thionyl chloride is added to a suspension of 4.5 g of sodium 5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-7-carboxylate in 35 ml of carbon tetrachloride with stirring, and the mixture is stirred under reflux for 3 hours. After cooling, the crystals are filtered off, washed with cool water and then with acetone, and dried to give 5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-7-carboxylic acid chloride melting at 234°-235°C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:23][C:24]([O:26]C)=[O:25]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([CH2:23][C:24]([OH:26])=[O:25])[C:15]2[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CBr
Reactant: Cc1ccc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cn1
Product: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cn1

Procedure:
prepared by reaction of 4-tert-butyl-N-(6-methyl-pyridin-3-yl)-benzenesulfonamide with methyl bromoacetate
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([CH3:23])[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[C:25]1([C:31]2[O:32][C:33]([CH3:49])=[C:34]([CH2:36][CH2:37]OS(C3C=CC(C)=CC=3)(=O)=O)[N:35]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:23][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[CH3:22])[O:15][C:5]([CH3:14])([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:37][CH2:36][C:34]2[N:35]=[C:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:32][C:33]=2[CH3:49])=[CH:9][CH:8]=1)[C:4]([OH:3])=[O:24]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C)c(C)c1
Product: Cc1ccc(OC(C)(Cc2ccc(OCCc3nc(-c4ccccc4)oc3C)cc2)C(=O)O)cc1C

Procedure:
The representative parallel synthesis procedure (B) was used to prepare the title compound from 2-(3,4-dimethyl-phenoxy)-3-(4-hydroxyphenyl)-2-methylpropionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-phenyl-5-methyl-oxazol-4-yl)-ethyl ester. 1H NMR (400 MHz, CDCl3) δ 8.01-7.99 (m, 2H), 7.48-7.46 (m, 3H), 7.18 (d, 2H, J=8.8 Hz), 6.99 (d, 1H, J=8.4 Hz), 6.82 (d, 2H, J=8.4 Hz), 6.70 (d, 1H, J=2.0 Hz), 6.63 (dd, 1H, J=8.4, 2.0 Hz), 6.28 (bs, 1H), 4.22 (t, 2H, J=6.4 Hz), 3.22 and 3.11 (d of Abq, 2H, J=13.6 Hz), 3.06 (t, 2H, J=6.4 Hz), 2.42 (s, 3H), 2.19 (s, 3H), 2.18 (s, 3H), 1.39 (s, 3H). IR (KBr) 3100, 2950, 1772, 1611, 1512, 1177 cm−1. HRMS (ES+) m/z exact mass calcd for C30H32NO5 486.2280, found 486.2295.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:12]=[N:13][C:14]([SH:17])=[N:15][CH:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH2:28][CH:27]([CH2:31][NH:32][C:33](=[O:36])[CH2:34]Cl)[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH2:28][CH:27]([CH2:31][NH:32][C:33](=[O:36])[CH2:34][S:17][C:14]2[N:13]=[CH:12][C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:16][N:15]=2)[CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: COc1ccc(-c2cnc(S)nc2)cc1OC
Reactant: CC(C)(C)OC(=O)N1CCCC(CNC(=O)CCl)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(-c2cnc(SCC(=O)NCC3CCCN(C(=O)OC(C)(C)C)C3)nc2)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
5-(3,4-Dimethoxy-phenyl)-pyrimidine-2-thiol 1f (0.75 g, 3 mmol) was added to a solution of the 2-chloroacetamide 1d (1.3 g, ˜80% purity, ˜3.6 mmol, obtained from step 3) and diisopropylethylamine (0.78 mL, 4.5 mmol, 1.5 equiv) in dry CH2Cl2. The resulting suspension was stirred at rt for about 2 h, at which time the reaction mixture became a dark brown solution and all the solid disappeared. The mixture was then concentrated and chromatographed on silica gel (ethyl acetate). The fractions containing the major product were combined and concentrated to an oily residue. Trituration of the oil with ether afforded 3-({2-[5-(3,4-dimethoxy-phenyl)-pyrimidin-2-ylsulfanyl]-acetylamino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester 1g (0.83 g, 55%) as a dark brown solid.
Reaction SMILES: C(OC([NH:8][CH:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:24][CH:23]=3)[C:18]2=[O:34])=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][CH:9]([C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:27]=3)[C:18]2=[O:34])=[CH:15][CH:16]=1)[CH3:10]
Reactant: COC(=O)CCc1ccc(C2CCN(c3ccc(C(C)NC(=O)OC(C)(C)C)cc3)C2=O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCc1ccc(C2CCN(c3ccc(C(C)N)cc3)C2=O)cc1

Procedure:
Prepared from 1-[4-[1-[(tert.butyloxycarbonyl)-amino]ethyl]-phenyl]-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-pyrrolidin-2-one by stirring for 2 hours in a 1:1 mixture of methylene chloride and trifluoroacetic acid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[C:10]([CH3:17])[CH:9]=1.CN(C=O)C.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>ClCCl>[Br:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:14])=[C:10]([CH3:17])[CH:9]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: C1COCCN1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(Br)ccc1C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 10.6 ml (47 mmol) oxalyl chloride in 30 ml dichloromethane is added dropwise to a iced-cooled solution of 5.21 g (23.5 mmol) 4-bromo-2-methyl-benzoic acid and 0.0087 ml DMF in 100 ml CH2Cl2. After complete addition, the cooling bath is removed and stirring maintained for 2 h at RT. The solvent is evaporated to dryness and the residue is dried in vacuo and dissolved in 100 ml dichloromethane and 8.21 ml N-ethyl-diisopropylamine is added. To this solution 2.5 ml (28 mmol) morpholine is added slowly. Stirring is continued for 0.5 h, then the reaction mixture is poured on water and extracted 3× with EtOAc. The combined organic layers are washed with water and saturated NaCl solution, dried over MgSO4, filtered and the filtrate is concentrated in vacuo to afford the title compound which is used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:25][C:26]1[NH:27][C:28]2[C:33]([C:34]=1[CH3:35])=[CH:32][C:31]([OH:36])=[CH:30][CH:29]=2>>[C:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)[N:5]=[CH:4][CH:3]=[C:2]2[O:36][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([CH3:25])=[C:34]2[CH3:35])#[N:13]
Reactant: Cc1[nH]c2ccc(O)cc2c1C
Reactant: CN1CCN(CCCOc2cc3nccc(Cl)c3cc2C#N)CC1
Product: Cc1[nH]c2ccc(Oc3ccnc4cc(OCCCN5CCN(C)CC5)c(C#N)cc34)cc2c1C
Yield: 70.7 %

Procedure:
Using an analogous procedure to that described in Example 20, 4-chloro-6-cyano-7-(3-(4methylpiperazin-1-yl)propoxy)quinoline (150 mg, 0.44 mmol), (prepared as described for the starting material in Example 12), was reacted with 2,3-dimethyl-5-hydroxyindole (84 mg, 0.52 mmol), (Arch. Pharm. 1972, 305, 159), to give 6-cyano-4-(2,3-dimethylindol-5-yloxy)-7-(3-(4-methylpiperazin-1-yl)propoxy)quinoline (146 mg, 60%).
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:17]=[C:18]([CH2:22][C:23]([OH:25])=O)[CH:19]=[CH:20][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(Cl)(=O)C([Cl:29])=O>C(Cl)Cl.CN(C)C=O>[CH2:1]([O:15][C:16]1[CH:17]=[C:18]([CH2:22][C:23]([Cl:29])=[O:25])[CH:19]=[CH:20][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCCCCCCCCCCOc1cccc(CC(=O)O)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCOc1cccc(CC(=O)Cl)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 101.1 %

Procedure:
A mixture of 20 g of m-tetradecyloxyphenylacetic acid, 10.93 g of oxalyl chloride and 41.95 mg of N,N-dimethylformamide in 250 ml of methylene chloride is stirred at ambient temperature for 5 hours. The solvent is removed and the concentrate dissolved in 1:1 ether:hexane and filtered through diatomaceous earth. The filtrate is evaporated to give 21.3 g of the desired product as a light yellow solid.
Reaction SMILES: Cl.Cl.[N:3]1([C:8]2[CH:9]=[C:10]([NH:14][C:15]([NH2:17])=[NH:16])[CH:11]=[CH:12][CH:13]=2)[CH:7]=[CH:6][N:5]=[CH:4]1.CN(C)[CH:20]=[C:21](C)[C:22]([C:24]1[O:25][CH:26]=[CH:27][CH:28]=1)=O.[OH-].[Na+]>C(O)CC>[O:25]1[CH:26]=[CH:27][CH:28]=[C:24]1[C:22]1[CH:21]=[CH:20][N:17]=[C:15]([NH:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([N:3]3[CH:7]=[CH:6][N:5]=[CH:4]3)[CH:9]=2)[N:16]=1
Reactant: N=C(N)Nc1cccc(-n2ccnc2)c1
Reactant: CC(=CN(C)C)C(=O)c1ccco1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCO
Product: c1cc(Nc2nccc(-c3ccco3)n2)cc(-n2ccnc2)c1
Yield: 44.5 %

Procedure:
Two and 73 hundredths grams of [3-(1H-imidazol-1-yl)phenyl]guanidine, dihydrochloride (2) from Example 1, 1.6 grams of 3-dimethylamino-1-(2-furyl)-2-methyl-2-propen-1-one, 25 ml of n-propanol and 2 equivalents (2 ml) of 10N NaOH at pH=11 is refluxed for twenty-four (24) hours. The products are isolated by quenching the reaction mixture including any precipitated solids into water followed by filtration. These filtered solids are re-suspended in water to remove inorganic salts, filtered and air dried to give 1.35 g (44.5% yield) of the desired product, mp 175°-178° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[N:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2Cl.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH3:27])([CH3:26])[C:24]#[N:25])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[N:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2[NH:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([CH3:27])([CH3:26])[C:24]#[N:25])=[CH:21][CH:22]=1
Reactant: CC(C)(C#N)c1ccc(N)cc1
Reactant: O=[N+]([O-])c1nnc2ccc(Br)cc2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C#N)c1ccc(Nc2c([N+](=O)[O-])nnc3ccc(Br)cc23)cc1
Yield: 99.9 %

Procedure:
A yellow suspension of 6-bromo-4-chloro-3-nitrocinnoline (1.75 g, 6.07 mmol), 2-(4-aminophenyl)-2-methylpropanenitrile (1.069 g, 6.67 mmol) and K2CO3 (1.677 g, 12.13 mmol) in MeCN (2 mL) was heated to reflux for 5 min. The workup followed general workup procedures, and the crude was purified on silica gel with PE/EtOAc as eluant to give 2-(4-(6-bromo-3-nitrocinnolin-4-ylamino)phenyl)-2-methylpropanenitrile as yellow solid (2.5 g, yield 100%). MS (m/z): 414 (M+H)+.
Reaction SMILES: [CH3:1][C:2](=[O:23])[C@@H:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2([CH3:16])[C@H:10]([CH2:11][C:12](=[O:22])[CH2:13][CH2:14]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.[CH3:24][Mg]Cl>COC(C)(C)C>[CH3:1][C:2]([C@@H:3]1[C@@:20]2([CH3:21])[CH2:19][CH2:18][C@@H:17]3[C@@:15]4([CH3:16])[CH2:14][CH2:13][C@:12]([OH:22])([CH3:24])[CH2:11][C@@H:10]4[CH2:9][CH2:8][C@H:7]3[C@@H:6]2[CH2:5][CH2:4]1)=[O:23]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: C[Mg]Cl
Solvent: COC(C)(C)C
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@](C)(O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 6 h

Procedure:
5α-Pregnane 3,20-dione (10 g) is reacted with a reagent obtained by reacting FeCl3 (5.2 g) and MeMgCl (4 equiv, based on FeCl3) in t-butyl methyl ether (anhydrous, 200 mf) at −25° C. for 3h. The reaction is quenched with acetic acid (32 ml). The reaction mixture is concentrated in vacuo and the residue is stirred with 3N HCI for 6 h. The solid is collected by filtration, washed with water and dried at 50° C. under vacuum to obtain crude ganaxolone. The crude product is dissolved in THF (33 mL) at reflux and filtered not. The filtrate is added with water (45 mL) to obtain a suspension, which is collected by filtration, washed with water and dried. The dried product is further slurried in ethyl acetate (50 mL) at 70° C. for 19 h, The suspension is cooled to 0° C. and filtered. The ethyl acetate slurry step was repeated second time to obtain purified ganaxolone.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([OH:9])=[C:4]([CH2:10][CH3:11])[N:3]=1.O.[OH-].[Li+].[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][CH:20]=[C:19]2[O:26][CH2:27][CH2:28][CH2:29]Br.ClCCl>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][CH2:29][CH2:28][CH2:27][O:26][C:19]2[C:18]3[C:23](=[CH:24][CH:25]=[C:16]([Cl:15])[CH:17]=3)[N:22]=[CH:21][CH:20]=2)=[C:4]([CH2:10][CH3:11])[N:3]=1
Reactant: Clc1ccc2nccc(OCCCBr)c2c1
Reactant: CCc1nc(N)nc(N)c1O
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CCc1nc(N)nc(N)c1OCCCOc1ccnc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
2,4-Diamino-6-ethyl-5-hydroxypyrimidine (1.39 g, 9 mmol) was added to a stirred solution of lithium hydroxide monohydrate (1.32 g, 31.50 mmol) in DMF (5 mL) and the reaction mixture was stirred at 25° C. for 1 hour. A solution of 3-(6-chloroquinolin-4-yloxy)propyl bromide (2.71 g, 9 mmol) in DMF (3 mL) was added and the reaction mixture was left stirring at 25° C. overnight. DMF was partially removed under reduced pressure to give residue. The residue was digested with dichloromethane and filtered to give white solid. Recrystallization with aqueous methanol and hot water afforded the desired diaminopyrimidine as white solid (1.85 g, 55%, m.p. 230-231° C. (dec.)). 1H NMR (500 MHz, DMSO-d6): 0.91 (3H, t, J=7.6 Hz), 2.26 (2H, q, J=7.6 Hz), 2.31 (2H, m), 3.86 (2H, t, J=6 Hz), 4.45 (2H, t, J=5.9 Hz), 5.59 (2H, s), 6.17, (2H, s), 7.15 (1H, d, J=5.3 Hz), 7.76 (1H, dd, J=9.0, 2.4 Hz), 7.98 (1H, d, J=9.0 Hz), 8.14 (1H, d, J=2.4 Hz), 8.77 (1H, d, J=5.2 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:33]=1)[O:7][CH2:8][C:9]1[CH:19]=[C:18]([CH2:20][N:21]3[C:25]4[CH:26]=[CH:27][CH:28]=[C:29]([OH:30])[C:24]=4[N:23]=[C:22]3[CH2:31][OH:32])[CH:17]=[CH:16][C:10]=1/[C:11]/2=[C:12](/[CH3:15])\[C:13]#[N:14].[CH2:34](O)[CH3:35]>>[CH2:34]([O:30][C:29]1[C:24]2[N:23]=[C:22]([CH2:31][OH:32])[N:21]([CH2:20][C:18]3[CH:17]=[CH:16][C:10]4/[C:11](=[C:12](/[CH3:15])\[C:13]#[N:14])/[C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:33][C:6]=5[O:7][CH2:8][C:9]=4[CH:19]=3)[C:25]=2[CH:26]=[CH:27][CH:28]=1)[CH3:35]
Reactant: CCO
Reactant: C/C(C#N)=C1/c2ccc(Cn3c(CO)nc4c(O)cccc43)cc2COc2cc(F)ccc21
Product: CCOc1cccc2c1nc(CO)n2Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Yield: 49.5 %

Procedure:
[step 1] Using (E)-2-(3-fluoro-8-{[4-hydroxy-2-(hydroxymethyl)-1H-benzo[d]imidazol-1-yl]methyl}dibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (201 mg, 0.46 mmol) obtained in Reference Example 2A, step 4, and ethanol (0.27 mL, 4.55 mmol) instead of deuterated methanol, and in the same manner as in Reference Example 2A, step 5, (E)-2-(8-{[4-ethoxy-2-(hydroxymethyl)-1H-benzo[d]imidazol-1-yl]methyl}-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (107 mg, 50%) was obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH:19]=O)=[C:9]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])[C:10]=1[CH3:11])=[O:5])C.[CH3:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][C:25](=[O:31])[NH:26]2.[OH-].[K+]>N1CCCCC1.C(O)C>[C:14]([CH2:13][CH2:12][C:9]1[C:10]([CH3:11])=[C:6]([C:4]([OH:3])=[O:5])[NH:7][C:8]=1[CH:19]=[C:24]1[C:23]2[C:27](=[CH:28][CH:29]=[CH:30][C:22]=2[CH3:21])[NH:26][C:25]1=[O:31])([OH:16])=[O:15]
Reactant: CCOC(=O)CCc1c(C=O)[nH]c(C(=O)OCC)c1C
Reactant: Cc1cccc2c1CC(=O)N2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cccc2c1C(=Cc1[nH]c(C(=O)O)c(C)c1CCC(=O)O)C(=O)N2
Temperature: 90 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
A mixture of 5-formyl-4-(2-ethoxycarbonylethyl)-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (281 mg), 4-methyl-2-oxindole (147 mg) and piperidine (2 drops) in ethanol (2 mL) was stirred at 90° C. for 2 hours. Potassium hydroxide (213 mg) was added, the temperature was increased to 95° C. and held there for 1 hour. The reaction mixture was cooled and concentrated. The residue was dissolved into water and acidified with 2 N hydrochloric acid to pH 2. The precipitate was filtered, washed with water and dried in a vacuum oven overnight to give 337 mg (95%) of 4-(2-carboxyethyl)-3-methyl-5-(4-methyl-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: N1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][N:7]=2)=[N:4][N:3]=N1.N1C=CC=CC=1.[C:19](OCC)(=[O:21])[CH3:20]>C(OC(=O)C)(=O)C>[CH3:20][C:19]1[O:21][C:5]([C:6]2[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][N:7]=2)=[N:4][N:3]=1
Reactant: Brc1ccc(-c2nnn[nH]2)nc1
Reactant: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: Cc1nnc(-c2ccc(Br)cn2)o1
Reaction time: 3 h
Yield: 80 %

Procedure:
In 130 ml of acetic anhydride was dissolved 8.6 g of 2-(tetrazol-5-yl)-5-bromopyridine prepared in the Preparation example 6. And then the solution was added with 15 ml of pyridine and stirred for 3 hours for reaction. The reaction mixture was added with ethyl acetate and extracted to separate organic layer. And then the organic layer was washed with water and brine. The organic layer was dehydrated, filtrated and concentrated in vacuo to give 7.3 g of the title compound. Yield 80%.