Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:22]=[CH:21][C:10]([CH:11](CO)[O:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)=[CH:9][C:8]=2[CH3:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:24](O)C>[C].[Pd]>[CH2:1]([C:7]1[CH:22]=[CH:21][C:10]([CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)=[CH:9][C:8]=1[CH3:23])[C:6]1[CH:24]=[CH:2][CH:3]=[CH:4][CH:5]=1
Reactant: CCO
Reactant: Cc1cc(C(CO)OC2CCCCO2)ccc1-c1ccccc1
Agent: [Pd]
Product: Cc1cc(COC2CCCCO2)ccc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
2-(4-Phenylhydroxymethyl-3-methylbenzyloxy)tetrahydropyran (2.5 g, 8 millimol) was dissolved in ethanol (20 ml). 5%-palladium carbon was added at a catalytic amount, and stirred at room temperature under hydrogen atmosphere for 6 days. After the insoluble material was distilled away, the filtrate was concentrated, and the residue was separated and purified by using a silica-gel column chromatography (ethyl acetatee:n-hexane=1:3) to give the title compound (1.65 g, 5.6 millimol).
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[Na].[CH:6]1([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:26])=[C:16]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[C:17]=3F)[C:12](=[O:27])[C:11]([C:28]([OH:30])=[O:29])=[CH:10]2)[CH2:8][CH2:7]1>C(O)C>[CH:6]1([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:26])=[C:16]([N:20]4[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]4)[C:17]=3[O:1][CH2:2][CH3:3])[C:12](=[O:27])[C:11]([C:28]([OH:30])=[O:29])=[CH:10]2)[CH2:7][CH2:8]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCNCC3)c(F)cc2c1=O
Reactant: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOc1c(N2CCNCC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reaction time: 52 h

Procedure:
To a solution of sodium ethoxide prepare from sodium (0.75 g) and absolute ethanol (30 ml) was added 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid (0.8 g) and the mixture in sealed tube was stirred for 52 hours at 140° to 150° C. and then concentrated. Water (60 ml) was added to the residue, and the solution was adjusted pH 7 with acetic acid and extracted with chloroform. The chloroform layer was washed with saturated saline solution, dried over anhydrous sodium sulfate and then concentrated. The resulting residue was purified by silica gel column chromatography eluting with chloroform-methanol (2:1) → chloroform-methanol-concentrated aqueous ammonia (20:6:1 → 10:10:1) and recrystallized from ethanol to give the title compound (75 mg) as light brown prisms, mp 119°-122° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]=1[C:11]([OH:13])=O.[NH:14]1[CH2:23][CH2:22][CH2:21][C@H:15]1[C:16]([O:18][CH2:19][CH3:20])=[O:17].CCOC(OC(OCC)=O)=O.C(N(CC)CC)C>C(OCC)(=O)C.CN(C=O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]=1[C:11]([N:14]1[CH2:23][CH2:22][CH2:21][C@H:15]1[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:13]
Reactant: O=C(O)C1=Cc2ccccc2CC1
Reactant: CCOC(=O)[C@@H]1CCCN1
Agent: CCOC(=O)OC(=O)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1CCCN1C(=O)C1=Cc2ccccc2CC1
Reaction time: 48 h
Yield: 92.7 %

Procedure:
To a DMF solution (60 ml) containing 3,4-dihydro-2-naphthoic acid (9a, 7.12 g, 40.0 mmole), and (S)(-)-ethyl prolinate (6.41 g, 44.8 mmole), a DMF solution (60 ml) containing DEPC (7.17 g, 44.0 mmole) and a DMF solution (60 ml) containing triethylamine (4.05 g, 40.0 mmole) are dropwise added at 0° C. in 5 minutes. The resultant mixture is stirred at 0° C. for 2 hours and then at room temperature for 2 days. The reaction mixture is diluted with ethyl acetate (1.8 liters), and the ethyl acetate solution is washed with 5% hydrochloric acid (130 ml×2), water (130 ml×2), a saturated aqueous solution of sodium chloride (130 ml×2), a saturated aqueous solution of sodium hydrogen carbonate (130 ml×2) and water (130 ml×2) in order and then dried over anhydrous magnesium sulfate. After filtration and evaporation, a crude product (10a) is obtained as a yellow caramel (13.9 g, 116%), which is purified by column chromatography (silica gel, 300 g; solvent, ether) to obtain an almost pure product (10a) as colorless needles (11.1 g, 91%). M.P. 55°-57° C. Recrystallization from ether-hexane affords an analytical sample as colorless needles melting at 56°-57° C. [α]D20 -18.6° (c=1.03, ethanol). IRνmaxNujol cm-1 : 1750 (ester), 1650 (C=C), 1610 (CON), NMR (in CDCl3): 1.27 (3H, t, J=7 Hz, CO2CH2CH3), 1.64-2.40 (4H, m, NCH2CH2CH2), 2.40-3.20 (4H, m, CH2CH2C=), 3.72 (2H, t, J=6 Hz, N--CH2), 4.16 (2H, q, J= 7 Hz, CO2CH2CH3), 4.58 (1H, t, J=6 Hz, NCHCO2), 6.77 (1H, s, CH=C), 7.12 (4H, s, aromatic proton).
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([N:10]2[CH2:30][CH2:29][C:13]3([N:17]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[NH:15][C:14]3=[O:28])[CH2:12][CH2:11]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH3:31][N:32]([CH3:44])[C:33]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)=[O:34].C([O-])([O-])=O.[Na+].[Na+].N#N>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.CCO>[CH3:31][N:32]([CH3:44])[C:33](=[O:34])[C:35]1[CH:36]=[CH:37][C:38]([C:2]2[S:6][C:5]([S:7]([N:10]3[CH2:11][CH2:12][C:13]4([N:17]=[C:16]([C:18]5[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:27])[F:26])[CH:19]=5)[NH:15][C:14]4=[O:28])[CH2:29][CH2:30]3)(=[O:8])=[O:9])=[CH:4][CH:3]=2)=[CH:39][CH:40]=1
Reactant: CN(C)C(=O)c1ccc(B(O)O)cc1
Reactant: O=C1NC(c2cccc(C(F)(F)F)c2)=NC12CCN(S(=O)(=O)c1ccc(Br)s1)CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)C(=O)c1ccc(-c2ccc(S(=O)(=O)N3CCC4(CC3)N=C(c3cccc(C(F)(F)F)c3)NC4=O)s2)cc1
Temperature: 25 °C
Yield: 77.5 %

Procedure:
A mixture of 8-(5-bromo-thiophene-2-sulfonyl)-2-(3-trifluoromethyl-phenyl)-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (11.1 mg, 0.0212 mmol), 4-(N,N-dimethylaminocarbonyl)phenylboronic acid (8.0 mg, 0.041 mmol), Pd(PPh3)4 (3.8 mg, 0.0033 mmol) and Na2CO3 (22.0 mg, 0.208 mmol) in toluene (0.12 ml)-EtOH (0.12 ml)-H2O (0.12 ml) was stirred at 85° C. for 20 hours in a sealed test tube in an N2 atmosphere. The reaction mixture was cooled to room temperature and extracted with AcOEt. The organic layer was washed with a saturated aqueous NH4Cl solution, and then dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (AcOEt) to give N,N-dimethyl-4-{5-[4-oxo-2-(3-trifluoromethyl-phenyl)-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-thiophen-2-yl}-benzamide (9.7 mg, 77%).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[C:12]1([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([N-]C(C)C)(C)C.[Li+].C(O)(=O)C>O1CCCC1.O.C1(C)C=CC=CC=1>[OH:5][C:4]1([CH:19]([CH2:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:20]([O:22][CH3:23])=[O:21])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:1][C:2]1=[O:3]
Reactant: COC(=O)CCc1ccccc1
Reactant: O=C1Nc2ccccc2C1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)C(Cc1ccccc1)C1(O)C(=O)Nc2ccccc21
Temperature: -5 °C
Reaction time: 1 h

Procedure:
To a cooled (-5° C.) suspension of isatin (8.85 g, 0.0602 mol), and methyl 3-phenylpropionate (9.88 g, 0.0602 mol) in 220 mL of dry tetrahydrofuran under a nitrogen atmosphere was added lithium diisopropylamide (LDA) (75 mL, 0.1275 mol of a 1.72M solution) over a 11/2 hour period. The reaction mixture was stirred at -5° C. for one hour and then poured into a cooled (0° to 5° C.) solution of toluene (140 mL), and acetic acid (30.6 g, 0.51 mol, 300% excess) over a 1/2 hour period under a nitrogen atmosphere. The transfer was completed with a 200 mL water wash.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](OS(C(F)(F)F)(=O)=O)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:24])[CH:11]=2)[CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:45]([N:48]([CH2:61][C:62]1[CH:67]=[CH:66][C:65]([O:68][CH3:69])=[CH:64][CH:63]=1)[S:49]([C:52]1[CH:57]=[CH:56][C:55](B(O)O)=[CH:54][CH:53]=1)(=[O:51])=[O:50])([CH3:47])[CH3:46].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:55]2[CH:54]=[CH:53][C:52]([S:49](=[O:50])(=[O:51])[N:48]([CH:45]([CH3:46])[CH3:47])[CH2:61][C:62]3[CH:63]=[CH:64][C:65]([O:68][CH3:69])=[CH:66][CH:67]=3)=[CH:57][CH:56]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:24])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(OS(=O)(=O)C(F)(F)F)c1C
Reactant: COc1ccc(CN(C(C)C)S(=O)(=O)c2ccc(B(O)O)cc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)N(Cc3ccc(OC)cc3)C(C)C)cc2)c1C
Temperature: 25 °C
Yield: 59.5 %

Procedure:
A stirred solution of (6-fluoro-3-methyl-4-trifluoromethanesulfonyloxy-naphthalen-2-yl)-acetic acid methyl ester (0.200 g, 0.52 mmol) in dimethoxyethane (10 mL) for 5 minutes at room temperature. Triphenylphosphine (0.031 g, 0.12 mmol), palladium (II) acetate (0.013 g, 0.060 mmol), 4-(N-isopropyl-N-(4-methoxybenzyl)sulfamoyl)phenyl-boronic acid (0.258 g, 0.71 mmol) and a 2 M aqueous solution of sodium carbonate (1.0 mL, 2.0 mmol) were added simultaneously to the reaction mixture at room temperature under argon. The reaction mixture was refluxed for 2 hours and then cooled to room temperature. Water was added and the mixture was extracted twice with ethyl acetate. The collected organic extracts were washed with water and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (Biotage, 5-10% ethyl acetate-hexane) to afford (6-fluoro-4-{4-[isopropyl-(4-methoxy-benzyl)-sulfamoyl]-phenyl}-3-methyl-naphthalen-2-yl)-acetic acid methyl ester (0.17 g, 61%) as a solid. MS calcd. for C31H31FNO5S [(M−H)−] 548, obsd. 548.4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](C=O)[CH:5]=[N:6][C:7]=1[CH3:8].[CH:11](OC)([O:14][CH3:15])[O:12][CH3:13].Cl>CO>[CH3:13][O:12][CH:11]([O:14][CH3:15])[C:4]1[CH:3]=[C:2]([Br:1])[C:7]([CH3:8])=[N:6][CH:5]=1
Reactant: COC(OC)OC
Reactant: Cc1ncc(C=O)cc1Br
Agent: Cl
Solvent: CO
Product: COC(OC)c1cnc(C)c(Br)c1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
In a sealed tube charged with a solution of 5-bromo-6-methyl-3-pyridinecarbaldehyde (for a synthesis see PB62797 Intermediate 69) (191 mg, 0.955 mmol) in MeOH (15 ml) was added trimethyl orthoformate (1.045 ml, 9.55 mmol) and HCl (4M solution in 1,4-dioxane, 0.573 ml, 2.292 mmol). The reaction mixture was stirred at 70° C. for 2 h 30 min. The solution was concentrated under vacuum and the residue was diluted with saturated NaHCO3 and EtOAc. The organic phase was extracted, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a pale oil. The crude was purified by flash chromatography using a 5 g Merck silica gel cartridge, and EtOAc/Hexane 1/9 as eluent to give 5-[bis(methyloxy)methyl]-3-bromo-2-methylpyridine (129.5 mg, 52%) as a yellow oil pure enough to be used in the next step.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]#[C:12][CH2:13][CH2:14]O)[CH:2]=1.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.[C:30]1([C:36]2[CH2:37][CH2:38][NH:39][CH2:40][CH:41]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)(O)[O-].[Na+]>CN(C)C1C=CN=CC=1>[C:30]1([C:36]2[CH2:41][CH2:40][N:39]([CH2:14][CH2:13][C:12]#[C:11][C:3]3[CH:2]=[N:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH2:38][CH:37]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: OCCC#Cc1cnc2ccccc2c1
Reactant: C1=C(c2ccccc2)CCNC1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Product: C(#Cc1cnc2ccccc2c1)CCN1CC=C(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A solution of the alcohol prepared in Step (a) (1.98 g, 0.01 mol), N,N-diisopropylethylamine (3.5 mL, 0.02 mol) and a catalytic amount of 4-dimethylaminopyridine is cooled to 0° C., and methanesulfonyl chloride (0.8 mL, 0.0105 mol) is added dropwise. The solution is stirred at 0° C. for 18 hours, and then concentrated under reduced pressure. The residue is taken up in dimethylformamide (20 mL), and to this solution is added 4-phenyl-1,2,3,6-tetrahydropyridine (2.41 g, 0.015 mol) and sodium bicarbonate (3.4 g, 0.04 mol). The mixture is heated at 40° C. for 5 hours, and the solvent is removed under reduced pressure. The residue is partitioned between 50 mL of ethyl acetate and 50 mL of water. The aqueous layer is extracted with 50 mL of ethyl acetate and the combined organic layers are dried (sodium sulfate), and the solvent is removed in vacuo. The residue is chromatographed (silica gel, 2% methanol/98% dichloromethane) to give the title compound, containing 0.4 mol of water; mp 94.3°-95.8° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:25](O)(=O)[CH3:26].C(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH3:26])[CH2:21][CH2:20]3)=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: Fc1ccc(-c2[nH]c(C3CCNCC3)cc2-c2ccncc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCN1CCC(c2cc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1
Reaction time: 2 h

Procedure:
To a suspension of 2-(4-fluorophenyl)-5-(piperidin-4-yl)-3-(4-pyridyl)-pyrrole (U.S. Pat. No. 5,792,77, 1000 mg, 3.11 mmol; hereinafter referred to as Compound A) and acetic acid (0.18 ml, 3.11 mmol) in anhydrous 1,2-dichloroethane (50 ml) under nitrogen at room temperature, acetaldehyde (0.21 ml, 3.73 mmol) and sodium triacetoxyborohydride (989 mg, 4.67 mmol) were added slowly. The resulting mixture was allowed to stir for 2 hours. The crude product was purified by flash silica gel column (MeOH-CH2Cl2, 8:92 v/v containing 1% NH4OH). After drying, 930 mg of 2-(4-fluorophenyl)-5-(N-ethylpiperidin-4-yl)-3-(4-pyridyl)pyrrole (Compound B) was obtained as the free base.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:13][C:14]1[CH:15]=[C:16]2[C:20]3=[C:21]([CH2:23][S:24][CH2:25][CH2:26][N:19]3[C@H:18]3[CH2:27][CH2:28][N:29](C(OC(C)(C)C)=O)[CH2:30][C@@H:17]23)[CH:22]=1>>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]([F:12])([F:11])[F:10])=[CH:3][C:2]=1[NH:13][C:14]1[CH:15]=[C:16]2[C:20]3=[C:21]([CH2:23][S:24][CH2:25][CH2:26][N:19]3[C@H:18]3[CH2:27][CH2:28][NH:29][CH2:30][C@@H:17]23)[CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCSC3
Reactant: FC(F)(F)c1ccc(Cl)c(Br)c1
Product: FC(F)(F)c1ccc(Cl)c(Nc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCSC3)c1

Procedure:
Using 3-bromo-4-chlorobenzotrifluoride and following the procedures described in EXAMPLE 33, Parts C and D, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 33, Part B was converted into the title compound of EXAMPLE 38 as a powder. 1H NMR (CDCl3, 300 MHz) 1.82-1.87 (m, 4H), 2.58-2.65 (m, 1H), 2.82-3.28 (m, 6H), 3.46-3.51 (m, 1H), 3.62-3.65 (m, 1H), 3.76 (s, 2H), 6.04 (s, 1H), 6.73 s, 1H), 6.83 (s, 1H), 6.91 (d, 1H, J=8 Hz), 7.14 (s, 1H), 7.37 (d, 1H, J=8 Hz). LRMS ES)+: 440 (M+H)+.
Reaction SMILES: [O:1]([CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH:26]([CH3:28])[CH3:27]>CN(C=O)C>[CH2:25]([N:13]1[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=[C:9]1[CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)CBr
Reactant: c1ccc(OCc2nc3ccccc3[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Cn1c(COc2ccccc2)nc2ccccc21
Temperature: 90 °C
Reaction time: 3 h
Yield: 81.6 %

Procedure:
A 500 mL flask fitted with a stir-bar, addition funnel, and Ar inlet was charged with 2-(phenoxymethyl)-1H-benzimidazole (61) (10.0 g, 44.6 mmol) and K2CO3 (12.3 g, 89.2 mmol). DMF (120 mL) was added followed by 1-bromo-2-methylpropane (9.17 g, 66.9 mmol). The suspension was heated in a 90° C. bath for 18 hr. Another 900 mg of 1-bromo-2-methylpropane were then added, and the mixture stirred another 3 hr until the starting material was down to 2% as measured by HPLC. The mixture was cooled to rt, and the solids were filtered off and rinsed with EtOAc (250 mL). The filtrate was then washed with saturated NH4Cl (2×200 mL), H2O (2×200 mL), and brine (100 mL), filtered through phase separation paper, and concentrated in vacuo to a yellow oil. Upon standing the oil crystallized, and was subsequently triturated with hexanes:EtOAc 20:1 (30 mL). The crystals were filtered and rinsed with hexanes (2×10 mL). Upon drying, 10.2 g of Compound #10 were obtained as an off-white, crystalline solid (84%). 1H NMR (300 MHz, CDCl3): δ 7.82 (m, 1H), 7.42-7.28 (m, 5H), 7.12 (d, 2H), 7.02 (t, 1H), 5.40 (s, 2H), 4.14 (d, 2H), 2.35 (sept, 1H), 0.98 (d, 6H) ppm. HPLC analysis (5:10:85 H2O:A1:MeOH) showed a purity of 98% with a retention time of 4.9 min and 2% starting material with a retention time of 3.4 min. Extension of the reaction time should reduce the percentage of starting material.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([N:22]=[C:23]=[O:24])(=[O:21])=[O:20]>C(Cl)Cl>[CH3:11][O:10][C:4]1[N:3]=[C:2]([NH:1][C:23]([NH:22][S:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[Cl:12])(=[O:20])=[O:21])=[O:24])[CH:7]=[C:6]([O:8][CH3:9])[N:5]=1
Reactant: O=C=NS(=O)(=O)c1ccccc1Cl
Reactant: COc1cc(N)nc(OC)n1
Solvent: ClCCl
Product: COc1cc(NC(=O)NS(=O)(=O)c2ccccc2Cl)nc(OC)n1
Reaction time: 0.5 h

Procedure:
To a mixture of 1.10 g of 4-amino-2,6-dimethoxypyrimidin in 40 ml methylene chloride at ambient temperature and pressure was added 1.60 g of 2-chlorobenzenesulfonylisocyanate. The reaction was stirred 30 minutes and then refluxed an additional 15 minutes. Volatiles were removed under reduced pressure and the solid thereby obtained was washed with a little diethyl ether; yield 2.30 g, m.p. 193°-196°.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:7]([CH3:8])[C:6]([C:9]2[CH:14]=[CH:13]N=C[CH:10]=2)=[N:5][N:4]=1.Cl.C(Cl)(=O)C1C=CC=[N:19][CH:18]=1>>[CH3:1][NH:2][C:3]1[N:7]([CH3:8])[C:6]([C:9]2[CH:10]=[N:19][CH:18]=[CH:13][CH:14]=2)=[N:5][N:4]=1
Reactant: CNc1nnc(-c2ccncc2)n1C
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Product: CNc1nnc(-c2cccnc2)n1C

Procedure:
The title compound is prepared according to the procedure for methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine (example 16a) from nicotinoyl chloride hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](N)=[CH:5][C:6]([N:12]1[CH2:18][CH2:17][CH2:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[CH2:13]1)=[N:7]2.N([O-])=O.[Na+].[Cl-:28].[Na+].C(=O)(O)[O-].[Na+]>Cl.O>[Cl:28][C:4]1[C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[Cl:1])[N:7]=[C:6]([N:12]2[CH2:18][CH2:17][CH2:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[CH2:13]2)[CH:5]=1
Reactant: [Cl-]
Reactant: Nc1cc(N2CCCc3ccccc3C2)nc2cccc(Cl)c12
Agent: Cl
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: O
Product: Clc1cccc2nc(N3CCCc4ccccc4C3)cc(Cl)c12
Reaction time: 0.5 h

Procedure:
To the suspension of 5-chloro-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-amine (1.5 g, 4.6 mmol) in concentrated hydrochloric acid (10 mL) was added a solution of sodium nitrite (390 mg, 5.6 mmol) in water at −10° C. After the addition, the reaction mixture was stirred for further 30 minutes, and then sodium chloride (2 g) was added. The resulting mixture was stirred at room temperature overnight and neutralized with saturated sodium bicarbonate, extracted with dichloromethane (50 mL×2). The organic layers were combined and dried over sodium sulfate, and then concentrated under reduced pressure to give the crude product. It was used in next step without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])=[N:4][CH:3]=1.[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.C(N(CC)CC)C.O>C(Cl)Cl>[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:22][C:2]2[N:7]=[N:6][C:5]([C:8]3[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=3[F:15])=[N:4][CH:3]=2)=[CH:19][CH:18]=1
Reactant: Fc1cccc(F)c1-c1ncc(Cl)nn1
Reactant: NCc1ccc(Cl)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Fc1cccc(F)c1-c1ncc(NCc2ccc(Cl)cc2)nn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.9 g of 6-chloro-3-(2,6-difluorophenyl)-[1,2,4]triazine is placed in 10 ml of methylene chloride, and 0.57 g of 4-chlorobenzylamine and 0.81 g of triethylamine are added. After being stirred at room temperature for 2 h, the reaction mixture is poured into water and extracted with methylene chloride; the organic phase is concentrated and the residue is purified by means of column chromatography over silica gel. In this way the title compound having a melting point of 200-205° C. is obtained.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:17])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH2:18]([O:20]C(Cl)=O)C.Cl>N1C=CC=CC=1>[CH3:17][N:3]1[C:2]2[NH:1][C:18](=[O:20])[C:16]3[C:11]([C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2)=[CH:12][CH:13]=[CH:14][CH:15]=3
Reactant: Cn1c(N)c(-c2ccccc2)c2ccccc21
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: Cn1c2ccccc2c2c3ccccc3c(=O)[nH]c21
Temperature: 75 °C
Yield: 46.3 %

Procedure:
To a solution of 2.59 g (0.01 mole) of 2-amino-1-methyl-3-phenylindole in 15 ml of pyridine, 2.84 g (0.026 mole) of ethylchlorocarbonate is added. The reaction mixture is heated to 75° C. for about 2 hours, allowed to cool and 2.84 g more of ethylchlorocarbonate is added. The reaction mixture, heated for a further 3 hours, is then poured into about 200 ml of aqueous 10% HCl solution, the product is extracted with ethyl ether and the organic layer washed with water. The resulting etheral solution, dried over sodium sulfate, is concentrated to a volume of about 30 ml, 20 ml of hexane is added and the solution is once again concentrated to 35 ml. The product, 2.3 g of 1-methyl-3-phenylindole-2-carbamic acid ethyl ester, is thus crystallized; (m.p. 159°-161° C.; yield 80%). A quantity of 1.4 g of the so obtained carbamate is heated to 270° C. for 15 minutes and the residue crystallized from dimethylformamide, yielding 1.15 g of 7-methylindolo[2,3-c]isoquinolin-5(6H)-one. M.p. 350° C. (with decomposition). Yield 95%.