Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:16]O>>[SH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:16])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(S)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(S)cc1

Procedure:
To a solution of 4-mercaptobenzoic acid (Apin, 1.72 g, 11.17 mmol) in anhydrous methyl alcohol (20.0 mL) was added concentrated sulfuric acid (0.43 mL). The reaction mixture is then warmed to reflux for 16 h, concentrated in vacuo, diluted with ethyl acetate (100 mL) and washed with saturated sodium bicarbonate (2×100 mL). The organic phase is then separated, dried over anhydrous magnesium sulfate and concentrated in vacuo to give 712 mg (Y: 38%) of the title product; 1H-NMR (CDCl3): δ 7.89 (d, J=8.7 Hz, 2H), 7.29 (d, J=8.7 Hz, 2H), 3.90 (s, 3H), 3.60 (s, 1H).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[O:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[F:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33](O)=[O:34])=[CH:25][CH:24]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33]([NH:1][CH:2]([CH2:12][C:13]2[O:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[CH:3]([C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)[OH:4])=[O:34])=[CH:25][CH:24]=1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: NC(Cc1ccc(C(F)(F)F)o1)C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1ccc(C(F)(F)F)o1)C(O)c1ccc(F)cc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(5-(trifluoromethyl)-2-furanyl)-1-propanol (300 mg, 0.99 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (188 mg, 0.99 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (283 mg, 1.48 mmol) and 1-hydroxy-1H-benzotriazole (151 mg, 0.99 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1). Recrystallization from ethyl acetate-hexane gave the title compound (191 mg, 41%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:21]([F:22])=[CH:20][C:19]([F:23])=[C:18]([NH2:24])[C:14]=3[C:15](=[O:17])[CH:16]=2)=[CH:7][C:6]=1[F:25])(=[O:3])[CH3:2].CN(C1C=CC=CN=1)C.[C:35](=O)([O:41]C(C)(C)C)[O:36][C:37]([CH3:40])([CH3:39])[CH3:38].O>CN(C)C=O>[C:1]([N:4]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:21]([F:22])=[CH:20][C:19]([F:23])=[C:18]([NH2:24])[C:14]=3[C:15](=[O:17])[CH:16]=2)=[CH:7][C:6]=1[F:25])[C:35]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:41])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N(C(=O)OC(C)(C)C)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
3.03 g (8.70 mmol) of Compound 27 obtained in Example 27 was dissolved in 200 ml of dimethylformamide, 109 mg of dimethylaminopyridine and 3.0 ml of di-tert-butyl carbonate were added and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution and the precipitated crystals were collected by filtration to give 3.44 g (88%) of 2-[4-[N-acetyl-N-(tert-butoxycarbonyl)amino]-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(N(CC)CC)C>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:10]([C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1)#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=Cc1cccc(Br)n1
Reactant: C#CCCCCCCCCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCC#Cc1cccc(C=O)n1
Temperature: 40 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
To a solution of 6-bromo-2-pyridinecarboxaldehyde (3.0 g) in tetrahydrofuran (10 ml), was added sequentially bis(triphenylphosphine)palladium(II) chloride (0.178 g), copper(I)iodide (0.024 g), 1-dodecyne (3.25 ml), and triethylamine (2.12 ml). The solution was stirred at 40° C. overnight. The reaction mixture was cooled to room temperature, charged again with bis(triphenylphosphine)palladium (11) chloride (0.024 g), copper (I) iodide (0.024 g), and triethylamine (2.12 ml), and 1-dodecyne (3.25 ml), and tetrahydrofuran (5.0 ml), and heated at 40° C. for 5 hrs. The reaction mixture was again cooled and recharged as above, and heated at 40° C. for 24 hrs. The cooled mixture was concentrated, taken up in ethyl acetate (100 ml), washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was taken up in ethyl acetate (100 ml) and filtered. The filtrate wets combined with material from a similar reaction run 1.43 g of the carboxaldehyde and proportionate amounts of the catalysts, 1-dodecyne, and solvent. The filtrate was concentrated. The residue was purified by flash chromatography using 1.5% ethyl acetate/hexane followed by 1% ethyl acetate/hexane as eluents. The appropriate fractions were collected and concentrated to yield 2.24 g (29%) of product, as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([O:8][CH2:9][C:10]([N:12]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([CH:22]3[CH2:24][CH2:23]3)=[O:21])[CH2:16][CH2:15]2)[CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:25][NH:26][CH3:27].O1CCCC1.[I-].[K+].C(N(CC)CC)C>C(O)CCC>[CH:22]1([C:20]([N:17]2[CH2:18][CH2:19][CH:14]([N:12]([CH3:13])[C:10](=[O:11])[CH2:9][O:8][C:5]3[N:6]=[N:7][C:2]([N:26]([CH3:27])[CH3:25])=[CH:3][CH:4]=3)[CH2:15][CH2:16]2)=[O:21])[CH2:24][CH2:23]1
Reactant: CNC
Reactant: CN(C(=O)COc1ccc(Cl)nn1)C1CCN(C(=O)C2CC2)CC1
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)c1ccc(OCC(=O)N(C)C2CCN(C(=O)C3CC3)CC2)nn1
Temperature: 110 °C
Reaction time: 48 h
Yield: 19 %

Procedure:
A mixture of Compound 135 (60 mg), 2M dimethylamine/tetrahydrofuran solution (766 μL), potassium iodide (2.82 mg), triethylamine (23.7 μL) and n-butanol (11.0 mL) was stirred at 110° C. for 2 days in a sealed tube. Subsequently, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3 to 99:1) to give 12.1 mg (19% yield) of the desired product as a pale yellow amorphous.
Reaction SMILES: [N:1]1([C:7]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10][CH2:9]C2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30](Cl)(=[O:32])=[O:31].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10][CH2:9]2)[CH2:6][CH2:5]1)(=[O:32])=[O:31]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CCOC(=O)C1(N2CCNCC2)CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1(N2CCN(S(=O)(=O)c3ccccc3Cl)CC2)CC1
Yield: 63 %

Procedure:
Ethyl 1-(piperazin-1-yl)cyclobutanecarboxylate (0.20 mmol) was dissolved in CH2Cl2 (1 ml). Triethylamine (0.30 ml, 2.2 mmol), followed by 2-chlorobenzenesulfonyl chloride (64 mg, 0.30 mmol), was added at room temperature. The orange-colored solution was stirred at room temperature for 18 h before saturated NaHCO3 solution was added. The mixture was extracted twice with EtOAc. Combined organic layers were washed once with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (SiO2, 25% EtOAc/hexanes) to give ethyl 1-(4-(2-chlorophenylsulfonyl)piperazin-1-yl)cyclopropanecarboxylate (47 mg, 63% 2 steps) as a white solid. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm: 0.85 (m, 2 H), 1.23 (t, J=7.5 Hz, 3 H), 1.23 (m, 2 H), 2.98 (bs, 4 H), 3.14 (bs, 4 H), 4.09 (q, J=7.2 Hz, 2 H), 7.37 (t, J=7.3 Hz, 1 H), 7.42-7.53 (m, 2 H), 8.00 (d, J=7.8 Hz, 1 H), 13C NMR (100 MHz, CHLOROFORM-D) δ ppm 14.3, 19.1, 45.7, 46.7, 48.8, 60.5, 126.9, 132.1, 132.2, 132.3, 133.6, 136.0, 173.8; ESI-MS: m/z 373.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]3[N:15]=[CH:16][C:17](I)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:19]([C:21]1[S:25][C:24]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:23][CH:22]=1)#[CH:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]3[N:15]=[CH:16][C:17]([C:20]#[C:19][C:21]4[S:25][C:24]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:23][CH:22]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc2c(I)cnn12
Reactant: C#Cc1ccc(S(N)(=O)=O)s1
Product: Cc1cc(-c2ccc(Cl)cc2)nc2c(C#Cc3ccc(S(N)(=O)=O)s3)cnn12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-3-iodo-7-methyl-pyrazolo[1,5-a]pyrimidine (example 292) (185 mg, 0.5 mmol) and 5-ethynyl-thiophene-2-sulfonic acid amide (example D.3) (94 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (94 mg, 44%). MS (ISP) 429.5 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:17]=[CH:18][CH:19]=[C:20]4[C:24]=3[NH:23][CH:22]=[C:21]4[CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:32]1N2CCN(CC2)C1.C(=O)(OC)OC>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:17]=[CH:18][CH:19]=[C:20]4[C:24]=3[N:23]([CH3:32])[CH:22]=[C:21]4[CH2:25][CH2:26][C:27]([OH:29])=[O:28])[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4ccc(OC)c(OC)c4)n3)cccc12
Reactant: C1CN2CCN1CC2
Solvent: COC(=O)OC
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(-c3cccc4c(CCC(=O)O)cn(C)c34)no2)cc1OC
Temperature: 50 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
Ethyl 3-(7-{5-[3,4-bis(methyloxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoate (100 mg) (D67), DABCO (27 mg) and N,N-dimethylformamide (3 mL) was added to dimethyl carbonate (10 mL) successively. The reaction vessel was sealed and heated in Biotage Initiator using initial normal to 150° C. for 2 h. After cooling the reaction, the solvent was removed in vacuo. The residue was dissolved in tetrahydrofuran (5 mL) and methanol (5 mL), and then NaOH (48 mg) in water (5 mL) was added. The mixture was stir at 50° C. for 8 h. The organic solvent was removed and the mixture was acidified with HCl (1 M) solution to pH around 1. Extracted with EtOAc (60 mL), the organic layer was separated and the organic solvent was evaporated off. The residue was purified by Mass Directed Auto Prep to afford 3-(7-{5-[3,4-bis(methyloxy)phenyl]-1,2,4-oxadiazol-3-yl}-1-methyl-1H-indol-3-yl)propanoic acid (E44) (56 mg). δH (DMSO-d6, 400 MHz): 2.60 (2H, t), 2.96 (2H, t), 3.62 (3H, s), 3.88 (6H, s), 7.17 (1H, t), 7.19 (1H, s), 7.22 (1H, d), 7.43 (1H, dd), 7.66 (1H, d), 7.79 (1H, dd), 7.82 (1H, dd), 12.12 (1H, s). MS (ES): C22H21N3O5 requires 407; found 408.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:9][CH2:10][OH:11])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C>ClCCl.CS(C)=O>[C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:9][CH:10]=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(CCO)C1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NC(CC=O)C1CCCCC1
Reaction time: 2 h

Procedure:
To a solution of (1-cyclohexyl-3-hydroxypropyl)carbamic acid tert-butyl ester (500 mg; 1.9 mmol) and N,N-diisopropylethylamine (1.35 mL; 7.8 mol) in dichloromethane (5 mL) was added a solution of pyridine sulfur trioxide complex (1.25 g; 7.8 mmol) in dimethyl sulfoxide (5 mL) at −20° C. The reaction mixture was stirred for 2 h and diluted with dichloromethane (20 mL). The reaction mixture was washed with 10% acetic acid in water (2×15 mL) The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude oil was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Br:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[CH3:14][C:15]([CH3:20])([CH3:19])[C:16](O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC(Cl)(Cl)C#N>C(#N)C>[Br:13][C:10]1[C:11]2[O:12][C:14]([C:15]([CH3:20])([CH3:19])[CH3:16])=[N:1][C:2]=2[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=1
Reactant: CC(C)(C)C(=O)O
Reactant: COC(=O)c1cc(N)c(O)c(Br)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: N#CC(Cl)(Cl)Cl
Solvent: CC#N
Product: COC(=O)c1cc(Br)c2oc(C(C)(C)C)nc2c1
Temperature: 150 °C
Yield: 19.3 %

Procedure:
To a solution of methyl 3-amino-5-bromo-4-hydroxybenzoate (2.00 g, 4.06 mmol, 50% purity), 2,2-dimethylpropanoic acid (0.83 g, 8.13 mmol), and solid support triphenylphosphine (75% by weight; 4.26 g, 12.2 mmol) in acetonitrile (20 mL) was added trichloroacetonitrile (815 μL, 8.13 mmol). The mixture was heated in a microwave reactor for 10 min at 150° C. The mixture was cooled to ambient temperature, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→70% hexanes/ethyl acetate) gave the title compound (245 mg). LC-MS [M]=312.1.
Reaction SMILES: [NH2:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:7][CH:6]=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:32]#[N:33])=[C:25]([CH:31]=1)[O:26][CH2:27][CH:28]1[O:30][CH2:29]1>C(O)(C)C>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:32]#[N:33])=[C:25]([CH:31]=1)[O:26][CH2:27][CH:28]([OH:30])[CH2:29][NH:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:9][CH:10]=1
Reactant: CC(C)(N)CNc1ccc(C2=NNC(=O)CC2)cc1
Reactant: N#Cc1ccc(Cl)cc1OCC1CO1
Solvent: CC(C)O
Product: CC(C)(CNc1ccc(C2=NNC(=O)CC2)cc1)NCC(O)COc1cc(Cl)ccc1C#N
Reaction time: 20 h
Yield: 87.4 %

Procedure:
5.2 g of 6-[4-(2-amino-2-methylpropylamino)-phenyl]-4,5-dihydro-3(2H)-pyridazinone obtained in Example 1, (3) and 4.4 g of 1-(5-chloro-2-cyanophenoxy)-2,3-epoxypropane were dissolved in 30 ml of isopropyl alcohol, and the solution was heated with stirring for 20 hours. The solution was then worked up as in Example 1, (5) to give 8.2 g of 6-[4-[2-[3-(5-chloro-2-cyanophenoxy)-2-hydroxypropylamino]-2-methylpropylamino]-phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]Br.[C:21]([O-:24])([O-])=O.[K+].[K+]>>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][N:10]([CH2:16][C:15]1[CH:18]=[CH:19][CH:20]=[C:13]([O:24][CH3:21])[CH:14]=1)[C:8]1[CH:7]=[CH:6][C:5]2[NH:1][CH:2]=[N:3][C:4]=2[CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: COc1cccc(CBr)c1
Agent: [K+]
Product: COc1cccc(CN(Cc2cccc(OC)c2)c2ccc3[nH]cnc3c2)c1

Procedure:
The compound was synthesized starting from benzimidazol-5-amine (133 mg; 1 mmol; 1 eq.), 3-methoxybenzylbromide (442 mg; 0.308 ml; 2.2 mmol; 2.2 eq.) and K2CO3 (304 mg; 2.2 mmol; 2.2 eq.) according to method 5; Yield: 0.143 g (38.3%); MS m/z: 374.1 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 3.68 (s, 6H); 4.64 (s, 4H); 6.69 (br s, 1H); 6.72 (dd, 1H, 4J=2.1 Hz, 3J=8.9 Hz); 6.78 (dd, 2H, 4J=2.4 Hz, 3J=7.9 Hz); 6.83-6.87 (m, 4H); 7.22 (t, 2H, 3J=7.9 Hz); 7.33 (d, 1H, 3J=8.9 Hz); 7.90 (s, 1H); 11.92 (br s, 1H); HPLC (METHOD [A]): rt 15.00 min (92.7%)
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH2:28]SC3C=CC(Cl)=CC=3)[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.O.[C:40]1(C)[CH:45]=[CH:44][C:43]([S:46]([OH:49])(=[O:48])=O)=[CH:42][CH:41]=1.[Cl:51]C1C=C(C=CC=1)C(OO)=O>ClCCl>[Cl:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH2:28][S:46]([C:43]3[CH:42]=[CH:41][C:40]([Cl:51])=[CH:45][CH:44]=3)(=[O:48])=[O:49])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cn(CSc2ccc(Cl)cc2)c2ccc(CN3CCOCC3)cc2c1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1)c1cn(CS(=O)(=O)c2ccc(Cl)cc2)c2ccc(CN3CCOCC3)cc2c1=O
Reaction time: 0.75 h
Yield: 77.5 %

Procedure:
A solution of N-(4-chlorobenzyl)-1-([(4-chlorophenyl)sulfanyl]methyl)-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.11 gm) from Example No. 101 in dichloromethane (2 mL) at 0° C. is treated with p-toluenesulfonic acid hydrate (0.04 gm) followed by m-chloroperoxybenzoic acid (˜85%) (0.09 gm). The mixture is stirred for 0.75 hr. The reaction mixture is diluted with dichloromethane, washed with saturated aqueous sodium sulfite, saturated aqueous sodium bicarbonate, brine, dried (Na2SO4) and concentrated under reduced pressure. The crude product is purified by recrystallization from acetonitrile to afford 0.09 gm of the title compound as a white solid.
Reaction SMILES: [C:1]12([C:11]([OH:13])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C1N=C[N:16](C(N2C=NC=C2)=O)C=1.[NH4+].[OH-]>CCOC(C)=O>[C:1]12([C:11]([NH2:16])=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: NC(=O)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.4 %

Procedure:
A solution of adamantane-1-carboxylic acid (2.00 g, 11.10 mmol) in EtOAc (20 mL) was treated with CDI (2.00 g, 12.33 mmol), stirred at RT for 20 minutes, treated with NH4OH (˜14M, 5 mL, ˜70 mmol) and stirred at RT for 20 minutes. The mixture was concentrated to dryness, treated with satd. NaHCO3 and the solids collected via filtration and dried to afford adamantane-1-carboxamide (1.74 g, 87%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 6.91 (s, 1H), 6.65 (s, 1H), 1.92 (m, 3H), 1.74-1.71 (m, 6H), 1.68-1.57 (m, 6H); MS (ESI) m/z: 180.1 (M+H+).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH:10]([OH:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1.[CH3:13]I.O>CN(C=O)C>[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([O:12][CH3:13])[CH3:11])[CH:5]=1
Reactant: CI
Reactant: CC(O)c1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(C)c1cccc(Br)c1
Reaction time: 4 h

Procedure:
To a stirred and ice-cooled mixture of 1.09 g (27.4 mmol) NaH (60% in mineral oil) in 20 mL dry DMF was added a solution of 5.00 g (24.9 mmol) 1-(3-bromo-phenyl)-ethanol in 10 mL dry DMF under argon atmosphere. The mixture was stirred for 30 min at 0° C. 1.70 mL (27.4 mmol) methyl iodide was added and stirring was continued for 4 h at RT. The mixture was worked up by adding water, followed by extraction with EtOAc. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (Cyc/EtOAc=9/1).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C([N:36]2[CH2:40][CH2:39][C:38](F)(F)[CH2:37]2)C2N=NNC=2N=1)(C)(C)C.[Cl:43]C1C=CN=CC=1CCl>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[C:40]([Cl:43])=[CH:39][CH:38]=[CH:37][N:36]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: ClCc1cnccc1Cl
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3ncccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 4-chloro-3-(chloromethyl)pyridine and isolated as light-yellow gum. MS (m/e): 408.3 (MH+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)(=O)C.[CH:11]([C:13]1[CH:62]=[CH:61][C:16]([C:17]([O:19][CH2:20][O:21][C:22]([N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]([CH2:33][C:34]([NH:47][C:48]([O:50][CH2:51][C:52]3[O:53][C:54]4[CH:60]=[CH:59][CH:58]=[CH:57][C:55]=4[CH:56]=3)=[O:49])([C:36](=[O:46])[NH:37][CH:38]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH3:39])[CH3:35])=[CH:25]2)=[O:23])=[O:18])=[CH:15][CH:14]=1)=O.C(=O)(O)[O-].[Na+].[Cl:68]CCl>>[ClH:68].[N:1]1([CH2:11][C:13]2[CH:62]=[CH:61][C:16]([C:17]([O:19][CH2:20][O:21][C:22]([N:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:26]([CH2:33][C:34]([NH:47][C:48]([O:50][CH2:51][C:52]4[O:53][C:54]5[CH:60]=[CH:59][CH:58]=[CH:57][C:55]=5[CH:56]=4)=[O:49])([C:36](=[O:46])[NH:37][CH:38]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[CH3:39])[CH3:35])=[CH:25]3)=[O:23])=[O:18])=[CH:15][CH:14]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: CC(NC(=O)C(C)(Cc1cn(C(=O)OCOC(=O)c2ccc(C=O)cc2)c2ccccc12)NC(=O)OCc1cc2ccccc2o1)c1ccccc1
Reactant: ClCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(NC(=O)C(C)(Cc1cn(C(=O)OCOC(=O)c2ccc(CN3CCOCC3)cc2)c2ccccc12)NC(=O)OCc1cc2ccccc2o1)c1ccccc1
Product: Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
Morpholine (0.164 mL, 1.88 mmol, 1.1 eq.) and acetic acid (0.108 mL, 1.88 mmol, 1.1 eq.) were added to a solution of compound 19 (1.2 g, 1.71 mmol) in dry dichloromethane (20 mL) under N2 in an ice bath. Then NaHB(OAC)3 (0.508 g, 2.39 mmol, 1.4 eq.) was added in three equal portions in 10 minutes. After the addition, the reaction mixture was stirred for 3 hours at room temperature. A solution of saturated sodium bicarbonate (30 mL) was added to the reaction mixture and stirred at room temperature for 30 minutes. The organic layer was separated and washed sequentially with a solution of saturated sodium bicarbonate (20 mL), a solution of saturated sodium chloride, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography eluting with CHCl3/MeOH (10:0.1) to give compound 20b as a white foam (0.921 g, 70%).