Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[Na].Cl[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=1>>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][O:5][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=1
Reactant: CN(C)CCO
Reactant: Nc1cc(Cl)ccn1
Agent: [Na]
Product: CN(C)CCOc1ccnc(N)c1
Temperature: 25 °C
Yield: 537.6 %

Procedure:
2-Dimethylaminoethanol (34.8 g, 39.0 mmol) was treated with sodium (2.7 g, 11.7 mmol) in a sealed tube and stirred at ambient temperature until homogeneous. 4-Chloropyridin-2-amine (5 g, 3.9 mmol) was added and reaction heated to 150° C. and stirred in sealed tube for 8 hours. The mixture was cooled to ambient temperature before concentrating and triturating with dichloromethane (50 mL) four times. The combined triturates were concentrated and purified by column chromatography to give 4-(2-(dimethylamino)ethoxy)pyridin-2-amine as a yellow solid (3.8 g).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.Br[C:14]1[CH:15]=[C:16]([S:20]([C:23]2[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=3[F:38])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1>O1CCCC1.[Cl-].[Zn+2].[Cl-].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>[F:38][C:32]1[CH:33]=[C:34]([F:37])[CH:35]=[CH:36][C:31]=1/[CH:30]=[CH:29]/[C:26]1[CH:27]=[CH:28][C:23]([S:20]([C:16]2[CH:17]=[C:18]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)[CH:19]=[CH:14][CH:15]=2)(=[O:22])=[O:21])=[CH:24][CH:25]=1
Reactant: O=S(=O)(c1ccc(/C=C/c2ccc(F)cc2F)cc1)c1cccc(Br)c1
Reactant: Brc1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(/C=C/c2ccc(F)cc2F)cc1)c1cccc(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 10 %

Procedure:
Butyllithium (1.6M in hexanes, 0.3 mL, 0.48 mmol) was added to a rapidly stirred solution of 2-bromopyridine (44 μL, 0.46 mmol) in tetrahydrofuran (1.2 mL) at −78° C. After 45 minutes, zinc chloride (1.0M in diethyl ether, 1.38 mL, 1.38 mmol) was added. The mixture was warmed to room temperature, tetrakis(triphenylphosphine)palladium(0) (27 mg) and 1-((E)-2-{4-[(3-bromophenyl)sulfonyl]phenyl}vinyl)-2,4-difluorobenzene (Example 109; 100 mg, 0.23 mmol) were added and the reaction heated to reflux overnight. The cooled reaction mixture was partitioned between ethyl acetate and 10% aqueous ethylenediaminetetraacetic acid, disodium salt. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 35% ethyl acetate/isohexane, to yield the title compound as a white solid (10 mg, 10%). δH (400 MHz, CDCl3): 8.69 (1H, d, J=4.7 Hz), 8.56 (1H, t, J=1.7 Hz), 8.23 (1H, d, J=7.8 Hz), 7.98-7.94 (3H, m), 7.80-7.74 (2H, m), 7.62-7.50 (4H, m), 7.29-7.23 (2H, m), 7.07 (1H, d, J=16.5 Hz), 6.90-6.80 (2H, m). m/z (ES+) 434 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Br:14])[CH:8]=[C:9]2[C:13]=1[NH:12][N:11]=[CH:10]2)=[O:4].I[CH:16]([CH3:18])[CH3:17]>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Br:14])[CH:8]=[C:9]2[C:13]=1[N:12]([CH:16]([CH3:18])[CH3:17])[N:11]=[CH:10]2)=[O:4]
Reactant: COC(=O)c1cc(Br)cc2cn[nH]c12
Reactant: CC(C)I
Product: COC(=O)c1cc(Br)cc2cnn(C(C)C)c12
Yield: 65 %

Procedure:
Compound 14 was prepared following general method 1, using 5-bromo-1H-indazole-7-carboxylic acid methyl ester as a starting material and 2-iodopropane as alkylating agent. Yield: 65%.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([CH2:10][OH:11])/[C:7](=[N:12]/[C:13](=[O:23])[C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])/[S:6]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CS(O[CH:31]([CH3:33])[CH3:32])(=O)=O>O1CCOCC1>[C:1]([N:5]1[CH:9]=[C:8]([CH2:10][O:11][CH:31]([CH3:33])[CH3:32])/[C:7](=[N:12]/[C:13](=[O:23])[C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])/[S:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)OS(C)(=O)=O
Reactant: COc1ccc(Cl)cc1C(=O)/N=c1\sn(C(C)(C)C)cc1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sn(C(C)(C)C)cc1COC(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 9.4 %

Procedure:
The product from Example 28A (50 mg, 0.14 mmol) in dioxane (5 mL) was treated with NaH (60%) (7 mg, 0.17 mmol) stirred at rt for 10 min and treated with isopropyl methanesulfonate (78 mg, 0.56 mmol). The reaction was heated at 85° C. for 12 hrs, quenched with H2O, the mixture was extracted with EtOAc (2×). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% Hexane in ethyl acetate) to afford 5.2 mg (9%) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 1.22 (d, J=6.14 Hz, 6 H) 1.81 (s, 9 H) 3.75-3.83 (m, 1 H) 4.12 (s, 3 H) 4.92 (s, 2 H) 7.10 (d, J=9.21 Hz, 1 H) 7.63 (dd, J=9.21, 2.76 Hz, 1 H) 8.18 (d, J=2.45 Hz, 1 H) 9.28 (s, 1 H); MS (DCI/NH4+) m/z 397 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11](=[O:33])/[CH:12]=[CH:13]/[C:14]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][C:23]3=[O:32])[CH2:18][CH2:17]2)=[O:15])[CH:5]=[CH:6][C:7]=1[N:8]([CH3:10])[CH3:9].C.[H][H].[K+].[Br-]>C(O)C.C1COCC1.[Pt]>[Cl:1][C:2]1[CH:3]=[C:4]([C:11](=[O:33])[CH2:12][CH2:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][C:23]3=[O:32])[CH2:18][CH2:17]2)=[O:15])[CH:5]=[CH:6][C:7]=1[N:8]([CH3:10])[CH3:9]
Reactant: CN(C)c1ccc(C(=O)/C=C/C(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)cc1Cl
Reactant: [H][H]
Agent: [Pt]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCO
Product: CN(C)c1ccc(C(=O)CCC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)cc1Cl

Procedure:
A solution of 1.05 g (2.248 mmol) of (E)-3-{1-[4-(3-chloro-4-dimethylaminophenyl)-1,4-dioxo-2-buten-1-yl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone (Item no. 104) in 110 ml of an ethanol-THF mixture (10/1 v/v) was hydrogenated at ambient temperature in the presence of 0.5 g of platinum on active charcoal until the uptake of hydrogen had ended. The mixture was freed from catalyst and solvent and purified by chromatography on silica gel using dichloromethane/methanol/conc. ammonia (95/5/0.3 v/v/v) as eluant. 0.36 g (34% of theoretical) of a colourless substance were obtained, Rf 0.31 (El A). IR (KBr): 1672, 1660 (C═O) MS: M+=468/470 (Cl)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C@:5]([OH:16])([CH3:15])[C@@H:6]([C@H:8]1[CH2:12][O:11][C:10]([CH3:14])([CH3:13])[O:9]1)[OH:7])[CH3:2].[C:18](Cl)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19]>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:17])[C@:5]([OH:16])([CH3:15])[C@@H:6]([C@H:8]1[CH2:12][O:11][C:10]([CH3:13])([CH3:14])[O:9]1)[O:7][C:18](=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:2]
Reactant: CCOC(=O)[C@@](C)(O)[C@H](O)[C@H]1COC(C)(C)O1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)[C@@](C)(O)[C@H](OC(=O)c1ccccc1)[C@H]1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.8 %

Procedure:
To a solution of compound 42 (245 mg, 0.99 mmol) in dry pyridine (3 mL) is added dropwise a solution of BzCl (300 mg, 2.1 mmol) in pyridine (1 mL). After the mixture is stirred at room temperature for 2 h, the reaction is quenched with H2O (1 mL). The mixture is concentrated to dryness and the residue is partitioned between CH2Cl2 and sat. NaHCO3 solution. The organic phase is dried (anh. Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography with 5% EtOAc in hexanes to give 43 (247 mg, 71%) as a solid. Anal. Calcd for C18H24O7: C, 61.35; H, 6.86. Found: C, 60.95; H, 6.73.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]([OH:18])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=2)[CH2:37][CH2:36]1>C1COCC1>[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([NH:48][C:16](=[O:18])[C:15]#[C:14][C:11]3[CH:10]=[CH:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[CH:13][CH:12]=3)=[CH:44][CH:43]=2)[CH2:37][CH2:36]1
Reactant: O=C(O)C#Cc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CN1CCN(Cc2ccc(NC(=O)C#Cc3ccc(-c4ccc(Cl)cc4)cc3)cc2)CC1

Procedure:
A solution of 0.26 g (1 mmol) of (4′-chlorobiphenyl-4-yl)propynoic acid and 0.12 mL (1.1 mmol) of N-methylmorpholine in 20 mL of absolute THF is combined at −15° C. with 0.14 mL (1.1 mmol) of isobutyl chloroformate and stirred for ten minutes. Then 0.226 g (1.1 mmol) of 4-(4-methylpiperazin-1-ylmethyl)phenylamine dissolved in 7 mL of THF is added and the reaction mixture is stirred for 2 hours until ambient temperature is reached. The reaction mixture is evaporated down and the residue is dissolved in dichloromethane. The organic phase is washed twice with water and then dried over sodium sulfate. The desiccant is filtered off and the solvent is distilled off. The residue is triturated with ether and suction filtered. The purification is carried out by column chromatography on silica gel (dichloromethane/methanol/ammonia (90/10/0.1)). Yield: 60 mg (14% of theory); melting point: 182° C.-185° C.; C27H26ClN3O (M=443.97); calc.: molecular ion peak (M+H)+: 444/446 (Cl); found: molecular ion peak (M+H)+: 444/446 (Cl); Rf value: 0.4 (silica gel, dichloromethane/methanolic ammonia (90:10:0.1)).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH:18]=O.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:18]2[C:5]3[NH:6][C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:4]=3[CH2:3][CH2:2][NH:1]2)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: NCCc1c[nH]c2ccccc12
Reactant: COc1ccc(C=O)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1ccc(C2NCCc3c2[nH]c2ccccc32)cc1OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of tryptamine (5.0 g, 0.0312 mol) and 3,4-dimethoxy benzaldehyde (5.7 g, 0.0312 mol) in CH2Cl2 (220 mL) was added TFA (4.5 mL, 0.0584 mol). The deep blue solution was stirred at room temperature for 20 h. The reaction mixture was neutralized with NaHCO3 (4.9 g, 0.0584 mol) in H2O (50 mL) and the organic layer washed with brine (2×100 mL). The reaction mixture was dried with MgSO4 and the solvent evaporated. Product was isolated by column chromatography (silica gel; CH3OH:EtOAc=1:9) as a yellowish oil, which solidified slowly upon standing at room temperature.
Reaction SMILES: Br/[CH:2]=[CH:3]/[C:4]1[O:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]([F:19])([F:18])[F:17])[CH:10]=2)=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]([NH2:34])=[O:33].CNCCNC>C1(C)C=CC=CC=1.[Cu]I>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[O:5][C:4](/[CH:3]=[CH:2]/[NH:34][C:32](=[O:33])[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=3)=[CH:8][CH:7]=2)=[CH:10][C:11]=1[C:16]([F:19])([F:18])[F:17]
Reactant: NC(=O)c1ccccn1
Reactant: FC(F)(F)c1cc(-c2ccc(/C=C/Br)o2)ccc1Cl
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O=C(N/C=C/c1ccc(-c2ccc(Cl)c(C(F)(F)F)c2)o1)c1ccccn1
Temperature: 25 °C
Yield: 8.5 %

Procedure:
(E)-2-(2-bromovinyl)-5-(4-chloro-3-(trifluoromethyl)phenyl)furan (0.501 g, 1.378 mmol) in toluene (2.4 ml) was added to a mixture of copper(I) iodide (0.014 g, 0.069 mmol), potassium carbonate (0.381 g, 2.756 mmol), picolinamide (0.202 g, 1.654 mmol) and N,N′-dimethylethylene diamine (0.0149 ml, 0.0138 mmol) under nitrogen. The reaction mixture was refluxed for 7.5 h and allowed to cool to RT. It was then filtrated through a layer of silica and the filter cake was washed with EtOAc. The filtrate was evaporated to dryness and purified with CombiFlash using heptane-DCM as eluent system affording 0.046 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 6.54 (d, 1H), 6.70 (d, 1H), 7.26 (d, 1H), 7.61-7.70 (m, 2H), 7.77 (d, 1H), 7.99-8.02 (m, 1H), 8.04-8.09 (m, 2H), 8.13 (m, 1H), 8.74 (m, 1H), 11.20 (d, 1H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([CH3:15])=[CH:9]2)[CH2:2][CH2:3][CH3:4].CC1NC2C(C=1[CH:26]=[O:27])=CC(OCCC)=CC=2>>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([CH3:15])=[C:9]2[CH:26]=[O:27])[CH2:2][CH2:3][CH3:4]
Reactant: CCCOc1ccc2[nH]c(C)c(C=O)c2c1
Reactant: CCCCOc1ccc2[nH]c(C)cc2c1
Product: CCCCOc1ccc2[nH]c(C)c(C=O)c2c1
Yield: 94 %

Procedure:
This compound was prepared from 408d (300 mg, 1.48 mmol) in a manner similar to that for 409b to yield a cream-colored powder (320 mg, 94%): mp 160-161° C. TLC Rf 0.45 (3:1 EtOAc/hexanes). 1H NMR (600 MHz, d6-DMSO) δ 11.85 (s, 1H), 10.00 (s, 1H), 7.55 (d, 1H, J=2.46 Hz), 7.26-7.25 (d, 1H, J=8.7 Hz), 6.79-6.77 (dd, 1H, J1=8.7 Hz, J2=2.46 Hz), 3.96-3.94 (t, 2H, J=6.48 Hz), 2.64 (s, 3H), 1.73-1.68 (quin, 2H, J=6.48 Hz), 1.49-1.42 (sex, 2H, J=7.38 Hz), 0.95-0.93 (t, 3H, J=7.38 Hz). 13C NMR (150 MHz, d6-DMSO) δ 185.0, 154.9, 148.5, 130.0, 126.4, 113.6, 112.26, 112.04, 103.2, 67.4, 31.0, 18.8, 13.8, 11.5. Elemental analysis calculated for C14H17NO2: C, 72.70; H, 7.41; N, 6.06. Found: C, 72.87; H, 7.47; N, 6.13.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[F:19][C:20]([F:33])([F:32])[O:21][C:22]1[CH:23]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1>>[O:15]=[C:13]1[NH:12][C:8]2=[N:9][CH:10]=[CH:11][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][S:28]([C:24]4[CH:25]=[CH:26][CH:27]=[C:22]([O:21][C:20]([F:19])([F:32])[F:33])[CH:23]=4)(=[O:30])=[O:29])[CH:18]=[CH:17][CH:16]=3)=[C:7]2[NH:14]1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Reactant: O=S(=O)(Cl)c1cccc(OC(F)(F)F)c1
Product: O=c1[nH]c2nccc(Oc3cccc(NS(=O)(=O)c4cccc(OC(F)(F)F)c4)c3)c2[nH]1
Yield: 84 %

Procedure:
Method K was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 3-(trifluoromethoxy)benzenesulfonyl chloride to afford the title compound as an off-white solid (51 mg, 84%). 1H-NMR (δ, ppm, DMSO-d6): 6.20 (br s, 1H, HPy,5), 6.78 (s, 1H, Harom), 6.86 (d, 1H, Harom, J=7.5 Hz), 6.98 (d, 1H, Harom, J=7.4 Hz), 7.31-7.35 (m, 1H, Harom), 7.64-7.86 (m, 5H, Harom), 10.57 (s, 1H, NHSO2), 11.13 (s, 1H, NHPy3), 11.39 (s, 1H, NHPy2). 13C-NMR (δ, ppm, DMSO-d6): 106.18, 110.92, 113.71, 115.35, 116.48, 118.88, 121.88, 125.77, 125.83, 130.96, 131.93, 138.77, 141.03, 141.15, 144.12, 147.19, 148.23, 154.15, 154.99. HRMS (EI): m/z [M+H] calcd for C19H14F3N4O5S: 467.0637; found: 467.0644.
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][C:5]1[C:6]([C:25](OC)=[O:26])=[C:7]([NH:10][C:11](=[O:24])[CH2:12][N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][C:14]2=[O:23])[S:8][CH:9]=1>C(O)C.[Cl-].[Na+].O>[NH:2]([C:25]([C:6]1[C:5]([CH3:4])=[CH:9][S:8][C:7]=1[NH:10][C:11](=[O:24])[CH2:12][N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][C:14]1=[O:23])=[O:26])[NH2:3]
Reactant: NN
Reactant: COC(=O)c1c(C)csc1NC(=O)CN1C(=O)CCc2ccccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1csc(NC(=O)CN2C(=O)CCc3ccccc32)c1C(=O)NN
Temperature: 50 °C
Reaction time: 24 h
Yield: 78.7 %

Procedure:
Hydrazine monohydrate (0.059 mL, 1.23 mmol) was added to a solution of methyl 4-methyl-2-(2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamido)thiophene-3-carboxylate (221 mg, 0.616 mmol) in ethanol (2 mL) and the resulting solution was stirred at 50° C. for 24 h. The mixture was diluted with brine and extracted with ethyl acetate. The organic phase was separated, dried (Na2SO4), filtered, concentrated under vacuum to give N-(3-(hydrazinecarbonyl)-4-methylthiophen-2-yl)-2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide (174 mg, 0.485 mmol, 79%). Retention time (min)=1.435, method [1], MS(ESI) 359.1 (M+H).
Reaction SMILES: [OH:1][C:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:8]1[CH:12]=[CH:11][S:10][CH:9]=1)[C:3]([O:5]CC)=[O:4]>C1COCC1.[OH-].[Na+]>[OH:1][C:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:8]1[CH:12]=[CH:11][S:10][CH:9]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(O)(c1ccccc1)c1ccsc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C(O)(c1ccccc1)c1ccsc1
Temperature: 60 °C
Yield: 79.6 %

Procedure:
To a stirred solution of ethyl 2-hydroxy-2-phenyl-2-(thiophen-3-yl)acetate (1.06 g, 4.02 mmol) in THF (10 mL), sodium hydroxide (10 mL, 2.0 M aqueous solution) was added. The reaction was heated at 60° C. for 24 hours. The reaction was allowed to cool to RT, and THF was removed under reduced pressure. The resultant residue was washed with diethyl ether (×3). The aqueous layer was acidified to pH 1 with 2.0 M aqueous hydrochloric acid and extracted with ethyl acetate (×3). The combined ethyl acetate layers were washed with saturated sodium chloride solution, dried (magnesium sulfate), filtered and concentrated in vacuo to afford the title compound (0.75 g, 79%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:4]=1[C:5]1([C:26]3[C:17](=[CH:18][C:19]4[O:24][CH2:23][CH2:22][O:21][C:20]=4[CH:25]=3)[O:16][CH2:15]1)[C:6](=[O:14])[NH:7]2.N1C2C(=CC=CC=2)[C@@]2(C3C(=C[C:40]4[O:45][CH2:44][CH2:43][O:42][C:41]=4[CH:46]=3)OC2)C1=O>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:4]=1[C:5]1([C:26]3[C:17](=[CH:18][C:19]4[O:24][CH2:23][CH2:22][O:21][C:20]=4[CH:25]=3)[O:16][CH2:15]1)[C:6](=[O:14])[N:7]2[CH2:46][CH2:41][O:42][CH2:43][CH2:44][O:45][CH3:40]
Reactant: COc1cc2c(c(OC)c1)C1(COc3cc4c(cc31)OCCO4)C(=O)N2
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Product: COCCOCCN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(OC)cc(OC)cc21

Procedure:
Following the procedure as described in EXAMPLE 9.70 and making non-critical variations using 4′,6′-dimethoxy-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace (8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, 4′,6′-dimethoxy-1′-[2-(2-methoxyethoxy)ethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (80%) as a colorless solid: mp 158-160° C.; 1H NMR (300 MHz, DMSO-d6) δ6.43 (s, 1H), 6.33 (d, J=4.2 Hz, 1H), 6.20 (s, 1H), 6.06 (d, J=4.2 Hz, 1H), 4.70-4.46 (m, 2H), 4.19-3.99 (m, 4H), 3.79-3.72 (m, 2H), 3.65-3.52 (m, 4H), 3.52-3.42 (m, 2H), 3.38-3.24 (m, 6H), 3.18-3.11 (m, 3H); 13C NMR (75 MHz, CDCl3) δ178.8, 162.0, 156.7, 155.6, 155.5, 144.7, 144.1, 137.6, 120.4, 110.9, 109.2, 98.8, 92.9, 89.2, 71.0, 70.4, 68.3, 64.4, 63.9, 59.0, 56.9, 55.6, 55.5, 40.3; MS (ES+) m/z 458.1 (M+1).
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[C:29]([CH3:30])=[CH:28][S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[N:25][CH:24]=[CH:23][N:22]=2)[N:20]=1>>[N:22]1[CH:23]=[CH:24][N:25]=[CH:26][C:21]=1[C:19]1[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:13][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[C:29]([CH3:30])=[CH:28][S:27][C:17]=2[N:18]=1
Reactant: NCCc1ccc2c(c1)OCCO2
Reactant: Cc1csc2nc(-c3cnccn3)nc(Cl)c12
Product: Cc1csc2nc(-c3cnccn3)nc(NCCc3ccc4c(c3)OCCO4)c12

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyrazin-2-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3,4-ethylenedioxyphenethylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH:29]=O)[CH:7]=2)[CH2:3][CH2:2]1.[CH3:32][N:33]([CH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)C(=O)OC(C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:27][CH2:28]3)[CH:18]=[C:17]4[CH2:29][N:44]3[CH2:45][CH2:46][CH:41]([NH:33][CH3:32])[CH2:42][CH2:43]3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CNC1CCN(Cc2cn(CC3CC3)c(=O)c3ccc(-c4cc(C(=O)NC5CC5)cc(F)c4C)cc23)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of the product of Example 75 step i) (320 mg) in dichloromethane (15 mL) was added methylpiperidine-4-yl-carbamic acid, tert-butyl ester (490 mg) and the reaction was stirred at room temperature for 10 minutes before the addition of sodium triacetoxyborohydride (490 mg). The reaction was then stirred at room temperature for 24 hours. The reaction mixture was diluted with dichloromethane (50 mL), washed with water (50 mL), dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was then dissolved in methanol (5 mL) and treated with hydrogen chloride (4N in 1,4-dioxane, 10 mL) and stirred at room temperature for 1 hour. The reaction mixture was evaporated in vacuo and the residue was purified (SiO2, chromatography eluting with 5% methanol in dichloromethane to 5% 7N ammonia/methanol in dichloromethane) to afford the title compound as a solid (250 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=O)[CH:13]([CH2:16][C:17](O)=[O:18])[C:12]3=[N:20][N:21]=[C:22]([CH3:23])[N:11]3[C:10]3[CH:24]=[CH:25][CH:26]=[CH:27][C:9]2=3)=[CH:4][CH:3]=1.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH:13]([CH2:16][CH2:17][OH:18])[C:12]3=[N:20][N:21]=[C:22]([CH3:23])[N:11]3[C:10]3[CH:24]=[CH:25][CH:26]=[CH:27][C:9]2=3)=[CH:4][CH:3]=1
Reactant: Cc1nnc2n1-c1ccccc1N(c1ccc(Cl)cc1)C(=O)C2CC(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1nnc2n1-c1ccccc1N(c1ccc(Cl)cc1)CC2CCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.2 %

Procedure:
To a solution of 2-(6-(4-chlorophenyl)-1-methyl-5-oxo-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-4-yl)acetic acid (500 mg, 1.32 mmol) in THF (300 ml) was added BH3 solution in THF (1 M, 6.5 mL) dropwise, the resulting mixture was stirred at room temperature overnight. NH4Cl aqueous (15 mL) was added, and then extracted with DCM (3×30 mL), the combined organic layers were dried over Na2SO4, and the solvent was removed in vacuum. The residue was purified by flash chromatography eluting with DCM:MeOH=40:1 to give 2-(6-(4-chlorophenyl)-1-methyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-4-yl)ethanol as an off-white solid (90 mg, 18.5%).