Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])=[CH:9][CH:10]=2)[C:5]([OH:20])=[C:4]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])[N:3]=1.[C:28]([Cu])#[N:29].C(Cl)Cl>CN(C=O)C>[C:28]([C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])=[CH:9][CH:10]=2)[C:5]([OH:20])=[C:4]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])[N:3]=1)#[N:29]
Reactant: CCCCOC(=O)c1nc(Br)c2ccc(Oc3ccccc3C)cc2c1O
Reactant: N#C[Cu]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3ccccc3C)cc2c1O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Butyl 1-bromo-4-hydroxy-6-(o-tolyloxy)isoquinoline-3-carb oxylate (130 mg, 0.30 mmol) and CuCN (54 mg, 0.61 mmol) were suspended in DMF (1.2 mL). The resulting mixture was heated to reflux for 40 minutes and then cooled to room temperature. The reaction crude was poured into CH2Cl2 (30 mL) and stirred vigorously for 10 minutes at room temperature. The resulting suspension was filtered through a pad of celite and the filtrate was washed with H2O and brine sequentially. The organic layer was dried over MgSO4, concentrated, and purified by flash chromatography (0-30% EtOAc/hexanes) to give the title compound in 65 mg. MS: (−) m/z 375.29 (M−1).
Reaction SMILES: Br[C:2]1[N:28]=[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][O:11][C:12]3[CH:17]=[CH:16][C:15]([C@@H:18]([C:25]#[C:26][CH3:27])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=3)=[CH:9][N:4]2[N:3]=1.CC1(C)C(C)(C)OB([C:37]2[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[CH:39][CH:38]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][C@@H:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:8]2[CH:7]=[CH:6][C:5]3[N:4]([N:3]=[C:2]([C:37]4[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[CH:39][CH:38]=4)[N:28]=3)[CH:9]=2)=[CH:13][CH:14]=1)[C:25]#[C:26][CH3:27])[CH3:24]
Reactant: CC#C[C@@H](CC(=O)OCC)c1ccc(OCc2ccc3nc(Br)nn3c2)cc1
Reactant: CC1(C)OB(c2ccc(C#N)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC#C[C@@H](CC(=O)OCC)c1ccc(OCc2ccc3nc(-c4ccc(C#N)cc4)nn3c2)cc1
Temperature: 100 °C
Yield: 73.2 %

Procedure:
To a stirred solution of ethyl (3S)-3-[4-[(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methoxy]phenyl]hex-4-ynoate (0.25 g, 0.57 mmol) and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile (0.14 g, 0.5 mmol) in dioxane (115 mL) is added K2CO3 (0.15 g, 1.134 mmol). The mixture is purged with argon for 30 minutes, Pd(PPh3)4 (0.032 g, 0.027 mmol) is added and the mixture is heated at 100° C. for 5 hours. The reaction mixture is cooled to room temperature, filtered through diatomaceous earth. The filtrate is evaporated under reduced pressure and concentrated to dryness. The crude material is purified by silica gel chromatography (combiflash) eluting with 30% EtOAc/hexane to give the title compound as a brown liquid (0.170 g, 68.75%). LCMS m/z 464 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([N:8]=[C:9]=[S:10])[CH:7]=1.[CH3:12][N:13]1[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([NH:8][C:9]([NH:18][C:15]2[CH:16]=[CH:17][N:13]([CH3:12])[N:14]=2)=[S:10])[CH:7]=1
Reactant: Cc1ccc(Cl)cc1N=C=S
Reactant: Cn1ccc(N)n1
Product: Cc1ccc(Cl)cc1NC(=S)Nc1ccn(C)n1
Yield: 94.2 %

Procedure:
Prepared using Method A from 4.73 g (27.5 mmol) of 5-chloro-2-methyl-phenyl isothiocyanate and 2.5 g (25.7 mmol) of 1-methyl-3-aminopyrazole to give 6.8 g of title compound as a white solid (95% yield, m.p. 217-218° C.).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([O:14]C)=[O:13])=[CH:6][C:5]=1[O:16][CH2:17][CH2:18][CH3:19])[CH3:2].[OH-].[K+].O>CO>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])=[CH:6][C:5]=1[O:16][CH2:17][CH2:18][CH3:19])[CH3:2]
Reactant: CCCOc1cc(/C=C/C(=O)OC)ccc1OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCOc1cc(/C=C/C(=O)O)ccc1OCC
Temperature: 70 °C

Procedure:
1.0 g (3.78 mmol) of methyl 3(E)-[4-ethoxy-3-propoxyphenyl]acrylate are suspended in 50 ml of a 10% solution of potassium hydroxide in methanol. 2 ml of water are then added and the mixture is heated to 70° C. for 3 hours and then cooled. Thereafter, the reaction mixture is partitioned between diethyl ether and water, the organic phase is washed several times with saturated sodium chloride solution and the combined aqueous phases are adjusted to pH 4 with a 25% hydrochloric acid solution and extracted several times with methylene chloride. The methylene chloride phases are then combined, dried over magnesium sulfate, filtered and evaporated down. This gives 3(E)-[4-ethoxy-3-propoxyphenyl]acrylic acid.
Reaction SMILES: [C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]CCCCC.[Na+].[C:22]([O-])(=[O:40])[CH2:23]CCCCCCCCCCCCCCCC.[K+].C([O:45]CCOCCO)C>>[C:13]1(=[O:45])[O:40][CH2:22][CH2:23][O:20][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CCOCCOCCO
Reactant: CCCCCCCCCCCCCCCCCC(=O)[O-]
Agent: [K+]
Agent: [Na+]
Product: O=C1CCCCCCCCCCCC(=O)OCCO1
Yield: 73.2 %

Procedure:
A mixed metal catalyst prepared similarly to that of Example X, except that sodium stearate was substituted for the potassium stearate and ethyl cellusolve replaced with diethylene glycol monoethyl ether, was employed for the continuous depolymerization of poly(ethylene brassylate) in accordance with the procedure and conditions of Example I. Ethylene brassylate was continuously produced and distilled from the reactor at a rapid rate and the overall yield was 73.2%. Comparable results are obtained with a catalyst comprised of sodium benzoate and aluminum tricellusolve (Al(OCH2CH2OC2H5)3).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12].[CH3:13][NH2:14]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:14][CH3:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12]
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Reactant: CN
Product: CNS(=O)(=O)c1ccc(Br)c(F)c1
Reaction time: 16 h
Yield: 85 %

Procedure:
According to general procedure A, 4-Bromo-3-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and methylamine (10 mL, 33% in ethanol) were stirred together for 16 hours. 4-bromo-3-fluoro-N-methylbenzenesulfonamide (0.33 g, 85%) was provided after purification. HRMS: calcd for C7H7BrFNO2S, 266.93649; found (EI, M+.), 266.9376. HPLC purity 100.0% at 210-370 nm, 8.7 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[CH3:9][O:10][C:11]1[C:16](B(O)O)=[CH:15][CH:14]=[CH:13][N:12]=1>>[Br:8][C:4]1[CH:3]=[C:2]([C:16]2[C:11]([O:10][CH3:9])=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)c1
Reactant: COc1ncccc1B(O)O
Product: COc1ncccc1-c1cccc(Br)c1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using 1,3-dibromo-benzene and 2-methoxy-3-pyridineboronic acid.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH3:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([CH3:27])[CH:26]=1)[CH:22]=O.O>CO>[CH3:18][C:19]1[CH:26]=[C:25]([CH:24]=[C:21]([CH3:22])[CH:20]=1)[CH2:27][NH:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4]
Reactant: Cc1cc(C)cc(C=O)c1
Reactant: C[C@H](N)[C@H](O)c1ccc(O)c(NS(C)(=O)=O)c1
Solvent: O
Solvent: CO
Product: Cc1cc(C)cc(CN[C@@H](C)[C@H](O)c2ccc(O)c(NS(C)(=O)=O)c2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 32.8 %

Procedure:
To a solution of the amine (4) (131 mg, 0.50 mmol) and 3,5-dimethylbenzaldehyde (90 μL, 0.65 mmol) in methanol (5 mL) was added borane-pyridine complex (160 μL, 1.50 mmol) at 40° C. and the resulting mixture was stirred for 1.5 hours. The reaction mixture was cooled to room temperature and water was added thereto, followed by extraction with a mixed solvent (ethyl acetate:methanol=10:1) and subsequent washing of the organic layer with saturated brine. The organic layer was dried and concentrated and the obtained crude product was purified by amine silica gel column chromatography (eluent; chloroform:methanol=7:1) to obtain the desired amine (9) as a white solid (62 mg, Yield: 33%).
Reaction SMILES: [C:1](=[O:22])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1.CCN(C(C)C)C(C)C.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:36][CH:35]=1>CN(C=O)C>[CH3:32][O:33][C:34]1[CH:35]=[CH:36][C:37]([N:40]2[CH2:45][CH2:44][N:43]([C:1]([O:2][CH2:3][CH2:4][N:5]3[CH2:6][CH2:7][N:8]([CH3:11])[CH2:9][CH2:10]3)=[O:22])[CH2:42][CH2:41]2)=[CH:38][CH:39]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: CN1CCN(CCOC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2CCN(C(=O)OCCN3CCN(C)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 17.2 %

Procedure:
2-(4-Methylpiperazin-1-yl)ethyl 4-nitrophenyl carbonate (Intermediate 4; 680 mg, 2.2 mmol) was dissolved in DMF (20 mL). DIPEA (0.76 mL, 4.4 mmol) and 4-(4-methoxyphenyl)piperazine (422 mg, 2.2 mmol) were added and the reaction mixture was stirred at room temperature for 24 hours, and the reaction mixture was then concentrated in vacuo. The residue was purified by normal phase column chromatography (eluting with DCM, followed by a 500:8:1 mixture of DCM:EtOH:NH3, followed by a 50:8:1 mixture of DCM:EtOH:NH3). The residue was recrystallised from EtOAc to give 2-(4-methyl-piperazin-1-yl)ethyl 4-(4-methoxyphenyl)piperazine-1-carboxylate (137 mg, 17%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]([OH:13])[C:9](OC)=[O:10])[CH:5]=[CH:4][CH:3]=1.[NH4+:14].[Cl-].N>CO>[Br:1][C:2]1[N:7]=[C:6]([CH:8]([OH:13])[C:9]([NH2:14])=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(O)c1cccc(Br)n1
Reactant: [NH4+]
Agent: N
Agent: [Cl-]
Solvent: CO
Product: NC(=O)C(O)c1cccc(Br)n1
Temperature: 25 °C

Procedure:
A mixture of methyl 2-(6-bromopyridin-2-yl)-2-hydroxyacetate (0.5, g, 2.03 mmol), NH4Cl (0.1, g) and NH3, (4N in MeOH) was shaken at room temperature over night. The solvent was removed under vacuum then added water (5, mL) and CHCl3, (20, mL) The organic layer was concentrated and purified by chromatographed over silica gel with 50% EtOAc in hexanes to yield 2-(6-bromopyridin-2-yl)-2-hydroxyacetamide as a yellow solid (0.2, g, 16%). 1H NMR (600, MHz, DMSO-d6) 7.77, (1H, dd, J=7.8, & 8.4, Hz), 7.58, (1H, d, J=8.4, Hz), 7.51-7.52, (2H, m), 7.35, (1 H, s), 6.23, (1H, d, J=0.5, Hz, —OH), 4.91 (1H, d, J=0.6, Hz).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:11]3[CH:12]=[C:13]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=3)[N:9]=[CH:10][C:3]=12.CC1(C)C(C)(C)[O:25][B:24](B2OC(C)(C)C(C)(C)O2)[O:23]1.C([O-])(=O)C.[K+].C(Cl)Cl>CS(C)=O>[S:17]([C:13]1[CH:12]=[C:11]([N:8]2[C:4]3=[N:5][CH:6]=[CH:7][C:2]([B:24]([OH:25])[OH:23])=[C:3]3[CH:10]=[N:9]2)[CH:16]=[CH:15][CH:14]=1)(=[O:19])(=[O:18])[NH2:20]
Reactant: NS(=O)(=O)c1cccc(-n2ncc3c(I)ccnc32)c1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: NS(=O)(=O)c1cccc(-n2ncc3c(B(O)O)ccnc32)c1
Temperature: 84 °C

Procedure:
To a 48 mL pressure bottle was added 3-(4-iodo-1H-pyrazolo[3,4-b]pyridin-1-yl)benzenesulfonamide, “dot” 2 1-methyl-2-pyrrolidinone complex (60 mg, 0.100 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (94.7 mg, 0.373 mmol), potassium acetate (24.4 mg, 0.249 mmol) and anhydrous DMSO (Volume: 2 mL). The reaction mixture was purged well with argon and treated with PdCl2(dppf).CH2Cl2 (12.5 mg, 0.017 mmol). The reaction mixture was then heated to 84° C. for 1 h to give the desired intermediate. LC/MS (Condition B): ret. T=2.4 min, (M+H)+ 318.98.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:14].S(Cl)(Cl)=O>CN(C)C=O>[CH3:15][C:2]1([CH3:1])[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[O:13])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:14]
Reactant: CC1(C)C(=O)Nc2cc(C(=O)O)ccc21
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CC1(C)C(=O)Nc2cc(C(=O)Nc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
8 g. 2,3-Dihydro-3,3-dimethyl-2-oxo-(1H)-indole-6-carboxylic acid and 1 drop of dimethylformamide were heated in 50 ml. thionyl chloride for 1 hour to the boil under reflux, the substance thereby going into solution. The thionyl chloride was removed under vacuum, the residue was suspended in dichloromethane and a solution of 1.6 ml. aniline and 2.7 ml. triethylamine in 30 ml. dichloromethane added dropwise thereto at an internal temperature of 15° C. The reaction mixture was stirred for 15 minutes at ambient temperature, the solvent was removed in a vacuum and the residue was digested with water, filtered off with suction and recrystallised from ethyl acetate. There were obtained 2.8 g. (56% of theory) of the title compound; m.p. 205-206° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)[CH3:17])[CH2:3][CH2:2]1.[CH3:28][C:29]([CH3:31])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CC(O)=O>[CH:29]([N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)[CH3:17])[CH2:3][CH2:2]1)([CH3:31])[CH3:28]
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1C1CCNCC1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)N1CCC(n2c([C@H](C)Nc3ncnc4[nH]cnc34)nc3ccccc32)CC1
Reaction time: 0.08 h
Yield: 24.4 %

Procedure:
To a mixture of (S)—N-(1-(1-(piperidin-4-yl)-1H-benzo[d]imidazol-2-yl)ethyl)-9H-Aurin-6-amine from Example 113 (81 mg, 0.223 mmol) in anhydrous DCM (2 mL) was added acetone (49 μL, 0.67 mmol) followed by AcOH (1 drop). After stirring for 5 min, sodium triacetoxyborohydride (71 mg, 0.335 mmol) was added and stirring was continued for 19 h. The crude reaction mixture was loaded into an Isolute® SCX-2 which was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo and the resulting residue was purified by preparative HPLC (Phenomenex Gemini 5 μm C18 on a 20 min gradient 5-40% 0.1% NH4OH in acetonitrile/water) followed by Isolute® SCX-2 purification. The cartridge was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo affording 131 as a pale yellow solid (22 mg, 24%). LCMS: RT 1.68 min [M+H]+ 405.1. 1H NMR (DMSO plus TFA, 400 MHz): δ 8.82 (1H, bs), 8.57 (1H, s), 8.22 (1H, d, J=8.16 Hz), 7.77 (1H, d, J=7.78 Hz), 7.64-7.52 (2H, m), 5.97 (1H, bs), 5.49-5.35 (1H, br), 3.79-3.58 (3H, m), 3.43-3.24 (2H, m), 3.00-2.78 (2H, m), 2.68-2.48 (3H, m), 2.38 (1H, bd, J=16.58 Hz), 1.89 (3H, d, J=6.93 Hz), 1.36 (6H, dd, J=6.61, 2.47 Hz)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH2:17])(=[O:16])=[O:15].[CH3:18][N:19]([CH3:24])[S:20](Cl)(=[O:22])=[O:21]>C(#N)C>[CH3:18][N:19]([CH3:24])[S:20]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH2:17])(=[O:15])=[O:16])(=[O:22])=[O:21]
Reactant: NS(=O)(=O)c1ccccc1O
Reactant: CN(C)S(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(C)S(=O)(=O)Oc1ccccc1S(N)(=O)=O
Reaction time: 0.17 h
Yield: 70.1 %

Procedure:
4.0 g (29 mmol) of potassium carbonate were added to a solution of 5.0 g (29 mmol) of 2-hydroxybenzenesulfonamide in 200 ml of acetonitrile at 25° C. Stirring was carried out for 10 minutes, after which 4.1 g (29 mmol) of dimethylaminosulfonyl chloride were added dropwise at 25° C. and stirring was continued for a further 16 hours at this temperature. The volatile constituents were removed under reduced pressure from a water pump, the residue was taken up in ethyl acetate, the solution was dried over Na2SO4 and the solvent was removed under reduced pressure from a water pump. The remaining residue was stirred vigorously for 1 hour with 100 ml of diethyl ether. The crystalline product was filtered off under suction and dried at 40° C. under reduced pressure. 5.7 g of the title compound were obtained in this manner.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.[CH2:26]([S:28](Cl)(=[O:30])=[O:29])[CH3:27].C(N(CC)CC)C>ClCCl>[CH3:1][N:2]([CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1)[S:28]([CH2:26][CH3:27])(=[O:30])=[O:29]
Reactant: CCS(=O)(=O)Cl
Reactant: CNC1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N(C)C1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
A mixture of compound 7B (15 mg, 0.044 mmol), ethanesulfonyl chloride (5 μL, 1.5 eq), triethylamine (15 μL, 3.0 eq) and dichloromethane (1 mL) was stirred at room temperature overnight. The clear solution was directly loaded on silica gel column and eluted with 0.5% ammonium hydroxide and 5% methanol in dichloromethane to give the desired product (12.5 mg, 82% yield)
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[NH2:41][C:42]1[CH:43]=[CH:44][C:45]([N:51]2[CH2:55][CH2:54][CH2:53][CH2:52]2)=[C:46]([CH:50]=1)[C:47]([OH:49])=[O:48]>ClCCl>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C@@:12]2([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[NH:10][C@@H:9]([C:28]([NH:41][C:42]3[CH:43]=[CH:44][C:45]([N:51]4[CH2:55][CH2:54][CH2:53][CH2:52]4)=[C:46]([CH:50]=3)[C:47]([OH:49])=[O:48])=[O:29])[C@@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:31])=[C:16]([F:22])[CH:17]=1
Reactant: Nc1ccc(N2CCCC2)c(C(=O)O)c1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(N3CCCC3)c(C(=O)O)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reaction time: 2 h
Yield: 17.4 %

Procedure:
To a stirred solution of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (60 mg, 0.128 mmol) in dichloromethane (5.00 ml) were added N,N-DIISOPROPYLETHYLAMINE (99.6 mg, 0.770 mmol) and N,N,N′,N′-tetramethyl-O-(7-aza-benzotriazol-1-yl)uranium hexafluorophosphate (HATU) (90.3 mg, 0.237 mmol, Chem-Impex) followed by 5-amino-2-(pyrrolidin-1-yl)benzoic acid (38.5 mg, 0.187 mmol, Array). The reaction mixture was stirred for 2 hr. The reaction mixture was diluted with CH2Cl2 (80 mL), washed with sat Na2CO3 (2×15 mL), water (2×15 mL) and evaporated. The crude material was purified by flash chromatography (silica gel, 8 g, 0.5% to 5% MeOH in CH2Cl2) to give rac-5-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2-pyrrolidin-1-yl-benzoic acid as white solid (14.6 mg, 15.4%). MS (ES+) m/z Calcd: [(M+H)+]: 655. found: 655.
Reaction SMILES: [CH3:1][C:2]1[S:22][C:5]2[NH:6][C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)[C:4]=2[CH:3]=1.[H-].[Na+].[CH:25](Br)([CH3:27])[CH3:26].O>CN(C)C=O>[CH3:1][C:2]1[S:22][C:5]2[N:6]([CH:25]([CH3:27])[CH3:26])[C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)[C:4]=2[CH:3]=1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2c(s1)N(C(C)C)c1ccccc1N=C2N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine (3.12 g) in dry dimethylformamide (50 ml) was added sodium hydride (0.63 g, 50% dispersion). The reaction mixture was stirred for 30 minutes at room temperature, then 30 minutes at 60-70° C. The reaction was cooled to 40° C., isopropyl bromide (1.13 ml) added and left for one hour. Water was added and the reaction extracted with ethyl acetate, washed with water, dried and evaporated under reduced pressure. Chromatography using 2% methanol/dichloromethane and flash silica gave the title compound, m.p. 120-121° C. Similarly prepared from the same starting material were:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[C:28]([F:31])([F:30])[F:29])[N:15]=[CH:14]3)/[S:6][C:5]1=[O:32].[C:33](OC(=O)C)(=[O:35])[CH3:34]>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:16]2[C:17]3[C:13](=[CH:12][C:11](/[CH:10]=[C:7]4/[C:8](=[O:9])[N:4]([CH2:3][CH2:2][NH:1][C:33](=[O:35])[CH3:34])[C:5](=[O:32])[S:6]/4)=[CH:19][CH:18]=3)[CH:14]=[N:15]2)=[C:22]([C:28]([F:30])([F:29])[F:31])[CH:23]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O
Product: CC(=O)NCCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
N-{2-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]ethyl}acetamide was prepared from 3-(2-aminoethyl)-(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione (from Example 49) and acetic anhydride following General Procedure U.
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[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:23][C:24]1[C:32]([OH:33])=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[CH:27][NH:28]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:23][C:24]1[C:32]([O:33][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[CH:27][NH:28]2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1
Reactant: Oc1ccc2[nH]ccc2c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3F)ncnc2cc1OCCCN1CCCC1
Temperature: 95 °C
Yield: 51.9 %

Procedure:
A solution of 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (1.76 g, 5.47 mmol), (prepared as described for the starting material in Example 9), 4-fluoro-5-hydroxyindole (0.992 g, 6.57 mmol), (prepared as described for the starting material in Example 242), in DMF (25 ml) containing potassium carbonate (1.14 g; 8.21 mmol) was heated at 95° C. for 1 hour. After cooling, the mixture was filtered and washed with DMF. The filtrate was evaporated and the residue was purified by column chromatography eluting with methanol/methylene chloride (1/9) followed by methanol/methanol chloride/methanol (containing ammonia) (16/80/4). The fractions containing the expected product were combined and evaporated. The residue was repurified by column chromatography eluting with a gradient of methylene chloride/methanol (80/20 to 40/60). The fractions containing the expected product were combined and evaporated. The residue was triturated in cold methanol and the solid was filtered, washed with ether and dried under vacuum to give 4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (1.24 g, 52%).