Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([C:12](=[N:14]O)[NH2:13])=[CH:10][CH:11]=1)=[O:4].[CH2:16]([O:18][C:19]([C:21]#[C:22][C:23]([O:25]CC)=O)=[O:20])[CH3:17].C[OH:29]>>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:14]=[C:21]([C:19]([O:18][CH2:16][CH3:17])=[O:20])[C:22]([OH:29])=[C:23]([OH:25])[N:13]=2)=[N:8][CH:7]=1)=[O:4]
Reactant: CO
Reactant: NC(=NO)c1ccc(NC(=O)CCl)cn1
Reactant: CCOC(=O)C#CC(=O)OCC
Product: CCOC(=O)c1nc(-c2ccc(NC(=O)CCl)cn2)nc(O)c1O
Temperature: 142.5 °C
Reaction time: 8 h

Procedure:
A mixture of compound of example 4 (2.0 g, 8.75 mmol) and diethylacetylene dicarboxylate (0.34 g, 2.36 mmol) was stirred in methanol (20 mL) at a temperature in the range of 60-65° C. for 4 hours. Methanol was removed under reduced pressure and xylene (20 mL) was added and the reaction mixture was heated at a temperature in the range of 140-145° C. for 18 hours. A brownish colored solid obtained was removed by filtration, and the reaction mixture was again stirred at the same temperature for 8 hours to obtain the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)=[O:5])[CH3:2].[Br:11][CH2:12][C:13]1[CH:24]=[CH:23][C:16]([CH:17]=[CH:18][C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=1>C(#N)C>[Br-:11].[CH2:1]([O:3][C:4]([N+:6]1[CH:10]=[CH:9][N:8]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH:17]=[CH:18][C:19]([O:21][CH3:22])=[O:20])=[CH:23][CH:24]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)n1ccnc1
Reactant: COC(=O)C=Cc1ccc(CBr)cc1
Solvent: CC#N
Product: CCOC(=O)[n+]1ccn(Cc2ccc(C=CC(=O)OC)cc2)c1
Product: [Br-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.4 %

Procedure:
To 5 ml of dry acetonitrile were added 1.4 g of 1-ethoxycarbonylimidazole and 2.55 g of methyl 4-bromomethylcinnamate, the mixture was stirred for 5 hours at room temperature. The precipitated crystals were collected by filtration and recrystallized from acetonitrile/diethyl ether to yield 2.9 g of 1-ethoxycarbonyl-3-[4-(2-methoxycarbonylvinyl)benzyl]imidazolium bromide.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5](Cl)[C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][N:8]=2)[N:3]=1.[CH3:17][N:18]([CH3:29])[CH2:19][CH2:20][O:21][C:22]1[N:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1>>[Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2[NH:28][C:25]1[CH:26]=[N:27][C:22]([O:21][CH2:20][CH2:19][N:18]([CH3:29])[CH3:17])=[CH:23][CH:24]=1
Reactant: CS(=O)(=O)c1cnc2ccc(Cl)nc2c1Cl
Reactant: CN(C)CCOc1ccc(N)cn1
Product: CN(C)CCOc1ccc(Nc2c(S(C)(=O)=O)cnc3ccc(Cl)nc23)cn1
Yield: 70.2 %

Procedure:
Following general procedure I, 2,8-dichloro-7-(methylsulfonyl)-1,5-naphthyridine (150 mg, 0.54 mmol) was reacted with 6-[2-(dimethylamino)ethoxy]pyridin-3-amine (120 mg, 0.65 mmol) to afford the desired product (160 mg, 70%) as a light yellow solid. 1H NMR (500 MHz, CDCl3) δ 9.03 (s, 1H), 8.98 (s, 1H), 8.17 (d, J=8.8 Hz, 1H), 7.98 (d, J=2.8 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.42 (dd, J=8.8, 2.8 Hz, 1H), 6.82 (d, J=8.8 Hz, 1H), 4.46 (t, J=5.5 Hz, 2H), 3.20 (s, 3H), 2.76 (t, J=5.6 Hz, 2H), 2.37 (s, 6H); ESI MS m/z 422 [M+H]+
Reaction SMILES: [N:1]1([CH:5]2[CH:14]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13]3[CH:12]=[C:11]([CH2:22][NH2:23])[CH:10]=[CH:9][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[CH3:24][N:25]1[CH:29]=[C:28]([S:30](Cl)(=[O:32])=[O:31])[N:27]=[CH:26]1>CN(C1C=CN=CC=1)C.ClCCl>[N:1]1([CH:5]2[CH:14]([CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:13]3[CH:12]=[C:11]([CH2:22][NH:23][S:30]([C:28]4[N:27]=[CH:26][N:25]([CH3:24])[CH:29]=4)(=[O:32])=[O:31])[CH:10]=[CH:9][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: NCc1ccc2c(c1)C(Cc1ccccc1)C(N1CCC1)CC2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cn1cnc(S(=O)(=O)NCc2ccc3c(c2)C(Cc2ccccc2)C(N2CCC2)CC3)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(7-(Azetidin-1-yl)-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl)methanamine (250 mg, 0.816 mmol) and N,N-dimethyl-4-aminopyridine (199 mg, 1.632 mmol) were dissolved in dichloromethane (18 mL). 1-Methyl-1H-imidazole-4-sulfonyl chloride (147 mg, 0.816 mmol) dissolved in dichloromethane (2 mL) was added dropwise. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with dichloromethane (20 mL) and washed successively with saturated ammonium chloride (3×15 mL) and water (2×10 mL). The organic phase was dried (MgSO4) and the solvent was evaporated in vacuo. The crude product was purified by flash chromatography (silica gel, dichloromethane, methanol). Yield: 64 mg (0.142 mmol, 17%).
Reaction SMILES: Cl.[CH3:2][NH:3][CH:4]1[CH2:19][C:8]2[C:9]3[NH:10][C:11](=[O:18])[C:12](=[O:17])[NH:13][C:14]=3[CH:15]=[CH:16][C:7]=2[CH2:6][CH2:5]1.[N+:20]([O-])([OH:22])=[O:21]>FC(F)(F)C(O)=O>[CH3:2][NH:3][CH:4]1[CH2:19][C:8]2[C:9]3[NH:10][C:11](=[O:18])[C:12](=[O:17])[NH:13][C:14]=3[CH:15]=[C:16]([N+:20]([O-:22])=[O:21])[C:7]=2[CH2:6][CH2:5]1
Reactant: O=[N+]([O-])O
Reactant: CNC1CCc2ccc3[nH]c(=O)c(=O)[nH]c3c2C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CNC1CCc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1

Procedure:
9-Methylamino-1,2,3,4,7,8,9,10-octahydrobenzo[f]quinoxaline-2,3-dione hydrochloride (1 g, 3.5 mmol) was nitrated using fuming nitric acid (1 mL) and trifluoroacetic acid (30 mL) from 0° C. to room temperature for 1 h. The solvent was removed and their residue triturated in acetone:water and collected by filtration and dried to give the product (1.1 g). Calc'd for C13H14N4O4.HCl: C, 47.79; H, 4.63; N, 17.15; found: C, 43.36; H, 4.22; N, 18.85. MS M+1 (291).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[Li]CCCC.[NH2:12][C:13]1[C:18]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])=[CH:17][C:16]([Cl:27])=[CH:15][C:14]=1[C:28](=[O:33])[C:29]([F:32])([F:31])[F:30]>C1COCC1>[NH2:12][C:13]1[C:18]([O:19][Si:20]([C:23]([CH3:26])([CH3:24])[CH3:25])([CH3:21])[CH3:22])=[CH:17][C:16]([Cl:27])=[CH:15][C:14]=1[C:28]([OH:33])([C:2]#[C:3][CH:4]1[CH2:6][CH2:5]1)[C:29]([F:32])([F:31])[F:30]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(Cl)cc(C(=O)C(F)(F)F)c1N
Reactant: C#CCCCCl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cc(Cl)cc(C(O)(C#CC2CC2)C(F)(F)F)c1N
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 70.4 %

Procedure:
To a stirred, cooled (0° C.) solution of 31.8 mL (300 mmol) of 5-chloro-1-pentyne in 250 mL of THF was added 252 mL (630 mmol) of 2.5 M n-BuLi in hexanes over 20 min. Over the course of the addition the internal temperature had warmed to ambient temperature, and the mixture was stirred at this temperature for 40 min. The reaction was cooled to −20° C. and treated with a solution of 32.7 g (97.4 mmol) of 2′-amino-5′-chloro-3′-(t-butyldimethylsilyloxy)-2,2,2-trifluoroacetophenone in 50 mL of THF over 10 min. The dark solution was stirred an additional 30 min. and the cold bath was removed. The reaction was stirred 5 min and poured into 800 mL of 0° C. 1 N citric acid with rapid stirring. The mixture was extracted twice with ether, and the combined organic extracts were washed with water then brine, dried (MgSO4), and concentrated under reduced pressure. Chromatography on silica gel (elution with hexanes then 3:1 hexanes-ether) afforded 28.8 g (70%) of (+/−)-2-(2-amino-5-chloro-3-(t-butyldimethylsilyloxy)phenyl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol as an off-white solid, mp 125-126° C. 1H NMR (300 MHz, CDCl3) δ7.22(d, 1H, J=2.2 Hz); 6.76(d, 1H, J=2.2 Hz) ; 4.86(br. s, 1H); 4.39(br. s, 2H); 1.32-1.43(m, 1H); 1.02(s, 9H); 0.79-0.92(m, 4H); 0.27(s, 3H); 0.26(s, 3H). High resolution mass spec: calculated for C19H26NO2ClF3Si(M+H)+: 420.1373, found: 420.1363.
Reaction SMILES: C(O[CH:5]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:12][C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)(=O)C.[NH2:19][CH:20]1[CH2:24][CH2:23][N:22]([CH2:25][CH3:26])[CH2:21]1>C1(C)C=CC=CC=1>[CH2:25]([N:22]1[CH2:23][CH2:24][CH:20]([NH:19][CH:5]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[O:12][C:13]3[C:18]2=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:21]1)[CH3:26]
Reactant: CC(=O)OC1c2ccccc2Oc2ccccc21
Reactant: CCN1CCC(N)C1
Solvent: Cc1ccccc1
Product: CCN1CCC(NC2c3ccccc3Oc3ccccc32)C1

Procedure:
Refluxing 4.0 g. of 9-acetoxyxanthene and 2.05 g. of 3-amino-1-ethylpyrrolidine in 175 ml. of dry toluene for 24 hours, then working up as in Example 1 gives N-(N-ethyl-3-pyrrolidinyl)-9 -xanthenylamine.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([S:20]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=2)[N:8]=1)=O.[CH:29]1[C:38]2[C:33](=[C:34]([NH:39][NH2:40])[CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][N:30]=1>>[CH2:24]([N:23]([CH2:26][CH3:27])[S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:39]([C:34]4[CH:35]=[CH:36][CH:37]=[C:38]5[C:33]=4[CH:32]=[CH:31][N:30]=[CH:29]5)[N:40]=[CH:3][CH:4]=3)=[N:8]2)[CH:15]=1)(=[O:22])=[O:21])[CH3:25]
Reactant: NNc1cccc2cnccc12
Reactant: CCN(CC)S(=O)(=O)c1cccc(-n2ccc(=O)c(C(=O)/C=C/N(C)C)n2)c1
Product: CCN(CC)S(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3cccc4cnccc34)n2)c1

Procedure:
The product was obtained starting from 3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-N,N-diethyl-benzenesulfonamide (A-21) and isoquinolin-5-yl-hydrazine according to the method described for example 91. MS: M=501.2 (M+H)+
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C@@H:4]([C:5]#[C:6][C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:8])[C@H:3]1[C:15]([OH:17])=[O:16].N1C2C(=CC=CC=2)C=CC=1>C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[CH3:18][C:2]1([CH3:1])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:8])[C@H:3]1[C:15]([OH:17])=[O:16]
Reactant: CCCCCOC(=O)C#C[C@H]1[C@@H](C(=O)O)C1(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: c1ccc2ncccc2c1
Product: CCCCCOC(=O)/C=C\[C@H]1[C@@H](C(=O)O)C1(C)C
Yield: 62 %

Procedure:
A mixture of 4.8 g of the product of Step B, 50 ml of ethyl acetate, 1 ml of quinoline, 1 g of 10% palladium hydroxide on barium sulfate in 50 ml of ethyl acetate was hydrogenated and the mixture was filtered. The filtrate was washed with N hydrochloric acid, then with water, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 70-30-1 cyclohexane-ethyl acetate-acetic acid mixture to obtain 3 g of (1R,cis) 2,2-dimethyl-3-[Z-2-(pentyloxycarbonyl)-ethenyl]-cyclopropane-carboxylic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12]O[C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C(=O)C=COC=1C)C1C=CC=CC=1.C([N:36]1C=C[C:39](=[O:42])[C:38](O)=[C:37]1C)(=O)C.OCCCN.OCCN>>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:36]([CH2:37][CH2:38][CH2:39][OH:42])[C:10]=1[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)n1ccc(=O)c(O)c1C
Reactant: Cc1occc(=O)c1OCc1ccccc1
Agent: NCCCO
Solvent: NCCO
Product: Cc1c(OCc2ccccc2)c(=O)ccn1CCCO

Procedure:
3-Benzyloxy-2-methyl-4-pyrone, prepared as described under (J), is reacted with 3-hydroxypropylamine under substantially similar conditions to those described under (K) for reaction with 2-hydroxyethylamine to give 3-benzyloxy-1-(3'-hydroxypropyl)-2-methylpyrid-4-one. This is deprotected using the procedure described under (K) to give 3-hydroxy-1-(3'-hydroxypropyl)-2-methylpyrid-4-one as white crystals, m.p. 111°-113° C.; δmax (nujol) 1630, 3150, 3350 cm-1, δ(d6DMSO) 1.8 (m, 2H), 2.4 (s, 3H), 3.35 (t, 2H), 4.33 (t, 2H), 7.3 (d, 1H), 8.2 (d, 1H).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCCCCCCCCCCCCCCC[CH2:26][O:27][C:28]([CH2:30][CH2:31]C1C=C(C(C)(C)C)[C:35]([OH:42])=[C:34]([C:43](C)(C)C)[CH:33]=1)=[O:29].CO>C1C2C(CCCC2)CCC1.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[C:28]([O:27][CH3:26])(=[O:29])[C:30]([CH3:31])=[CH2:1].[C:35]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:42])[C:34]([CH3:43])=[CH2:33]
Reactant: OCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCOC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CO
Solvent: C1CCC2CCCCC2C1
Product: C=C(C)C(=O)OC
Product: C=C(C)C(=O)OCc1ccccc1
Temperature: 185 °C

Procedure:
350 grams (3.5 mole) of polymethylmethacrylate (Plexiglass VO 44 from Rohm & Haas), 378 grams of benzyl alcohol (3.5 mole) and 0.54 gram (0.1 mole %) of an antioxidant Irganox 1076 were heated to 180° C. to dissolve them in 550 cc of decalin. 13.86 grams of tetraisopropyl titanate was added and the temperature was maintained at 180-190° C. for 14 hours, and during this time 23 ml of distillate containing methanol was collected and the reaction was stopped. The polymer was precipitated in methanol then washed with hexane. After drying at 55° C. overnight in an vacuum oven, 404 gram of polymer were recovered with a DSC melting point of 93-94° C. NMR analysis showed a 22.6% conversion of methyl ester to benzyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([OH:14])=[C:12]([C:15](OCC)=[O:16])[C:11](=[O:20])[N:10]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:9]2=[O:28])=[CH:4][CH:3]=1.C1(CNC([CH:39](C(OCC)=O)[C:40]([O:42]CC)=[O:41])=O)C=CC=CC=1.[H-].[Na+].ClC1C=CC([N:59]=C=O)=CC=1.Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13]([OH:14])=[C:12]([C:15]([NH:59][CH2:39][C:40]([OH:42])=[O:41])=[O:16])[C:11](=[O:20])[N:10]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:9]2=[O:28])=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CCOC(=O)C(C(=O)NCc1ccccc1)C(=O)OCC
Reactant: CCOC(=O)c1c(O)n(-c2ccc(Cl)cc2)c(=O)n(Cc2ccccc2)c1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)CNC(=O)c1c(O)n(-c2ccc(Cl)cc2)c(=O)n(Cc2ccccc2)c1=O
Reaction time: 0.17 h
Yield: 56 %

Procedure:
Ethyl 1-(4-chlorophenyl)-6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate. Diethyl {[(phenylmethyl)amino]carbonyl}propanedioate (293 mg, 1.0 mmoles) was added to a suspension of sodium hydride (60% suspension in mineral oil, 100 mg, 2.5 mmoles) in dry tetrahydrofuran (50 mL) and stirred for 10 minutes under argon. 4-Chlorophenyl isocyanate was added and the mixture was heated under reflux for 2 hours, cooled, acidified with 1 molar hydrochloric acid and extracted with ethyl acetate. Flash chromatography (hexane-ethyl acetate) afforded the title compound (225 mg, 56%) 1H NMR (400 MHz, DMSO-d6) δ ppm 1.06 (t, J=7.07 Hz, 3 H) 3.45 (q, J=7.07 Hz, 2 H) 5.00 (s, 2 H) 7.25-7.28 (m, 1 H) 7.30-7.37 (m, 6 H) 7.53 (d, J=8.59 Hz, 2 H).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:34][O:35][C:36](=[O:39])[CH2:37]Br>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9](=[O:10])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:37][C:36]([O:35][CH3:34])=[O:39])=[C:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CBr
Reactant: O=C(OCc1ccccc1)c1ccc(O)c(C(=O)OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1ccc(C(=O)OCc2ccccc2)cc1C(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 120 h
Yield: 54.3 %

Procedure:
In DMF (15 mL) was stirred 4-hydroxy-1,3-benzenedicarboxylate dibenzyl ester (500 mg, 1.4 mmol) and potassium carbonate (276 mg, 2.0 mmol). To this was added methylbromoacetate (230 mg, 1.5 mmol) and the solution warmed to 50° C. and stirred 120 hours. The mixture filtered free of insoluble material and the DMF solution evaporated at reduced pressure to give a red oil. The oil was dissolved in ethyl acetate (50 mL) and washed successively with 10% citric acid (50 ML), saturated sodium bicarbonate solution (50 mL), and brine (50 mL). The organic phase dried over magnesium sulfate and evaporated at reduced pressure to give an oil. The oil was purified by MPLC (90 g silica gel, 2:1[hexane:ethyl acetate]) to give 330 mg (54%) of a clear oil. MS: M+1=435.2.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])=[O:10])=[C:5]([F:17])[CH:4]=1.[NH4+:18].[OH-]>C1COCC1.CO>[NH2:18][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])=[O:10])=[C:5]([F:17])[CH:4]=1
Reactant: [NH4+]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(CBr)cc1F
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1ccc(CN)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(bromomethyl)-N-tert-butyl-2-fluorobenzenesulfonamide (500 mg) in THF/MeOH (1:1, 15 ml) was added NH4OH (4.5 ml). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated and partitioned between EtOAc/H2O and the aq phase was extracted by EtOAc (3×). The organic phase was then combined, washed with brine, dried over Na2SO4 and concentrated to give 4-(aminomethyl)-N-tert-butyl-2-fluorobenzenesulfonamide as a viscous oil, which was used in the next step without further purification.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[C:15]([F:21])[CH:16]=[C:17]([F:20])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[N:23]1[C:28]2[O:29][CH2:30][CH2:31][O:32][C:27]=2[CH:26]=[C:25]([CH:33]=[O:34])[N:24]=1>>[CH:11]([OH:22])=[O:29].[CH:33]([OH:34])=[O:22].[N:23]1[C:28]2[O:29][CH2:30][CH2:31][O:32][C:27]=2[CH:26]=[C:25]([CH2:33][NH:1][CH:2]2[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]3[C:19]4[C:14](=[C:15]([F:21])[CH:16]=[C:17]([F:20])[CH:18]=4)[CH:13]=[CH:12][C:11]3=[O:22])[CH2:6][CH2:7]2)[N:24]=1
Reactant: O=Cc1cc2c(nn1)OCCO2
Reactant: NC1CCN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC1
Product: O=CO
Product: O=c1ccc2c(F)cc(F)cc2n1CCN1CCC(NCc2cc3c(nn2)OCCO3)CC1

Procedure:
The title compound was prepared by the general method of Example 32(g) using 1-[2-(4-amino-1-piperidinyl)ethyl]-5,7-difluoro-2(1H)-quinolinone and 6,7-dihydro[1,4]dioxino[2,3-c]pyridazine-3-carbaldehyde to give the desired product directly as the diformate salt (34 mg; 15%).
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:9][CH2:10][S:11][CH3:12])[C:6]([OH:8])=O)(=[O:3])[CH3:2].S(Cl)(Cl)=O.C(N(CC)CC)C.[CH2:24]([NH2:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>ClCCl>[C:1]([O:4][CH:5]([CH2:9][CH2:10][S:11][CH3:12])[C:6]([NH:32][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:8])(=[O:3])[CH3:2]
Reactant: CCCCCCCCN
Reactant: CSCCC(OC(C)=O)C(=O)O
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCCCCCCNC(=O)C(CCSC)OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-acetoxy-4-(methylthio)butanoic acid (6.10 g, 31.7 mmol) in dichloromethane (100 mL) at 0° C. was added thionyl chloride (11.53 mL, 158.5 mmol) slowly over 30 min. The reaction was allowed to warm to room temperature with stirring overnight. The solvent was evaporated and the resulting oil was dried on the high vacuum for 3 hrs. To a solution of the resulting oil in dichloromethane (100 mL) at 0° C. was added triethylamine (8.84 mL, 63.4 mmol) and then octylamine (5.24 mL, 31.7 mmol) and the reaction was allowed to warm to room temperature with stirring overnight. The reaction was evaporated, redissolved in EtOAc (150 mL) and washed with 1N HCl (3×100 mL), saturated sodium bicarbonate (3×100 mL), and brine (1×100 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated to give an oil. The oil was purified by silica gel chromatography with 0-30% EtOAc/heptane to give a yellow oil. (6.61 g, 69%). m/z 304 (MH+).
Reaction SMILES: N1C2C(=CC(C(OCC3C=CC=CC=3)=O)=CC=2)C=C1.Br[CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=1[O:32][CH3:33].[I-:34].[K+]>CN(C)C=O>[I:34][CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=1[O:32][CH3:33]
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Reactant: [I-]
Agent: O=C(OCc1ccccc1)c1ccc2[nH]ccc2c1
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CI)c(OC)c1
Yield: 26.3 %

Procedure:
A solution of benzyl indole-5-carboxylate (86.8 g), methyl 4-bromomethyl-3-methoxybenzoate (89.5 g) and potassium iodide (57.4 g) in N,N-dimethylformamide (900 mL) was heated to 80° C. for 10 hours. The reaction mixture was evaporated and partitioned between diethyl ether and water. The organic layer was separated and washed with water. The aqueous washes were combined and extracted with diethyl ether. The combined organic extract was dried (MgSO4) and evaporated. The residue was purified by flash chromatography, eluting sequentially with 0:1:1, 2:48:50, 4:46:50, 5:45:50, and 10:40:50 ethyl acetate:hexane:methylene chloride, to afford methyl 4-iodomethyl-3-methoxybenzoate (27.8 g), recovered benzyl indole-5-carboxylate (29.6 g), and the crude product as a tan solid (50.6 g). Treatment of the recovered benzyl indole-5-carboxylate (29.6 g) in N,N-dimethylformamide (250 mL) with methyl 4-iodomethyl-3-metboxybenzoate (29.8 g) at 80° C. for 12 hours, followed by evaporation, gave a dark residue, which was dissolved in diethyl ether and washed with water (3 times). The aqueous washes were combined and extracted with diethyl ether. The combined organic extract was dried (MgSO4) and evaporated. The residue was purified by flash chromatography, eluting sequentially with 0:1:1, 2:48:50, 5:45:50, and 10:40:50 ethyl acetate:hexane:methylene chloride, to give further crude product as a tan solid (31.9 g). The combined crude product (82.5 g) was suspended in diethyl ether (400 mL), heated to reflux for 30 min, cooled and filtered to obtain methyl 4-(5-benzyloxycarbonylindol-3-ylmethyl)-3-methoxybenzoate as an ivory solid (46.1 g, 31%); partial NMR (250 MHz, CDCl3): 3.84 (s, 3H, CO2CH3), 3.88 (s, 3H, OCH3), 4.14 (s, 2H, CH2), 5.35 (s, 2H, OCH2), 6.97 (d, 1H, indole-H(2)), 8.15 (br, 1 H, NH), 8.37 (s, 1H, indole-H(4)).
Reaction SMILES: Br[C:2]1[C:3]([CH3:23])=[C:4]([C:7]([NH:9][C:10]2[CH:15]=[C:14]([C:16](=[O:21])[NH:17][CH:18]3[CH2:20][CH2:19]3)[CH:13]=[CH:12][C:11]=2[CH3:22])=[O:8])[S:5][CH:6]=1.[F:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:30]=1>>[CH:18]1([NH:17][C:16]([C:14]2[CH:13]=[CH:12][C:11]([CH3:22])=[C:10]([NH:9][C:7]([C:4]3[S:5][CH:6]=[C:2]([C:29]4[CH:28]=[N:27][CH:26]=[C:25]([F:24])[CH:30]=4)[C:3]=3[CH3:23])=[O:8])[CH:15]=2)=[O:21])[CH2:20][CH2:19]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1scc(Br)c1C
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1scc(-c2cncc(F)c2)c1C

Procedure:
The title compound was prepared by coupling 4-bromo-N-(5-(cyclopropylcarbamoyl)-2-methylphenyl)-3-methylthiophene-2-carboxamide with commercially available 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine using the method described in Step B of Example 136 to afford a white solid (Example 200). HPLC Ret time=2.98 min. LCMS [M+H]+ 410.22.