Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH3:10])[CH:3]=1.[Mg].[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>O1CCCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:19])=[CH:3][C:4]=1[CH3:10]
Reactant: COc1ccc(Br)cc1C
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2ccccc2)cc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
The corresponding Grignard reagent was prepared from 10 g of 4-bromo-2-methylanisole and 1.21 g of magnesium shavings in 30 ml of tetrahydrofuran and was added dropwise to a solution, pre-cooled to -72°, of 7 g of benzoyl chloride in 80 ml of tetrahydrofuran. In so doing, the temperature was held at below -65°. After the dropwise addition the mixture was stirred at 20° for 0.5 hour, whereupon it was hydrolyzed with 400 ml of ice-water. The solution, acidified with dilute hydrochloric acid, was extracted with ether and the organic phase was dried and evaporated. By chromatography of the residue on silica gel with hexane:ethyl acetate (7:3) there were obtained 6.17 g (55%) of 4-methoxy-3-methylbenzophenone as a yellowish oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2.[CH3:17][N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1.C[O-].[Na+]>CO>[CH3:17][N:18]1[CH2:23][CH2:22][C:21]([C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[C:8]([O:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH:9]=3)[NH:13][CH:12]=2)=[CH:20][CH2:19]1
Reactant: c1ccc(Oc2ccc3[nH]ccc3c2)nc1
Reactant: CN1CCC(=O)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CN1CC=C(c2c[nH]c3ccc(Oc4ccccn4)cc23)CC1

Procedure:
5-(Pyrid-2-yloxy)indole (0.22 g, 1.04 mmol), 1-methylpiperid-4-one (0.235 g, 2.08 mmol) and sodium methoxide (0.337 g) were heated at reflux in MeOH (20 mL) for 48 hr, over activated molecular sieves. After cooling and work-up, the residue was chromatographed (silica gel; CH2Cl2 /MeOH; 0-25%) to give 3-(1-methyl-1,2,5,6-tetrahydropyrid-4-yl)-5-(pyrid-2-yloxy)indole, a gum, 0.083 g (26%). This free base was treated with oxalic acid in MeOH/Et2O to give: 3-(1-methyl-1,2,5,6-tetrahydropyrid-4-yl)-5-(pyrid-2-yloxy)indole oxalate, m.p. 240°-45° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]2[C:4](=[C:5](Br)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[C:22]=1B(O)O.O>COCCOC.O.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>[CH3:1][C:2]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]2[C:4](=[C:5]([C:22]3[C:23]([CH3:28])=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=3[CH3:20])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(C)c(B(O)O)c(C)c1
Reactant: Cc1cc(Oc2ccccc2)c2cccc(Br)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: O
Product: Cc1cc(C)c(-c2cccc3c(Oc4ccccc4)cc(C)nc23)c(C)c1
Temperature: 80 °C
Yield: 72 %

Procedure:
Part C: To a solution of 5.2 g (16.5 mmol) of 2-methyl-4-phenoxy-8-bromo-quinoline in 175 ml DME-water (6:1), 3.3 g (20 mmol) of 2,4,6-tri-methyl-phenyl-boronic acid, 12.6 g (40 mmol) of Ba(OH)2.8H2O and 0.46 g (0.4 mmol) of tetrakis(triphenylphosphine)palladium were added. After heating at 80° C. for 16 hours the mixture was cooled to room temperature, water was added and the mixture was extracted with CH2Cl2. The organic layer was dried over magnesium sulphate and concentrated in vacuo. The product was purified on a silicagel column using CH2Cl2 as the eluent. A total of 4.2 g of 2-methyl-4-phenoxy-8-(2,4,6-trimethylphenyl)-quinoline was obtained (73% yield)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH:25]1([C:28]2[CH:29]=[C:30]([OH:34])[CH:31]=[CH:32][CH:33]=2)[CH2:27][CH2:26]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:34][C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([CH:25]4[CH2:27][CH2:26]4)[CH:29]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: Oc1cccc(C2CC2)c1
Product: CC(NC(=O)c1coc(Oc2cccc(C3CC3)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 83.8 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 3-cyclopropyl-phenol (35.2 mg, 0.26 mmol) to give the title compound (52 mg, 83%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.C([Li])CCC.[CH2:14]([N:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCOCC>[CH2:14]([N:21]1[CH2:26][CH2:25][C:24]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=2)([OH:27])[CH2:23][CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Brc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: OC1(c2cccc(Br)c2)CCN(Cc2ccccc2)CC1
Temperature: -75 °C
Reaction time: 2.5 h
Yield: 81.7 %

Procedure:
A solution of 23.6 g (100 mmol) of 1,3-dibromobenzene in 250 ml of absolute ether was cooled to -75° C. A solution of 62.5 ml (100 mmol) of n-butyllithium (1.6M in hexane) was added dropwise within 45 minutes. The resulting suspension was stirred at -75° C. for 2.5 hours. Subsequently, a solution of 19.0 g (100 mmol) of 1-benzyl-4-piperidone in 100 ml of absolute ether was added dropwise within 30 minutes at -70° C. to -75° C. and thereafter the mixture was stirred for 2 hours. Subsequently, the mixture was partitioned between ether and saturated ammonium chloride solution, the organic phase was dried over magnesium sulphate and finally the solvent was removed under reduced pressure. The crude product was purified by chromatography on silica gel with a 1:1 mixture of methylene chloride and hexane as the eluent. There were obtained 28.3 g (82% of theory) of 1-benzyl-4-(3-bromophenyl)-piperidin-4-ol as a yellow oil; MS: 345, 347 (M)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[F:21][C:22]([F:31])([F:30])[C:23]1[CH:24]=[C:25]([SH:29])[CH:26]=[CH:27][CH:28]=1.C(N(C(C)C)CC)(C)C.O>CN(C)C=O>[CH2:19]([O:18][C:16]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[S:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([C:22]([F:21])([F:30])[F:31])[CH:24]=1)=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=2)=[O:17])[CH3:20]
Reactant: CCOC(=O)c1cnc2ccc(C(F)(F)F)cc2c1Cl
Reactant: FC(F)(F)c1cccc(S)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2ccc(C(F)(F)F)cc2c1Sc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.3 %

Procedure:
The reaction mixture of 151.8 mg (0.50 mmol) of 4-chloro-3-ethoxycarbonyl-6-trifluoromethylquinoline, 106.9 mg (0.60 mmol) of 3-trifluoromethylthiophenol and 100 μL of diisopropylethylamine in 2.0 mL of N,N-dimethylformamide was stirred at room temperature for 2 h and cooled. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulphate and concentrated. The resulting residue was purified on silica gel column eluting with ethyl acetate-hexane (1:3) to give 76.4 mg (34%) of the title compound.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][N:6]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:5][CH2:4][N:3]1[CH2:20][C:21]([O:23]C(C)(C)C)=[O:22].[ClH:28]>>[ClH:28].[ClH:28].[CH3:1][C@@H:2]1[CH2:7][N:6]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:5][CH2:4][N:3]1[CH2:20][C:21]([OH:23])=[O:22]
Reactant: C[C@@H]1CN(C2CCCCC2c2ccccc2)CCN1CC(=O)OC(C)(C)C
Agent: Cl
Product: C[C@@H]1CN(C2CCCCC2c2ccccc2)CCN1CC(=O)O
Reaction time: 3 h
Yield: 97.9 %

Procedure:
A mixture of tert-butyl 2-((R)-2-methyl-4-(2-phenylcyclohexyl)piperazin-1-yl)acetate (430 mg, 1.154 mmol) in 3 mL of 37% HCl was stirred at 50 C for 3 h. After LCMS showed complete conversion to the product, the solution was evaporated under high vacuum to dryness. The residue was crashed out of diethyl ether and dried to give 2-((R)-2-methyl-4-(2-phenylcyclohexyl)piperazin-1-yl)acetic acid dihydrochloride (440 mg, 97.9% yield) as an off white solid. MS (ESI, pos. ion) m/z: 317.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([N:15]3[CH2:18][CH:17]([OH:19])[CH2:16]3)=[O:14])=[N:10][N:9]=2)=[CH:4][CH:3]=1.ClC1C=CC(C2OC(C(OC)=O)=NN=2)=CC=1.C(N(CC)CC)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>ClCCl>[CH3:43][S:44]([O:19][CH:17]1[CH2:16][N:15]([C:13]([C:11]2[O:12][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:9][N:10]=2)=[O:14])[CH2:18]1)(=[O:46])=[O:45]
Reactant: O=C(c1nnc(-c2ccc(Cl)cc2)o1)N1CC(O)C1
Reactant: CS(=O)(=O)Cl
Agent: COC(=O)c1nnc(-c2ccc(Cl)cc2)o1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CN(C(=O)c2nnc(-c3ccc(Cl)cc3)o2)C1
Reaction time: 7 h
Yield: 75 %

Procedure:
A suspension of 2B —which contained approximately 50% of methyl 5-(4-chlorophenyl)-1,3,4-oxadiazole-2-carboxylate as an impurity—(1.38 g, 2.47 mmol) in dichloromethane (50 mL) was cooled in an ice-bath. Triethylamine (0.51 mL, 3.70 mmol) was added followed by methanesulfonyl chloride (0.27 mL, 3.45 mmol). After the addition, the cooling bath was removed. The mixture was stirred for 7 h. The reaction mixture was transferred to a reparatory funnel and was washed with water followed by aqueous NaHCO3. The organic solution was dried (phase separator) and evaporated. Dichloromethane (50 mL) and diethyl ether (200 mL) were added and the solid product was collected by filtration. The solid was washed twice with diethyl ether and then dried in vacuo. The product was purified using flash column chromatography first eluting with dichloromethane and then with a mixture of dichloromethane and methanol containing 2M NH3 (20:1). There was obtained 0.66 g (75%) of 2C as a solid. 1H NMR (500 MHz, CDCl3): δ 3.13 (s, 3H), 4.43 (dd, 1H), 4.65 (dd, 1H), 4.87 (dd, 1H), 5.12 (dd, 1H), 5.41 (m, 1H), 7.53 (d, 2H), 8.10 (d, 2H), MS (APCI+) m/z 358 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Mg]Br)C.[CH3:24][C:25]1([CH3:33])[C:27]([CH3:29])([CH3:28])[CH:26]1[C:30](Cl)=[O:31]>[Cl-].[Zn+2].[Cl-]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[NH:14][CH:13]=[C:12]2[C:30]([CH:26]1[C:27]([CH3:29])([CH3:28])[C:25]1([CH3:33])[CH3:24])=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2[nH]ccc2cc1OCc1ccccc1
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Product: COc1cc2[nH]cc(C(=O)C3C(C)(C)C3(C)C)c2cc1OCc1ccccc1
Yield: 65.8 %

Procedure:
A mixture of 5-benzyloxy-6-methoxyindole (Sigma, 2.0 g, 7.9 mmol), ethylmagnesium bromide (1.0 M solution in THF, 9.5 mL, 9.5 mmol), zinc chloride (1.0 M solution in Et2O, 9.5 mL, 9.5 mmol) and the product of Example 1A (12 mmol) was processed as described in Example 1B to provide the title compound (2.0 g, 5.2 mmol, 66% yield). MS (DCI/NH3) m/z 378 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:13]=[CH:14][C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24]([C:27](O)=[O:28])[CH:25]=[CH:26][C:17]=4[C:16]=3[N:30]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:62][CH2:63][CH2:64][NH:65][C:66](=[O:72])[O:67][C:68]([CH3:71])([CH3:70])[CH3:69]>CN(C=O)C.O>[C:68]([O:67][C:66](=[O:72])[NH:65][CH2:64][CH2:63][NH:62][C:27]([C:24]1[CH:25]=[CH:26][C:17]2[C:16]3[N:30]=[C:12]([NH:11][C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:13]=[CH:14][C:15]=3[CH2:21][C:20](=[O:22])[NH:19][C:18]=2[CH:23]=1)=[O:28])([CH3:69])([CH3:71])[CH3:70]
Reactant: COc1ccc(Nc2ncc3c(n2)-c2ccc(C(=O)O)cc2NC(=O)C3)cc1OC
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Nc2ncc3c(n2)-c2ccc(C(=O)NCCNC(=O)OC(C)(C)C)cc2NC(=O)C3)cc1OC
Temperature: 22 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(3,4-dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-9-carboxylic acid (I-53) (75 mg, 0.18 mmol) in DMF (5 mL) was added N,N-diisopropylethylamine (0.10 mL, 0.55 mmol), TBTU (65 mg, 0.20 mmol), and tert-butyl 2-aminoethylcarbamate (35.5 mg, 0.22 mmol). The reaction stirred at 22° C. overnight. The reaction mixture was diluted with H2O, and the precipitate that formed was filtered, washed with H2O and dried to give I-71-a [MS m/z═549 (M+H)] which was carried on crude to the deprotection.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C:4]([N:6]([C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20](=[O:39])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)(=[O:31])=[O:30])=[CH:25][CH:24]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.C([O-])([O-])=O.[K+].[K+]>CO>[CH3:1][O:2][C:3]([C:4]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]2[C:14]([C:20](=[O:39])[C:21]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([N:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)(=[O:30])=[O:31])=[CH:25][CH:24]=1)=[CH:15][CH:16]=[C:17]([Cl:19])[CH:18]=2)=[O:40]
Reactant: COC(=O)C(=O)N(c1ccccc1)c1cc(Cl)ccc1C(=O)CCc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1c(Cc2ccc(S(=O)(=O)N3CCN(C)CC3)cc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1

Procedure:
A mixture of N-(5-chloro-2-{3-[4-(4-methylpiperazine-1-sulfonyl)-phenyl]-propionyl}-phenyl)-N-phenyl-oxalamic acid methyl ester (1.1 mmol) and K2CO3 (282 mg) in MeOH (60 mL) was heated at reflux for 1 h. The reaction mixture was then cooled and evaporated under reduced pressure. The residue was partitioned between water and EtOAc, the organic layer separated, and the aqueous layer extracted with EtOAc (2×25 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to give an orange-brown oil. The crude residue was purified twice by flash chromatography (DCM/MeOH) to give 7-chloro-3-[4-(4-methyl-piperazine-1-sulfonyl)-benzyl]-4-oxo-1-phenyl-1,4-dihydroquinoline-2-carboxylic acid methyl ester as light brown solid. MS=566 [M+H]+; MP=223.3-226.6° C.
Reaction SMILES: [C:1]([O:9]CC)(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:12][C:13]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]#[N:24])=[CH:18][CH:17]=1)([CH3:15])[CH3:14].CC(C)([O-])C.[K+]>C(O)(C)(C)C.O>[C:23]([CH:22]([C:19]1[CH:20]=[CH:21][C:16]([C:13]([CH3:15])([CH3:14])[CH3:12])=[CH:17][CH:18]=1)[C:1]([C:2]1[CH:3]=[CH:4][N:5]=[CH:6][CH:7]=1)=[O:9])#[N:24]
Reactant: CCOC(=O)c1ccncc1
Reactant: CC(C)(C)c1ccc(CC#N)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)c1ccc(C(C#N)C(=O)c2ccncc2)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 34.8 %

Procedure:
To a solution of ethyl isonicotinate (12 g) and 4-(1,1-Dimethylethyl)phenylacetonitrile (9.1 g) in tert-butyl alcohol (36 mL), was added potassium tert-butoxide (7.3 g), and the mixture was stirred at 100° C. for 3 h. After cooling, the resulting mixture was dissolved in water and washed with isopropyl ether. The aqueous phase was adjusted to pH 7.0 with 2 N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried, And the solvent was evaporated. The crystalline residue was recrystallized from ethyl acetate-isopropyl ether to obtain 2-cyano-2-[4-(1,1-dimethylethyl)phenyl]-1-(4-pyridyl)ethanone (5.09 g, yield 35%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[CH3:8][C:9]1([CH3:16])[C:13](=[O:14])[CH:12]=[C:11]([CH3:15])[O:10]1.[OH-].[Na+].[Cl-].[Na+]>C(O)C>[CH3:8][C:9]1([CH3:16])[C:13](=[O:14])[CH:12]=[C:11]([CH:15]=[CH:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[O:10]1
Reactant: CC1=CC(=O)C(C)(C)O1
Reactant: O=Cc1cccs1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)OC(C=Cc2cccs2)=CC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 43 %

Procedure:
To a solution of 2-thiophenecarboxaldehyde (2.1 g, 19 mM) and 2,2,5-trimethyl-3(2H)-furanone (2.0 g, 15.9 mM) in ethanol (100 mL), was added 1N aqueous sodium hydroxide (1.6 mL, 1.6 mM). The reaction solution was stirred at room temperature for one day. After saturated aqueous sodium chloride (400 mL) was added, the aqueous layer was extracted with diethyl ether (3×100 mL). The combined ethereal extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated to give a yellow solid. The product was recrystallized from hexane to afford a yellow crystalline solid (1.5 g, 43% yield), m.p. 75°-77° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:19][C:20]1[CH:35]=[CH:34][C:23]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[CH:22][C:21]=1[O:36][CH3:37].ClCCl>O1CCOCC1.CO>[CH2:27]([O:26][C:24]([C:23]1[CH:34]=[CH:35][C:20]([NH:19][C:2]2[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=2)=[C:21]([O:36][CH3:37])[CH:22]=1)=[O:25])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: COc1cc(C(=O)OCc2ccccc2)ccc1N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: COc1cc(C(=O)OCc2ccccc2)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Temperature: 100 °C
Reaction time: 30 h

Procedure:
2 g (9.217 mmol) 2,4-dichloro-5-trifluoromethylpyrimidine are dissolved in 4 ml dioxane and combined with 6.01 g (18.430 mmol) caesium carbonate and 2.16 g (7.363 mmol) benzyl 4-amino-3-methoxybenzoate (WO 9825901). This suspension is stirred for 30 h at 100° C. The suspension is combined with 50 ml dichloromethane and methanol and filtered to remove the insoluble constituents. The solvent is eliminated in vacuo and the residue is purified by column chromatography. The carrier used is silica gel and the eluant used is a mixture of 85% cyclohexane and 15% ethyl acetate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24]C)=[C:19]([O:22]C)[CH:20]=3)[CH2:15][CH2:14][N:13]2[CH3:26])[CH2:11][CH2:10][CH2:9]1.Br>C(O)(=O)C>[BrH:1].[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH:12]2[C:21]3[C:16](=[CH:17][C:18]([OH:24])=[C:19]([OH:22])[CH:20]=3)[CH2:15][CH2:14][N:13]2[CH3:26])[CH2:11][CH2:10][CH2:9]1
Reactant: COc1cc2c(cc1OC)C(C1(c3ccccc3Br)CCC1)N(C)CC2
Agent: Br
Solvent: CC(=O)O
Product: CN1CCc2cc(O)c(O)cc2C1C1(c2ccccc2Br)CCC1

Procedure:
A mixture of (-)-1-[1-(2-bromophenyl)cyclobutyl]-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (1.46 g), 48% aqueous hydrobromic acid (20 ml) and glacial acetic acid (20 ml) was heated under reflux for 5 hours. The solvent was removed by evaporation and the residue dried by repeated azeotropic distillation with propan-2-ol. The residue was dissolved in propan-2-ol and precipitated with ether. The resulting solid was dried in vacuo at 45° C. to yield (+)-1-[1-(2-bromo-phenyl)cyclobutyl] -6,7-dihydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrobromide [m.p. 207°-209° C. (dec)] which had a specific optical rotation αD of +38.2°.
Reaction SMILES: C(N1C2C(=CC(S(N)(=O)=O)=CC=2)CC1)C.[Cl:16][C:17]1[CH:18]=[C:19]([CH2:24][C:25]([N:27]2[C:35]3[C:30](=[CH:31][C:32]([S:36]([NH2:39])(=[O:38])=[O:37])=[CH:33][CH:34]=3)[CH2:29][CH2:28]2)=O)[CH:20]=[CH:21][C:22]=1[Cl:23]>>[Cl:16][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:24][CH2:25][N:27]1[C:35]2[C:30](=[CH:31][C:32]([S:36]([NH2:39])(=[O:38])=[O:37])=[CH:33][CH:34]=2)[CH2:29][CH2:28]1
Reactant: NS(=O)(=O)c1ccc2c(c1)CCN2C(=O)Cc1ccc(Cl)c(Cl)c1
Agent: CCN1CCc2cc(S(N)(=O)=O)ccc21
Product: NS(=O)(=O)c1ccc2c(c1)CCN2CCc1ccc(Cl)c(Cl)c1
Yield: 66 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 53, 1-(2-(3,4-dichlorophenyl)acetyl)indoline-5-sulfonamide (Intermediate 64, 140 mg, 0.363 mmol) was converted to the title compound (89 mg, 66%) after purification using preparative HPLC. 1H NMR (DMSO-d6) δ 7.64-7.63 (m, 1H), 7.54 (d, J=8.1 Hz, 1H), 7.43 (dd, J=8.4, 2.0 Hz, 1H), 7.39 (d, J=1.5 Hz, 1H), 7.33 (dd, J=8.3 Hz, 2.1 Hz, 1H), 6.90 (s, 2H), 6.56 (d, J=8.4 Hz, 1H), 3.49 (t, J=8.7 Hz, 2H), 3.42-3.38 (m, 2H), 2.95 (t, J=8.5 Hz, 2H), 2.84 (t, J=7.5 Hz, 2H); MS(ESI+) m/z 371.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[N:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][N:32]=1>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:37][C:34]1[CH:35]=[CH:36][N:31]=[N:32][CH:33]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccccc1
Reactant: Nc1ccnnc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Nc1ccnnc1)c1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Solid 5-bromo-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 5, method C; 200 mg, 0.651 mmol) was added to a stirred suspension of CDI (106 mg, 0.651 mmol) in THF (10 ml) under nitrogen at 20° C. The reaction mixture was stirred at room temperature for 10 min and 4-pyridazinamine (may be prepared as described in Description 11; 61.9 mg, 0.65 mmol) was added dropwise. After refluxing for 14 h, the reaction mixture was concentrated. Water was added to the residue and the mixture was extracted with ethyl acetate (3×50 ml). The organic phase was washed with saturated brine (25 ml), dried over sodium sulphate and evaporated in vacuo. The residue was washed with methanol to yield the title compound as a white solid. 95 mg.