Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[CH:19]1[C:32]2[C:23](=[CH:24][C:25]3[C:30]([C:31]=2B(O)O)=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C(Cl)(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:24]4[C:25]5[C:30]([CH:31]=[C:32]6[C:23]=4[CH:22]=[CH:21][CH:20]=[CH:19]6)=[CH:29][CH:28]=[CH:27][CH:26]=5)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: OB(O)c1c2ccccc2cc2ccccc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4c5ccccc5cc5ccccc45)cc3CC[C@@H]12
Yield: 42.5 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 9-anthracenylboronic acid (159 mg, 0.78 mmol), 0.65 mL of sodium carbonate and 2 mL of toluene, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 48 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (EtOAc eluent) to give 112 mg (43%) of the title compound as an amorphous solid. mp 95°-110°. FDMS: m/e=405. α[D]589 =+45.73 (c=0.66, chloroform).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:22][CH3:23])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH2:20][CH3:21])[CH:11]=3)=[CH:4][CH:3]=1.CCN(CC)CC.[CH:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1.O>C1COCC1.C(OCC)(=O)C>[C:17]([C:16]1[C:15]2[C:10](=[CH:11][C:12]([O:19][CH2:20][CH3:21])=[CH:13][CH:14]=2)[N:9]([CH2:22][CH3:23])[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:34]([CH:31]2[CH2:33][CH2:32]2)=[O:35])=[CH:7][CH:6]=1)#[N:18]
Reactant: O=C(Cl)C1CC1
Reactant: CCOc1ccc2c(C#N)c(-c3ccc(N)cc3)n(CC)c2c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOc1ccc2c(C#N)c(-c3ccc(NC(=O)C4CC4)cc3)n(CC)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a solution of compound 2-(4-aminophenyl)-6-ethoxy-1-ethyl-1H-indole-3-carbonitrile (3.66 g, 12 mmol), prepared as described in example 1 Gb, in 20 mL of THF is added Et3N (3.37 ml) and cyclopropanecarbonyl chloride (1.6 mL, 18 mmol). The mixture is stirred for 3 h at room temperature. Then water and ethyl acetate are added to the reaction mixture. The organic layer is separated, washed with brine (2×), dried over anhydrous Na2SO4, filtered and concentrated. The residue is recrystallized with ethyl acetate and hexane to yield 99% of cyclopropanecarboxylic acid [4-(3-cyano-6-ethoxy-1-ethyl-1H-indol-2-yl)-phenyl]-amide.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH2:15])=[O:14].C(OP(C#N)(=O)OCC)C.[C:26]([O:30][C:31]([NH:33][C@@H:34]([CH2:50][C@@H:51]([CH:67]([CH3:69])[CH3:68])[CH2:52][C:53]1[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[C:55]([O:61][CH2:62][CH2:63][CH2:64][O:65][CH3:66])[CH:54]=1)[C@@H:35]([O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])[CH2:36][C@@H:37]([CH3:41])[C:38](O)=[O:39])=[O:32])([CH3:29])([CH3:28])[CH3:27]>CN(C)C=O>[C:13]([CH2:12][CH2:11][CH2:10][NH:9][C:38](=[O:39])[C@H:37]([CH3:41])[CH2:36][C@H:35]([O:42][Si:43]([C:46]([CH3:47])([CH3:49])[CH3:48])([CH3:45])[CH3:44])[C@@H:34]([NH:33][C:31]([O:30][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:32])[CH2:50][C@@H:51]([CH:67]([CH3:68])[CH3:69])[CH2:52][C:53]1[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[C:55]([O:61][CH2:62][CH2:63][CH2:64][O:65][CH3:66])[CH:54]=1)(=[O:14])[NH2:15]
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@H](C[C@@H](C)C(=O)O)O[Si](C)(C)C(C)(C)C)C(C)C)ccc1OC
Reactant: NCCCC(N)=O
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@H](C[C@@H](C)C(=O)NCCCC(N)=O)O[Si](C)(C)C(C)(C)C)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
67 μl of triethylamine, 34 mg of 4-aminobutyric acid amide hydrochloride and 38 μl of cyanophosphonic acid diethyl ester are added in suscession to 128 mg of 5(S)-tert-butoxycarbonylamino-4(S)-tert-butyldimethylsilyloxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoic acid in 8 ml of dimethylformamide at 0° C. The reaction mixture is stirred for a further 18 hours at room temperature. The reaction mixture is concentrated by evaporation and 20 ml of 10% citric acid solution and ice are added to the residue. The mixture is extracted repeatedly with ethyl acetate and the organic phases are then washed with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution. After concentration by evaporation, the residue is purified by means of FC (70 g of silica gel, dichloromethane/methanol=9:1). The title compound is obtained: Rf (dichloromethane/methanol=9:1)=0.38.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[S:23][C:22]([CH2:24]O)=[CH:21][CH:20]=3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:51]1[CH2:54][CH:53]([C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH2:52]1.C(N(CC)C(C)C)(C)C>>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[S:23][C:22]([CH2:24][N:51]4[CH2:54][CH:53]([C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH2:52]4)=[CH:21][CH:20]=3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccc(-c2noc(-c3ccc(Oc4ccccc4)cc3)n2)s1
Reactant: CCOC(=O)C1CNC1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CN(Cc2ccc(-c3noc(-c4ccc(Oc5ccccc5)cc4)n3)s2)C1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 1 (1f) using {5-[5-(4-phenoxyphenyl)-1,2,4-oxadiazol-3-yl]-2-thienyl}methanol (97 m g, 0.28 mmol) that was obtained in Example 5 (5a), carbon tetrabromide (0.19 g, 0.56 mmol), triphenylphosphine (0.15 g, 0.56 mmol), ethyl 3-azetidinecarboxylate hydrochloride (70 mg, 0.42 mmol), and N,N-diisopropylethylamine (0.18 ml, 1.1 mmol). Subsequently, the crude product of the title compound thus obtained was purified by thin layer chromatography on a silica gel plate using a mixed solvent of ethyl acetate and hexane (4:3) as the developing solvent to afford the title compound (93 mg) in a yield of 72% as a colourless oily product.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[NH:18][C:17]2[C:16](=[O:19])[N:14]([CH3:15])[C:13](=[O:20])[N:12]([CH3:21])[C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:24]([O:26][CH2:27][CH2:28][CH:29]([C:33](O)=[O:34])[C:30](O)=[O:31])[CH3:25]>CN(C)C=O>[CH2:1]([N:8]1[C:9]2=[N:10][C:11]3[N:12]([CH3:21])[C:13](=[O:20])[N:14]([CH3:15])[C:16](=[O:19])[C:17]=3[N:18]2[C:33]([OH:34])=[C:29]([CH2:28][CH2:27][O:26][CH2:24][CH3:25])[C:30]1=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOCCC(C(=O)O)C(=O)O
Reactant: Cn1c(=O)c2[nH]c(NCc3ccccc3)nc2n(C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCCc1c(O)n2c3c(=O)n(C)c(=O)n(C)c3nc2n(Cc2ccccc2)c1=O
Temperature: 50 °C

Procedure:
To a stirred suspension of 7.43 g of 8-benzylaminotheophylline in 104 ml of dry N,N-dimethyl-formamide add portionwise over 10 minutes 1.19 g of a 60% dispersion of sodium hydride. Heat the mixture to 50° C. under a nitrogen atmosphere for 30 minutes. Add 13.30 g of the diethyl ester of β-ethoxyethylmalonic acid. Heat the mixture to 150° C. under a nitrogen atmosphere for approximately 37 hours. Allow the system to cool to room temperature and remove the solvent in vacuo. Add a mixture of water:chloroform (1:2.5) to the resulting semisolid. Acidify the aqueous portion with 3M HCl. Extract the product from the aqueous portion with chloroform. Wash the chloroform extracts with brine, dry over anhydrous sodium sulfate, filter and remove the solvent in vacuo to give the crude product. Triturate the crude product with ether. Purify the crude product by column chromatography on silica gel and triturate the major fraction with hexane to give the title compound, mp 156.5°-157.5° C.
Reaction SMILES: [F:1][CH:2]([F:16])[CH2:3][O:4][C:5]1[N:10]=[C:9]([O:11][CH3:12])[C:8]([C:13](=O)[CH3:14])=[CH:7][CH:6]=1.[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[F:1][CH:2]([F:16])[CH2:3][O:4][C:5]1[N:10]=[C:9]([O:11][CH3:12])[C:8]([CH:13]([NH:23][S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH3:14])=[CH:7][CH:6]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: COc1nc(OCC(F)F)ccc1C(C)=O
Product: COc1nc(OCC(F)F)ccc1C(C)N[S@](=O)C(C)(C)C
Yield: 73 %

Procedure:
The title compound is prepared in 73% yield (400 mg, clear colorless oil) from 1-(6-(2,2-difluoroethoxy)-2-methoxypyridin-3-yl)ethanone (380 mg, 1.6 mmol, Step-5) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[O:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][C@@H:17]1[CH2:26][NH2:27]>>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:27]([CH2:26][C@H:17]2[CH2:18][CH2:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:16]2)[CH:10]=1
Reactant: NC[C@H]1CCc2ccccc2O1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Agent: Cl
Product: N=c1c(C(N)=O)cc(Cl)cn1C[C@H]1CCc2ccccc2O1

Procedure:
According to the method of Example 160, 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide was reacted with 1-[(2R)-3,4-dihydro-2H-chromen-2-yl]methanamine hydrochloride to give the title compound.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[F:11].[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1B(O)O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[F:11]
Reactant: O=C(O)c1ccc(F)c(Br)n1
Reactant: OB(O)c1ccc(F)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: O=C(O)c1ccc(F)c(-c2ccc(F)cc2F)n1
Yield: 79 %

Procedure:
Method 1 was followed using 6-bromo-5-fluoropicolinic acid (1.0 equiv.) and 2,4-difluorophenylboronic acid (1.3 equiv.) and Pd(dppf)Cl2-DCM (0.05 equiv.) to give 6-(2,4-difluorophenyl)-5-fluoropicolinic acid in 79% yield. LC/MS=254.1 (M+H), Rt=0.75 min.
Reaction SMILES: F[C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)[S:8][C:4]=2[CH:3]=1.[Cl:29]C1SC2C=C(Cl)C=CC=2N=1>>[Cl:29][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)[S:8][C:4]=2[CH:3]=1
Reactant: Clc1ccc2nc(Cl)sc2c1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccc(F)cc2s1
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccc(Cl)cc2s1

Procedure:
Same procedure as 3-(6-fluorobenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine except using 2,6-dichloro-1,3-benzothiazole in place of 2-chloro-6-fluorobenzothiazole to afford the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.10-2.30 (m, 4H), 3.06-3.18 (m, 2H), 3.41 (d, J=13.2 Hz, 2H), 4.52 (ddd, J=14.8, 10.6, 4.2 Hz, 1H), 7.62 (dd, J=8.8, 1.8 Hz, 1H), 8.05 (s, 1H), 8.12 (d, J=8.8 Hz, 1H), 8.31 (br. s., 1H), 8.37 (br. s., 2H), 8.53 (s, 1H). MS (ES+): m/z=411.08 [MH+]. HPLC: tR=2.30 min (ZQ2, polar—5 min).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[C@@H:4]2[O:14][C@H:3]12.[F:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][NH:23][C:22](=[O:25])[C:21]=2[CH:26]=1>>[F:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][N:23]=[C:22]([O:25][C@@H:4]3[C:5]4[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=4)[O:11][C:2]([CH3:1])([CH3:15])[C@H:3]3[OH:14])[C:21]=2[CH:26]=1
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H]2O[C@@H]21
Reactant: O=c1[nH]oc2ccc(F)cc12
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](Oc2noc3ccc(F)cc23)[C@@H]1O

Procedure:
Following the procedure in Example 1, using (S,S)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and 5-fluoro-benzo[d]isoxazol-3-one as starting materials, the title compound was prepared as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].ClCCl.[NH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1.C(N(CC)CC)C>O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:17][CH2:18][CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)(=[O:12])=[O:11])([O-:3])=[O:2]
Reactant: NCCc1cccnc1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCc1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.9 %

Procedure:
2-Nitrobenzene sulfonyl chloride(11.64 g) was added to a dichloromethane solution (100 ml) of 3-(2-aminoethyl)pyridine(6.11 g) and triethylamine(9 ml) at 0° C. The mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried with anhydrous sodium sulfate, and condensed under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound(5.06 g) as a yellow powder.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]2[C:14]=1[NH:13][C:12](=[O:15])[CH2:11][CH2:10]2)[C:2]#[CH:3].[CH2:17]([CH:19]1[O:21][CH2:20]1)Cl.C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([O:16][CH2:17][CH:19]2[O:21][CH2:20]2)=[C:9]2[C:14]=1[NH:13][C:12](=[O:15])[CH2:11][CH2:10]2)[C:2]#[CH:3]
Reactant: ClCC1CO1
Reactant: C#CCOc1ccc(O)c2c1NC(=O)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CCOc1ccc(OCC2CO2)c2c1NC(=O)CC2
Yield: 68.3 %

Procedure:
To 78 g of 8-(2-propynyloxy)-5-hydroxy-3,4-dihydrocarbostyril were added 102 g of epichlorohydrin, 60 g of potassium carbonate and 600 ml of methanol, and the resulting mixture was heated while refluxing for 2.5 hours on a water bath. After completion of the reaction, the methanol was evaporated, and water was added to the residue followed by extracting with chloroform. The chloroform layer was washed with water and dried over anhydrous sodium sulfate. The chloroform was evaporated under reduced pressure, and the residual crystals were recrystallized from isopropanol to obtain 67 g of 8-(2-propynyloxy)-5-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril having a melting point of 142°-143.5° C.
Reaction SMILES: C([O:3][C:4]1[C:12]2[CH:8]([C:9](O)([C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:10][N:11]=2)[CH2:7][CH2:6][CH:5]=1)C>CCO.Cl>[O:3]=[C:4]1[C:12]2[C:8](=[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:10][N:11]=2)[CH2:7][CH2:6][CH2:5]1
Reactant: CCOC(=O)C1(O)ON=C2C(OCC)=CCCC21
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1onc2c1CCCC2=O
Yield: 34.3 %

Procedure:
To a solution of ethyl 7-ethoxy-3-hydroxy-3,3a,4,5-tetrahydro-2,1-benzisoxazole-3-carboxylate 1.35 g (5.29 mmol) in 10 mL of EtOH, 1 mL of HCl 36% was added. The mixture was stirred at reflux for 2 hours. After cooling the solvent was removed under reduced pressure and the crude solid was purified by flash chromatography on silica gel (eluant: AcOEt/Hexane 2/8) to afford 0.380 g (35% yield) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][C:21](O)=[O:22])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][C:15]([F:18])([F:17])[F:16])[CH:7]=1.[CH:24]([NH:27][NH:28][C:29]([CH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)=[O:30])([CH3:26])[CH3:25].C(NC(C)C)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][C:21]([N:27]([CH:24]([CH3:26])[CH3:25])[NH:28][C:29]([CH:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[O:30])=[O:22])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][C:15]([F:18])([F:16])[F:17])[CH:7]=1
Reactant: O=C(O)COc1ccc(F)cc1-c1ccccc1OC(F)(F)F
Reactant: CC(C)NNC(=O)C1CCOCC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CC(C)N(NC(=O)C1CCOCC1)C(=O)COc1ccc(F)cc1-c1ccccc1OC(F)(F)F
Yield: 61.8 %

Procedure:
A solution of (5-fluoro-2′-trifluoromethoxy-biphenyl-2-yloxy)-acetic acid (280 mg, 0.85 mmol) and tetrahydro-pyran-4-carboxylic acid N′-isopropyl-hydrazide (1.2 eq. 190 mg, 1.02 mmol) in DMF (3 ml) was treated with diisopropyl amine (0.370 ml, 2.12 mmol) and PyBroP (595 mg, 1.275 mmol) at room temperature overnight. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was successively washed with saturated sodium bicarbonate and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 50-100% ethyl acetate/hexanes gradient to afford the product as a white solid (262 mg, 62%). MS m/e 499.23 (M+H+)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[CH2:9]([O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[C:16]([CH2:23][CH2:24]Cl)[CH:15]=1)[CH2:10][CH2:11][CH3:12]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:24][CH2:23][C:16]3[C:17](=[CH:21][CH:22]=[C:14]([O:13][CH2:9][CH2:10][CH2:11][CH3:12])[CH:15]=3)[C:18]2=[O:19])=[CH:4][CH:3]=1
Reactant: CCCCOc1ccc(C(=O)Cl)c(CCCl)c1
Reactant: Nc1ccc(Br)cc1
Product: CCCCOc1ccc2c(c1)CCN(c1ccc(Br)cc1)C2=O

Procedure:
According to Method A, 4-bromo-phenylamine was reacted with 4-butoxy-2-(2-chloroethyl)-benzoyl chloride. In this way the product was obtained with molecular weight 374.28 (C19H20BrNO2); MS (ESI): 374 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:19])=[CH:4][C:5]([F:18])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.[CH2:20]([O:22][CH2:23]Cl)[CH3:21]>>[Cl:1][C:2]1[C:3]([F:19])=[CH:4][C:5]([F:18])=[C:6]([S:8](/[N:11]=[C:12]2/[N:13]=[CH:14][N:15]([CH2:23][O:22][CH2:20][CH3:21])[CH:16]=[CH:17]/2)(=[O:9])=[O:10])[CH:7]=1
Reactant: CCOCCl
Reactant: O=S(=O)(Nc1ccncn1)c1cc(Cl)c(F)cc1F
Product: CCOCn1cc/c(=N\S(=O)(=O)c2cc(Cl)c(F)cc2F)nc1

Procedure:
Prepared according to the process of Preparation 716 using 5-chloro-2,4-difluoro-N-pyrimidin-4-ylbenzenesulfonamide, Preparation 723 and chloromethyl ethyl ether. The product was a mixture of three regioisomers that were not separated and used in subsequent reactions as a mixture.
Reaction SMILES: [CH2:1]1[N:12]2[C:13]3[C:3](=[CH:4][CH:5]=[CH:6][C:7]=3[C:8](=O)[NH:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=32)[CH2:2]1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:28]2)=CC=1>C1(C)C=CC=CC=1>[CH2:1]1[N:12]2[C:13]3[C:3](=[CH:4][CH:5]=[CH:6][C:7]=3[C:8](=[S:28])[NH:9][C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=32)[CH2:2]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1Nc2ccccc2N2CCc3cccc1c32
Solvent: Cc1ccccc1
Product: S=C1Nc2ccccc2N2CCc3cccc1c32
Reaction time: 8 h
Yield: 60.2 %

Procedure:
To 1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepin6-one (67 g) in 1 l of toluene, under nitrogen, was added 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (45 g). The mixture was refluxed for 1 hr and allowed to stand overnight. The precipitate was collected and recrystallized from chloroform to afford 43 g, (60.2%) of product, mp 185°-186° C.
Reaction SMILES: [C:1]1(=[O:24])[N:5]([CH:6]2[CH2:13][CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]2=[O:18])[C:4](=[O:19])[C:3]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:2]12.CC(C)([O-])C.[K+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].O>CN(C)C=O>[CH2:36]([O:35][C:33]([CH2:32][N:8]1[C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[CH2:11][CH2:12][CH2:13][CH:6]([N:5]2[C:4](=[O:19])[C:3]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:2]3[C:1]2=[O:24])[C:7]1=[O:18])=[O:34])[CH3:37]
Reactant: O=C1Nc2ccccc2CCCC1N1C(=O)c2ccccc2C1=O
Reactant: CCOC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN1C(=O)C(N2C(=O)c3ccccc3C2=O)CCCc2ccccc21
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of 3-phthalimido-3,4,5,6-tetrahydro-1-benzazocin-2(1H)one (1.7 g) in dimethylformamide (10 ml) is stirred at 0° C. under a nitrogen atmosphere. A solution of potassium t-butoxide (0.75 g) in dimethylformamide (6 ml) is added and the reaction mixture is stirred at 0° C. for five minutes. A solution of ethyl bromoacetate (1.0 g) in dimethylformamide (5 ml) is added and the reaction mixture stirred at 0° C. for 11/2 hours. Water (3 ml) is added, and the reaction mixture is evaporated under high vacuum. The residue is distributed between ethyl acetate (100 ml) and water (50 ml) and the aqueous layer is washed with water (50 ml) and dried over sodium sulfate. The residue is recrystallized from methanol/ether to give 1-ethoxycarbonylmethyl-3-phthalimido-3,4,5,6-tetrahydro-1-benzazocin-2(1H)one, mp 79°-81° C. used in the next synthetic step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]([N:12]2[CH2:17][CH2:16][O:15][C:14]3[CH:18]=[CH:19][N:20]=[CH:21][C:13]2=3)=[O:11])[CH:5]=[C:6]([Br:9])[C:7]=1[OH:8].[OH-].[Na+:23]>O1CCCC1>[Na+:23].[Br:9][C:6]1[CH:5]=[C:4]([C:10]([N:12]2[CH2:17][CH2:16][O:15][C:14]3[CH:18]=[CH:19][N:20]=[CH:21][C:13]2=3)=[O:11])[CH:3]=[C:2]([Br:1])[C:7]=1[O-:8]
Reactant: O=C(c1cc(Br)c(O)c(Br)c1)N1CCOc2ccncc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(c1cc(Br)c([O-])c(Br)c1)N1CCOc2ccncc21
Temperature: 25 °C

Procedure:
In a 100 ml flask, (3,5-dibromo-4-hydroxy-phenyl)-(2,3-dihydro-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone (500 mg, 1.20 mmol) was suspended in tetrahydrofuran (40 ml) and the mixture was dissolved under heating. After cooling to room temperature, 10N sodium hydroxide solution was added thereto dropwise. The solvent was evaporated under reduced pressure, and the residue was dissolved in a solvent of acetonitrile and water (1:1 ratio, 80 ml) to obtain the target compound 72 as white non-crystalline form (240 mg, 48%).
Reaction SMILES: [C:1]1([NH:7][S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14]3)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][C:22]1[C:26]([C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])=[C:25]([CH3:36])[NH:24][C:23]=1[CH:37]=O>>[C:1]1([NH:7][S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[C:14]3=[CH:37][C:23]2[NH:24][C:25]([CH3:36])=[C:26]([C:27]([N:29]3[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]3)=[O:28])[C:22]=2[CH3:21])(=[O:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Reactant: O=C1Cc2cc(S(=O)(=O)Nc3ccccc3)ccc2N1
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(S(=O)(=O)Nc4ccccc4)cc32)c(C)c1C(=O)N1CCN(C)CC1
Yield: 24.1 %

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid phenylamide (110 mg, 0.4 mmol) was condensed with 3,5-dimethyl-4-(4-methylpiperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (100 mg) to give 50 mg (24%) of the title compound as a yellow solid.