Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[CH2:17][CH:16]4[C:18]5([CH2:22][N:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[S:20](=[O:29])(=[O:28])[NH:19]5)[CH:13]([CH2:14][CH2:15]4)[CH2:12][C:11]=3[CH:30]=2)=[N:4][CH:3]=1.[N:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[N:31]1[CH:36]=[CH:35][C:34]([C:2]2[S:6][C:5]([C:7]3[CH:8]=[CH:9][C:10]4[CH2:17][CH:16]5[C:18]6([CH2:22][N:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[S:20](=[O:29])(=[O:28])[NH:19]6)[CH:13]([CH2:14][CH2:15]5)[CH2:12][C:11]=4[CH:30]=3)=[N:4][CH:3]=2)=[CH:33][CH:32]=1
Reactant: OB(O)c1ccncc1
Reactant: O=S1(=O)NC2(CN1CC(F)(F)F)C1CCC2Cc2cc(-c3ncc(Br)s3)ccc2C1
Product: O=S1(=O)NC2(CN1CC(F)(F)F)C1CCC2Cc2cc(-c3ncc(-c4ccncc4)s3)ccc2C1

Procedure:
Prepared using the bromide from Example 36 Step 2 and 4-pyridylboronic acid by the method described for Example 36 Step 3. MS (ES+) 521 ([MH]+).
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=O>>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:26][N:4]2[CH2:5][CH2:6][CH2:7][N:1]([C:8]3[CH:9]=[CH:10][C:11]4[N:12]([C:14]([C:17]([F:18])([F:19])[F:20])=[N:15][N:16]=4)[N:13]=3)[CH2:2][CH2:3]2)[CH:28]=[CH:29][CH:30]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCCNCC3)nn12
Reactant: COc1cccc(C=O)c1
Product: COc1cccc(CN2CCCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1

Procedure:
Reductive amination of 6-(1,4-diazepan-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-methoxybenzaldehyde was carried out according to General Synthetic Method 8. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(3-methoxyphenyl)methyl]-1,4-diazepan-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [Na].C(O[C:5](=[O:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[CH3:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:16]#[N:17].Cl>CCO>[CH2:9]([O:8][C:6](=[O:7])[C:5](=[O:11])[CH2:12][C:13]1[CH:14]=[C:15]([C:16]#[N:17])[CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[CH3:10]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1cc(C#N)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=O)Cc1cc(C#N)ccc1[N+](=O)[O-]

Procedure:
Dissolve sodium metal (0.345 g) in absolute EtOH (25 mL), add diethyloxalate (10 mL) and then add 3-methyl-4-nitrobenzonitrile (1a, m=0, 1.6 g, Aldrich) as an EtOH solution (25 mL). Stir reaction mixture at rt for 16 h, neutralize the reaction by addition of 5N HCl (3 mL) and remove the EtOH under reduced pressure. Partition the residue between CH2Cl2 (100 mL) and H2O (50 mL). Wash the organic layer successively with H2O (50 mL) and brine (50 mL), dry (MgSO4) and concentrate to give a crude oil. Purify the oil by chromatography on SiO2 (cyclohexane-EtOAc, 70-30 v/v) to give after drying (40° C., house vacuum), the title compound (1.2 g) as yellow crystals.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[O:9][CH2:10][C:11]1([CH2:30][O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[C:15](=[O:16])[N:14]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=2)[C:13](=[O:29])[NH:12]1.CN(C)[CH:40]=[O:41]>>[C:4]([O:41][CH2:40][C:6]#[C:7][CH2:8][N:12]1[C:11]([CH2:10][O:9][CH:4]2[CH2:5][CH2:6][CH2:7][CH2:8][O:3]2)([CH2:30][O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[C:15](=[O:16])[N:14]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:26])[F:27])[CH:18]=2)[C:13]1=[O:29])(=[O:3])[CH3:5]
Reactant: CN(C)C=O
Reactant: N#Cc1ccc(N2C(=O)NC(COC3CCCCO3)(COC3CCCCO3)C2=O)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Product: CC(=O)OCC#CCN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C1(COC1CCCCO1)COC1CCCCO1
Reaction time: 0.5 h

Procedure:
416 mg of 50% sodium hydride and dropwise 4 g of the product obtained in Stage 5 of Example 1 and 15 ml of dimethylformamide are introduced and the resultant mixture is rinsed with 1 ml of dimethylformamide. 10 minutes after the end of the release of hydrogen, 3.2 g of 4-bromo-2-butyne-1-ol acetate prepared as described in J. W. Lown GENE 149, 81 (1994) and 2 ml of dimethylformamide are added, and rinsing is carried out with 0.5 ml of dimethylformamide. After one hour 30 minutes, the reaction medium is poured into 100 ml of water containing 0.5 g of monopotassium phosphate, extraction is carried out 4 times with ether, the organic phase is washed with water and with salt water and dried. Purification is carried out by chromatography on silica eluting with methylene chloride-acetone: 95-5 and 4.47 g of expected product (orange resin) is obtained.
Reaction SMILES: [Br:1]Br.[CH3:3][CH:4]([CH3:25])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:8]=1)=[O:6].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:4]([CH3:25])([CH3:3])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:8]=1)=[O:6]
Reactant: BrBr
Reactant: COC(=O)CC(c1ccccc1)c1ccc(C(=O)C(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)CC(c1ccccc1)c1ccc(C(=O)C(C)(C)Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.9 %

Procedure:
A solution of 29.4 g (0.184 mol) of bromine in 50 ml of methylene chloride is added drop wise at room temperature to a mixture of 52.0 g (0.168 mol) of methyl 3-[4-(2-methylpropionyl)phenyl]-3-phenylpropanoate in 250 ml of methylene chloride. A small exotherm is controlled using a water bath. The mixture is stirred for 16 hours at room temperature. The reaction mixture is poured into a 5% aqueous sodium thiosulfate solution and stirred for 10 minutes. The organic layer is washed twice with 5% aqueous sodium thiosulfate solution, once with 10% sodium bicarbonate solution, dried over sodium sulfate, and concentrated to give 64.0 grams (98% yield) of methyl 3-[4-(2-bromo-2-methylpropionyl)phenyl]-3-phenylpropanoate.
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:19]=[CH:18][CH:17]=[C:16]([S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[Cl:28][C:29]1[C:30]([F:37])=[C:31]([NH:35][NH2:36])[CH:32]=[CH:33][CH:34]=1>>[Cl:28][C:29]1[C:30]([F:37])=[C:31]([N:35]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([C:23]([F:26])([F:24])[F:25])(=[O:22])=[O:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:36]2)[CH:32]=[CH:33][CH:34]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)C(F)(F)F)c2)ccc1=O
Reactant: NNc1cccc(Cl)c1F
Product: O=c1ccn(-c2cccc(S(=O)(=O)C(F)(F)F)c2)nc1-c1ccnn1-c1cccc(Cl)c1F

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethansulfonyl-phenyl)-1H-pyridazin-4-one (A-33) and 3-chloro-2-fluoro-phenylhydrazine according to the method described for example 1. MS: M=499.0 (M+H)+
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[N:7]([CH3:14])[C:8]3[C:13]([C:5]2([CH3:15])[CH2:4][CH2:3]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.F[B-](F)(F)F.[O:21]=[N+:22]=[O:23].C([O-])(O)=O.[Na+].C(Cl)Cl>C(#N)C>[N+:22]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:14])[CH:6]1[N:2]([CH3:1])[CH2:3][CH2:4][C:5]21[CH3:15])([O-:23])=[O:21]
Reactant: O=[N+]=O
Reactant: CN1CCC2(C)c3ccccc3N(C)C12
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: CN1CCC2(C)c3cc([N+](=O)[O-])ccc3N(C)C12
Temperature: 0 °C
Reaction time: 1 h
Yield: 25.2 %

Procedure:
To a stirred solution of 1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indole (25.0 g) in acetonitrile (500 ml) at 0° C. was added nitronium tetrafluoroborate (18.65 g) dissolved in acetonitrile (500 ml) in a dropwise manner over a period of 0.5 hour. The reaction mixture was stirred at 0° C. for 1 hour and allowed to warm to room temperature for an additional hour. Ice and a dilute NaHCO3 solution were added followed by methylene chloride (800 ml). The layers were separated and the aqueous layer was extracted with methylene chloride (2×200 ml). The organic layers were combined, dried (Na2SO4), and concentrated to give an oil which was chromatographed twice on silica gel, first eluting with 2.5% methanol/ethyl acetate and then with 2% methanol/methylene chloride to give 1,2,3,3a,8,8a-hexahydro-5-nitro-1,3a,8-trimethylpyrrolo[2,3-b]indole (7.7 g).
Reaction SMILES: [OH-:1].[K+].[CH2:3]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:21]=[C:20]([CH2:22]Cl)[C:19]([C:24]([O:26]CC)=[O:25])=[CH:18][N:17]=2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[CH2:3]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:21]=[C:20]([CH2:22][OH:1])[C:19]([C:24]([OH:26])=[O:25])=[CH:18][N:17]=2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [OH-]
Reactant: CCOC(=O)c1cnc(N2CCN(Cc3ccccc3)CC2)nc1CCl
Agent: [K+]
Solvent: CCO
Product: O=C(O)c1cnc(N2CCN(Cc3ccccc3)CC2)nc1CO
Yield: 44.2 %

Procedure:
Ethanol (80 ml) and 2.64 g (40.0 mmoles) of 85% potassium hydroxide were added to 5.0 g (13.3 mmoles) of ethyl 2-(4-benzylpiperazino)-4-chloromethylpyrimidine-5-carboxylate (produced in accordance with Referential Example 41 of Japanese Laid-Open Patent Publication No. 140568/1986), and the mixture was refluxed for 30 minutes. Ethanol was evaporated under reduced pressure. The residue was dissolved in water, and adjusted to pH about 4 with concentrated hydrochloric acid. The crystals that formed were collected by filtration, and washed with acetone to give 1.93 g (yield 44%) of 2-(4-benzylpiperazino)-4-hydroxymethylpyrimidine-5-carboxylic acid as crystals.
Reaction SMILES: [NH2:1][C:2]([C:4]1[C:5]2[CH2:20][CH2:19][CH2:18][CH2:17][C:6]=2[S:7][C:8]=1[NH:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:3]>O>[O:3]=[C:2]1[NH:1][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:9][C:8]2[S:7][C:6]3[CH2:17][CH2:18][CH2:19][CH2:20][C:5]=3[C:4]1=2
Reactant: CCOC(=O)C(=O)Nc1sc2c(c1C(N)=O)CCCC2
Solvent: O
Product: CCOC(=O)c1nc2sc3c(c2c(=O)[nH]1)CCCC3
Reaction time: 0.17 h
Yield: 48 %

Procedure:
The product of Procedure 1, 8.89 g. (0.030 mole) is melted in a round bottom flask equipped with a magnetic stirring bar and immersed in an oil bath at 261° C. The molten material is heated with stirring until the evolution of water as is evidenced by bubbling of the reaction mixture is no longer evident. About 5-15 min. is sufficient. The molten mass is then dissolved in dimethylformamide and the warm solution is poured into a volume of methanol larger than the reaction mixture. The precipitate is collected, and recrystallized from a mixture of dimethylformamide and methanol to yield 4.92 g. (48%) of the desired product as fine yellow needles, m.p. 207.0°-209.0° C.
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.[CH3:14][C:15]([NH2:19])([CH3:18])[CH2:16][CH3:17]>>[Cl:11][C:9]1[S:10][C:5]2[S:4](=[O:13])(=[O:12])[N:3]=[C:2]([NH:19][C:15]([CH3:18])([CH3:14])[CH2:16][CH3:17])[NH:7][C:6]=2[CH:8]=1
Reactant: CCC(C)(C)N
Reactant: O=S1(=O)N=C(Cl)Nc2cc(Cl)sc21
Product: CCC(C)(C)NC1=NS(=O)(=O)c2sc(Cl)cc2N1
Yield: 56.5 %

Procedure:
A solution of 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (5.0 g, 19.45 mmol) in 1,1-dimethylpropylamine (10 ml, 85.7 mmol) was stirred for 30 h at 125° C. in a sealed flask. The cooled solution was concentrated in vacuo and the residue was stirred with water (25 ml) followed by adjustment to pH 2 with 4M hydrochloric acid. The resulting precipitate was isolated by filtration, washed with water, and then redissolved by slightly heating in 1N sodium hydroxide (130 ml) followed by treatment with decolorising charcoal. After filtration, the clear solution was acidified to pH 2 and the precipitate was filtered off and recrystallised from methanol to give 3.38 g (56%) of the pure title compound; mp 359-360° C.; 1H-NMR (DMSO-d6): δ0.82 (t, 3H), 1.31 (s, 6H), 1,73 (q, 2H), 6.67 (br s, 1H), 7,12 (s, 1H), 10.57 (br s, 1H); MS: m/e 307/309 (M+); (C10H14N3Cl1O2S2) calc. C, 39.02; H, 4.58; N, 13.65; Cl, 11.52; S, 20.83; found C, 39.10; H, 4.58; N, 13.48; Cl, 11.69; S, 20.97.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH:8]=[CH:7][C:6]=2[C:5]([Cl:14])=[CH:4][C:3]=1[F:15].Cl[C:17](OC(Cl)(Cl)Cl)=[O:18]>C1(C)C=CC=CC=1>[Cl:14][C:5]1[C:6]2[CH:7]=[CH:8][C:9]([CH3:13])([CH3:12])[O:10][C:11]=2[C:2]([N:1]=[C:17]=[O:18])=[C:3]([F:15])[CH:4]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC1(C)C=Cc2c(Cl)cc(F)c(N)c2O1
Solvent: Cc1ccccc1
Product: CC1(C)C=Cc2c(Cl)cc(F)c(N=C=O)c2O1
Yield: 110.4 %

Procedure:
By the method of Example 1, Step F, 1.3 grams (0.005 mole) of 8-amino-5-chloro-2,2-dimethyl-7-fluoro-2H-1-benzopyran and 1.1 grams (0.005 mole) of trichloromethyl chloroformate were reacted in 50 mL of toluene, yielding about 1.4 grams of 5-chloro-2,2-dimethyl-7-fluoro-2H-1-benzopyran-8-yl isocyanate. The product was taken to the next step without further characterization.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]1=[N:12][NH2:13].[CH3:14][N:15]1[CH:19]=[CH:18][N:17]=[C:16]1[CH:20]=O.Cl.[OH-].[Na+]>C(O)C>[CH3:2][N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5]/[C:4]/1=[N:12]/[N:13]=[CH:20][C:16]1[N:15]([CH3:14])[CH:19]=[CH:18][N:17]=1
Reactant: Cn1ccnc1C=O
Reactant: Cn1c(=NN)sc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1ccnc1C=N/N=c1/sc2ccccc2n1C

Procedure:
As in Example 1, 1.27 g (5.45 mmol) of 2,3-dihydro-3-methyl-2-benzothiazolone hydra-zone hydrochloride and 0.60 g (5.45 mmol) of 1-methyl-2-imidazolecarboxaldehyde in 40 mL of a mixture of HCl and ethanol (1:2) were stirred at room temperature for 30 minutes. The mixture was then rendered slightly alkaline with 2N sodium hydroxide solution. The precipitated product was suction-filtered off, washed with water and dried under vacuum.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH3:14])([CH3:13])[C:5]1=[O:15])(=O)C>Cl>[CH3:13][C:6]1([CH3:14])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][C:5]1=[O:15]
Reactant: CC(=O)N1C(=O)C(C)(C)c2ccccc21
Agent: Cl
Product: CC1(C)C(=O)Nc2ccccc21
Yield: 97 %

Procedure:
To a stirred solution of 2a (3.2 g, 18.29 mmol) in dry THF (100 mL) was added MeI (2.6 mL, 41.75 mmol, 2.3 eq), followed by the addition of 18-crown-6 (0.51 g, 4.57 mmol, 0.25 eq) at −78° C. under nitrogen. Potassium tert-butoxide (5.12 g, 45.73 mmol, 2.5 eq) was added portionwise. The resulting slurry was stirred at −78° C. for 1 h. The mixture was stirred at −78° C. to rt for 3 h. Cooled in an ice bath, sat'd NH4Cl was added. It was extracted with EtOAc, washed with H2O, brine, dried over MgSO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, hexanes/EtOAc) to give pure 1-acetyl-3,3-dimethylindolin-2-one (1.3 g) (LC-MS ESI 204 (M+H)) and pure 3,3-dimethylindolin-2-one (1.0 g) (LC-MS ESI 162 (M+H)) respectively. 1-Acetyl-3,3-dimethylindolin-2-one (1.3 g) was heated in 6N HCl at reflux for 1 h. After cooling, it was poured into crushed ice. It was extracted with Et2O, washed with sat'd NaHCO3, H2O, brine, dried over Na2SO4, filtered, and concentrated to dryness to give almost pure 2b (1.0 g).
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:19])[C@@H:6]([CH3:18])[NH:7]C(OCC1C=CC=CC=1)=O)([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[CH:1]([NH:4][C:5](=[O:19])[C@@H:6]([CH3:18])[NH2:7])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)NC(=O)[C@@H](C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)NC(=O)[C@@H](C)N

Procedure:
N-Benzyloxycarbonyl-D-alanine isopropyl amide (1.322 g, 5 mmol) is hydrogenated in 20 mL MeOH over 100 mg 10% Pd/C in a Parr Apparatus at 40 psi and room temperature until no more hydrogen is consumed. The methanolic suspension is filtered through a Celite pad to remove the catalyst and the filtrate is evaporated to dryness. The desired product is purified by conversion into a crystalline amino acid amide salt.
Reaction SMILES: P(Br)(Br)[Br:2].[S:5]1[C:9]([CH2:10]O)=[CH:8][C:7]2[CH:12]=[CH:13][C:14]3[C:19]([C:6]1=2)=[CH:18][CH:17]=[CH:16][CH:15]=3>C(Cl)(Cl)Cl>[Br:2][CH2:10][C:9]1[S:5][C:6]2[C:19]3[C:14]([CH:13]=[CH:12][C:7]=2[CH:8]=1)=[CH:15][CH:16]=[CH:17][CH:18]=3
Reactant: OCc1cc2ccc3ccccc3c2s1
Reactant: BrP(Br)Br
Solvent: ClC(Cl)Cl
Product: BrCc1cc2ccc3ccccc3c2s1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A solution of 10.8 g (0.04 mole) of phosphorus tribromide in 150 ml of chloroform is added dropwise at 5° within 45 minutes, with stirring, to a suspension of 21.4 g (0.1 mole) of naphtho [1,2-b]thiophene-2-methanol in 110 ml of chloroform, with the gradual formation of a solution. The reaction mixture is stirred for a further 5 hours at 5°, and ice water is subsequently added. The organic phase is separated, washed twice with water and, after drying over sodium sulphate, concentrated at a maximum of 40° in vacuo. The 2-(bromomethyl)-naphtho[1,2-b] thiophene obtained as residue crystallises on addition of diethyl ether, and melts at 75°-78°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=O.[CH3:11][C:12]1([CH3:19])[C:16](=[O:17])[CH:15]=[C:14]([CH3:18])[O:13]1.[OH-].[Na+].[Cl-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:18][C:14]2[O:13][C:12]([CH3:19])([CH3:11])[C:16](=[O:17])[CH:15]=2)[CH:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Reactant: CC1=CC(=O)C(C)(C)O1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)OC(C=Cc2cc(Cl)cc(Cl)c2)=CC1=O
Temperature: 60 °C
Yield: 45.7 %

Procedure:
To a solution of 3,5-dichlorobenzaldehyde (2.3 g, 13.2 mM) and 2,2,5-trimethyl-3(2H)-furanone (2.0 gm, 15.9 mM) in ethanol (100 mL), was added 1N aqueous sodium hydroxide (1.6 mL, 1.6 mM). The reaction solution was heated at 60° C. for 4 hours. After the reaction solution was cooled, 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 crude product was purified by chromatography (silica gel, pet. ether/ethyl acetate) to afford a light yellow solid (1.7 g, 45% yield), m.p. 129°-131° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[C:9](Cl)(Cl)=[S:10]>C(Cl)Cl.O>[Cl:8][C:5]1[CH:4]=[CH:3][C:2]([N:1]=[C:9]=[S:10])=[CH:7][N:6]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: S=C(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: S=C=Nc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 101.5 %

Procedure:
A mixture of 5-amino-2-chloropyridine (5.0 g, 38.11 mmol) and thiophosgene (3.6 ml, 45.73 mmol) in DCM (75 ml) and water (35 ml) was stirred at r.t. for 18 h. The organic phase was dried (Na2SO4) and evaporated in vacuo to give the title compound as an off-white solid (6.6 g, 95%). δH (CDCl3) 8.35 (1H, dd, J 0.5, 2.2 Hz), 7.54 (1H, dd, J 2.2, 8.5 Hz), 7.40 (1H, dd, J 0.5, 8.5 Hz). LCMS (ES+) RT 3.61 minutes, 171 (M+H)+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[CH:9]=[C:10]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)[CH:11]=[CH:12][C:13]=2[C:14]([CH3:18])([CH3:17])[CH2:15][CH:16]=1)(=O)=O.[CH:34]#[C:35][CH2:36][CH2:37][CH3:38]>C(NCC)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][C:14]1([CH3:18])[C:13]2[CH:12]=[CH:11][C:10]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)=[CH:9][C:8]=2[C:7]([C:34]#[C:35][CH2:36][CH2:37][CH3:38])=[CH:16][CH2:15]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CCC3(C)C)cc1
Reactant: C#CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCNCC
Product: CCCC#CC1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)OCC)cc3)cc21
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A solution (flushed with argon) of 201.3 mg (0.42 mmol) of ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 66), 286.5 mg (4.21 mmol) of 1-pentyne, 59.5 mg (0.08 mmol) of bis(triphenylphosphine)palladium(II) chloride and 32.0 mg (0.17 mmol) of cuprous iodide in 2.5 ml of diethylamine was heated to 70° C. in a pressure vial for 6 hours. After stirring overnight at room temperature, the mixture was diluted with EtOAc (25 ml) and washed with water and brine. The organic phase was dried over MgSO4, concentrated in vacuo and purified by column chromatography (silica, 5% Et2O--hexanes) to give the title compound as a colorless, air-sensitive oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:5][CH:4]=1.[CH2:17]([NH2:21])[CH2:18][CH2:19][CH3:20]>O1CCCC1>[CH2:17]([NH:21][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:5][CH:4]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCN
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Solvent: C1CCOC1
Product: CCCCNCc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4'-bromomethyl-2-cyanobiphenyl (10.0 g) in tetrahydrofuran (100 ml) was added butylamine (26.8 g). The mixture was stirred for 3 hours at room temperature. The reaction mixture was concentrated and diluted with water, followed by extraction with chloroform. The extract was washed with water and dried. The solvent was distilled under reduced pressure. The residue was purified by column chromatography on silica gel to afford the title compound as a pale yellow oil (10.7 g, quantitatively).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[Cl:20][C:21]1[CH:31]=[CH:30][C:24]2[NH:25][C:26](=[O:29])[O:27][CH2:28][C:23]=2[CH:22]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[Cl:20][C:21]1[CH:31]=[CH:30][C:24]2[N:25]([CH2:2][C:3]([N:5]3[CH2:10][CH2:9][N:8]([C:11]4[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=4)[CH2:7][CH2:6]3)=[O:4])[C:26](=[O:29])[O:27][CH2:28][C:23]=2[CH:22]=1
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl
Reactant: O=C1Nc2ccc(Cl)cc2CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(N2CCN(C(=O)CN3C(=O)OCc4cc(Cl)ccc43)CC2)ccc1Cl
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 2-chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (303 mg, 1 mmol, 1 equiv), 6-chloro-1,4-dihydro-benzo[d][1,3]oxazin-2-one (72) (183 mg, 1 equiv), and Cs2CO3 (56 μL, 4 equiv) in 2 ml of DMF was stirred at 60° C. overnight. The reaction solution was then diluted with EtOAc (50 mL) and washed with water. The organic layer was dried over sodium sulfate and concentrated in vacuo. The resultant crude residue was purified by flash chromatography to give 6-chloro-1-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-1,4-dihydro-benzo[d][1,3]oxazin-2-one (73): MS (ES) [M+H]+ expected 450.1, found 450.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)[CH:11]=[C:10]([CH3:22])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][N:25]=1>>[Cl:21][C:16]1[CH:15]=[C:14]([C:12]2[CH:11]=[C:10]([CH3:22])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:27]4[CH:28]=[CH:29][C:24]([NH2:23])=[N:25][CH:26]=4)[CH:7]=[CH:6][CH:5]=3)[N:13]=2)[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2cccc(Br)c2)n1
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2cccc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(3,4-dichloro-phenyl)-6-methyl-pyrimidine (example E.62) (0.2 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as an off-white solid (0.11 g, 54%). MS (ISP) 407.4 [(M+H)+]; mp 170.5° C.