Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][C:5]1([CH3:18])[C:10]2[CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:9]=2[CH2:8][CH2:7][O:6]1.[OH-].[Na+]>CO.O>[CH3:18][C:5]1([CH2:4][C:3]([OH:19])=[O:2])[C:10]2[CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:9]=2[CH2:8][CH2:7][O:6]1
Reactant: COC(=O)CC1(C)OCCC2=C1Cc1ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(CC(=O)O)OCCC2=C1Cc1ccccc12
Reaction time: 8 h

Procedure:
Hydrolysis of this ester to the title compound is effected as follows: The latter ester (11.5 g) is dissolved in 400 ml of methanol and the solution mixed with a solution of 12 g of sodium hydroxide in 100 ml of water. The resulting mixture is kept at room temperature overnight. Methanol is removed by evaporation. The residue is diluted with water. The aqueous solution is extracted repeatedly with ether, and acidified with 6N hydrochloric acid. The resulting precipitate is extracted with ether. The ether extract is dried (MgSO4), filtered and concentrated. The residue is crystallized from benzene to give the title compound, m.p. 179°-180° C, nmr (CDCl3) δ 1.45 (s, 3H), 2.51 (m, 2H), 2.73 (s, 2H), 3.25 (t, 2H), 4.02 (t, 2H), 7.26 (m, 4H), 9.80 (broad, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CS(N1C2C=CC=CC=2N=N1)(=O)=O.CCN(C(C)C)C(C)C>C1COCC1>[NH2:1][C:2]1[C:7]([C:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1
Reactant: Nc1ncc(Br)cc1C(=O)O
Reactant: Nc1ccccc1
Agent: CS(=O)(=O)n1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Nc1ncc(Br)cc1C(=O)Nc1ccccc1
Temperature: 160 °C
Yield: 63.7 %

Procedure:
A mixture of 2-amino-5-bromo-pyridine-3-carboxylic acid (203 mg, 0.9354 mmol), aniline (87.11 mg, 85.23 μL, 0.9354 mmol), 1-methylsulfonylbenzotriazole (276.7 mg, 1.403 mmol) and DIPEA (241.8 mg, 325.9 μL, 1.871 mmol) in THF (2.0 mL) was heated in the microwave at 160° C. for 10 mins. The reaction mixture was concentrated and the residue partitioned between EtOAc and 2M NaOH. The organic phase was washed with brine, dried (MgSO4) and concentrated in vacuo to give the product as a yellow solid (174 mg, 64% Yield). 1H NMR (400.0 MHz, DMSO) δ 7.77 (br s, 2H), 8.18 (d, 1H) and 8.32 (d, 1H); ppm; MS (ES+) 293.94.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([C:14]3[C:15](=[O:26])[C:16]4[C:21]([C:22](=[O:25])[C:23]=3Cl)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C[OH:28].[OH-].[K+].Cl>O>[CH:18]1[CH:19]=[CH:20][C:21]2[C:22]([C:23]([OH:28])=[C:14]([C@@H:11]3[CH2:10][CH2:9][C@@H:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH2:13][CH2:12]3)[C:15](=[O:26])[C:16]=2[CH:17]=1)=[O:25]
Reactant: CO
Reactant: O=C1C(Cl)=C(C2CCC(c3ccc(Cl)cc3)CC2)C(=O)c2ccccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C1C(O)=C([C@H]2CC[C@H](c3ccc(Cl)cc3)CC2)C(=O)c2ccccc21
Temperature: 27.5 °C
Reaction time: 6 h

Procedure:
2-[4-(4-Chlorophenyl)cyclohexyl-3-chloro-1,4-naphthoquinone (20 gm) was added to methanol (400 ml) at 25-30° C., the contents were heated to reflux and then potassium hydroxide solution (20 gm) in water (200 ml) was slowly added for 30 minutes at reflux. The reaction mass was stirred for 6 hours at reflux, to the resulting mass added hydrochloric acid (72 ml) slowly for 15 to 20 minutes at reflux and then cooled to 25-30° C. The resulting mass was further cooled to 0° C. and then stirred for 1 hour at 0-5° C. The solid was filtered, washed with water and then dried at 50-60° C. to give 18.1 gm of atovaquone.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26]([OH:28])=O)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:30]=[C:31]([NH2:38])[CH2:32][CH2:33][O:34][CH:35]([CH3:37])[CH3:36]>>[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:20][CH:21]=3)[CH2:13][CH:12]([C:26]3[O:28][N:38]=[C:31]([CH2:32][CH2:33][O:34][CH:35]([CH3:37])[CH3:36])[N:30]=3)[CH2:11]2)=[O:9])[CH2:6][CH2:7]1
Reactant: CC(C)OCCC(N)=NO
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Product: CC(C)OCCc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCC(O)CC3)C2)n1

Procedure:
100 mg (0.25 mmol) of the compound from Example 99A and 61 mg (0.38 mmol) of the compound from Example 65A were reacted according to the General Method 2. Yield: 82 mg (61% of theory)
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:41][C:42]([N:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1)=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:33]=[CH:34][C:35]([O:38][CH2:41][CH2:42][N:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]2)=[CH:36][CH:37]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(CCl)N1CCCCC1
Product: CCN(Cc1ccc(OCCN2CCCCC2)cc1)c1cc(OC)c(OC)cc1C1CCc2cc(O)ccc2C1
Yield: 3.6 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 2-chloro-1-piperidin-1-ylethanone (11 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (0.7 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:34]=[CH:33][C:20]([C:21]([N:23]([CH3:32])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH2:30][OH:31])=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[O-][O-].[Mg+2].CO.C(OCC)C>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([N:23]([CH3:32])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH:30]=[O:31])=[O:22])=[CH:33][CH:34]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3CO)cc2)cc1
Agent: [Mg+2]
Agent: [O-][O-]
Solvent: CO
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3C=O)cc2)cc1
Yield: 93.3 %

Procedure:
A mixture of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-(2-hydroxymethylphenyl)benzamide (225 mg) and magnesium dioxide (651 mg) in chloroform (10 ml) was refluxed for 3 hours and the solution was filtered through Celite. The filtrate was evaporated in vacuo to give a crude oil and the oil was subjected to silica gel column (1% methanol in chloroform). The product was solidified with diethyl ether to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-(2-formylphenyl)benzamide (209 mg) as a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].C(Cl)Cl.C1C=CC(N[S:26]([C:29]([F:32])([F:31])[F:30])(=[O:28])=[O:27])=CC=1>CN(C1C=CN=CC=1)C>[F:30][C:29]([F:32])([F:31])[S:26]([O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:28])=[O:27]
Reactant: COC(=O)c1ccc(O)c(C(=O)OC)c1
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C(=O)OC)c1
Reaction time: 21 h
Yield: 96 %

Procedure:
To a stirred solution of dimethyl 4-hydroxyisophthalate T9.1 (commercially available from Chem Service) (37.7 g, 179 mmol) in DCM (256 mL, 179 mmol) at 23° C. was added TEA (30 mL, 215 mmol), and a catalytic amount of DMAP. N-phenyltriflamide (70 g, 197 mmol) was then added, and stirring was continued at room temperature for 21 hours. The solvent was removed, and the residue was purified on silica gel (0-10% EtOAc in hexanes) to yield T9.2 dimethyl 4-(trifluoromethylsulfonyloxy)isophthalate as a colorless oil (59.00 g, 96% yield). MS ESI (pos.) m/e: 360.0 (M+H2O)+, 343.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:18])=O>CN(C)C=O.ClCCCl>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([Cl:18])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)cc1Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc([N+](=O)[O-])c(F)cc1Cl

Procedure:
A mixture of 2-chloro-4-fluoro-5-nitrobenzoic acid (50.0 g, 0.228 mol) and N,N-dimethylformamide (5 drops) in 1,2-dichloroethane is treated dropwise with oxalyl chloride (30.8 mL, 0.353 mol), refluxed for 3 hours, cooled, and concentrated in vacuo to obtain the title product as an orange solid which is identified by NMR spectral analyses.
Reaction SMILES: [F:1][C:2]1[C:11]([CH2:12][C:13]([NH:15][NH2:16])=O)=[C:10]([F:17])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Cl:18][C:19]1[N:20]=[N:21][C:22](Cl)=[CH:23][CH:24]=1>C(O)CCC>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]2[N:15]([C:13]([CH2:12][C:11]3[C:2]([F:1])=[C:3]4[C:8](=[CH:9][C:10]=3[F:17])[N:7]=[CH:6][CH:5]=[CH:4]4)=[N:20][N:21]=2)[N:16]=1
Reactant: NNC(=O)Cc1c(F)cc2ncccc2c1F
Reactant: Clc1ccc(Cl)nn1
Solvent: CCCCO
Product: Fc1cc2ncccc2c(F)c1Cc1nnc2ccc(Cl)nn12
Yield: 58.8 %

Procedure:
A solution of (5,7-difluoro-quinolin-6-yl)-acetic acid hydrazide (1.024 g, 4.32 mmol) and 3,6-dichloropyridazine (0.772 g, 5.18 mmol) in 60 mL of butan-1-ol was heated at 135° C. in a sealed tube for 16 h. The solvent was removed in vacuo, and the residue was purified by flash chromatography to afford 842 mg of the title compound as gray solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.96 (dd, 1H), 8.26 (d, 1H), 7.60-7.66 (m, 2H), 7.45 (d, 1H), 4.81 (s, 2H). LCMS (method B): [MH]+=332, tR=4.88 min.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][N:37]([CH2:40][C:41]([NH:43][C:44]4[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=4)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:50][CH2:51][CH3:52])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:53](I)[CH3:54].[H-].[Na+]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][N:37]([CH2:40][C:41]([N:43]([CH2:53][CH3:54])[C:44]4[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=4)=[O:42])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:50][CH2:51][CH3:52])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCI
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)Nc2cccnc2)CC1
Agent: [H-]
Agent: [Na+]
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(CC)c2cccnc2)CC1

Procedure:
2-{4-[(4S,5R)-2-(6-tert-Butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N-pyridin-3-yl-acetamide (example 127) was treated with ethyl iodide (Aldrich) and sodium hydride to give the title compound. HR-MS (ES, m/z) calculated for C42H50Cl2N7O3 [(M+H)+] 770.3347, observed 770.3347.
Reaction SMILES: COC1C=C(OC)C=CC=1C[O:6][N:7]1[C:12](=[O:13])[C:11]2[O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[NH:9][C:8]1=[O:21].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:9]1[C:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][C:11]=2[C:12](=[O:13])[N:7]([OH:6])[C:8]1=[O:21])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(COn2c(=O)[nH]c3c(oc4ccccc43)c2=O)c(OC)c1
Product: O=c1c2oc3ccccc3c2n(Cc2ccccc2)c(=O)n1O

Procedure:
Following general procedure B2 and D1, 3-(2,4-Dimethoxy-benzyloxy)-1H-benzo[4,5]furo[3,2-d]pyrimidine-2,4-dione was alkylated with benzyl bromide and subsequently deprotected to provide the title compound as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ 5.57 (s, 2H); 7.22-7.39 (m, 6H); 7.61 (dd, J=8 Hz, 1H); 7.78-7.82 (m, 2H); Ret. time=2.36 min., m/z=309.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[NH2:27][CH2:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:27][CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: NCc1cccnc1
Product: O=C(NCc1cccnc1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 3-(aminomethyl)pyridine via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(pyridin-3-ylmethyl)terephthalamide. MS (Q1) 477 (M)+.
Reaction SMILES: C[O:2][C:3](=[O:14])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[CH:6][CH:5]=1.[CH2:15]([OH:19])[CH2:16][CH2:17][OH:18]>>[CH2:15]([OH:19])[CH2:16][CH2:17][OH:18].[C:8]([OH:10])(=[O:9])[C:7]1[CH:12]=[CH:13][C:4]([C:3]([OH:14])=[O:2])=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Solvent: OCCCO
Product: O=C(O)c1ccc(C(=O)O)cc1
Temperature: 237 °C

Procedure:
Using an apparatus of the type indicated in the drawings, together with an ester exchanger, a 76.4 lb./hr (34.7 kg/hr) stream of dimethylterephthalate was preheated to a temperature of 185° C. and continuously mixed with a 44.9 lb./hr (20.4 kg/hr) stream of catalyzed 1,3-propanediol which was also preheated to a temperature of 185° C., to form a mixture having a mole ratio of 1.5 moles of 1,3-propanediol per mole of dimethylterephthalate. The catalyst was tetraisopropyl titanate (Tyzor® TPT, available from E. I. du Pont de Nemours and Company, Wilmington, Del.), DuPont Performance Chemicals), which was added to the 1,3-propanediol in an amount sufficient to yield 50 ppm by weight of titanium based on the total weight of poly(trimethylene terephthalate) formed in the process. The dimethylterephthalate/catalyzed 1,3-propanediol mixture was fed into the base of an ester exchanger, where the temperature of the liquid reactants was maintained at 237° C., and the pressure at the base of the ester exchanger was maintained at 900 to 950 mm Hg (119,970 to 126,635 Pa). The pressure at the top of the ester exchange column was atmospheric. In the ester exchanger, the 1,3-propanediol reacted with the dimethylterephthalate to form bis-3-hydroxypropyl terephthalate monomer and low molecular weight oligomers of 1,3-propanediol and terephthalic acid, liberating methanol vapor, which was continuously removed from the top of the ester exchanger. The monomer/oligomer mixture was continuously removed from the base of the ester exchanger and fed to the base of a prepolymerizer. In the prepolymerizer, the monomers and oligomers reacted to form a poly(trimethylene terephthalate) prepolymer, liberating 1,3-propanediol vapor. The 1,3-propanediol vapor and other gaseous by-products were removed from the top of the prepolymerizer and condensed. The poly(trimethylene terephthalate) prepolymer was continuously withdrawn from the uppermost plate of the prepolymerizer and fed to the inlet end of a finisher vessel. The temperature of the liquid reactants in the finisher was maintained at 255° C. In the finisher, the poly(trimethylene terephthalate) prepolymer reacted to form a higher molecular weight polymer, liberating additional 1,3-propanediol vapor. The 1,3-propanediol vapor and other gaseous by-products were continuously removed from the finisher. The poly(trimethylene terephthalate) was continuously removed from the finisher and pelletized. The conditions and results for the continuous polymerization are set forth in Table I for the prepolymerizer and Table II for the finisher.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:10][CH:9]=[C:8](/[CH:11]=[CH:12]/[C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:16]([OH:18])=O)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:32]=[C:33]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=2)[NH2:34])[CH2:27][CH2:26]1)[CH3:24]>>[NH2:1][C:2]1[C:3]2[S:10][CH:9]=[C:8](/[CH:11]=[CH:12]/[C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:16]([NH:34][C:33]3[CH:35]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:37]=[C:31]([N:28]4[CH2:29][CH2:30][N:25]([CH2:23][CH3:24])[CH2:26][CH2:27]4)[CH:32]=3)=[O:18])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccc(C(=O)O)cc1/C=C/c1csc2c(N)ncnc12
Reactant: CCN1CCN(c2cc(N)cc(C(F)(F)F)c2)CC1
Product: CCN1CCN(c2cc(NC(=O)c3ccc(C)c(/C=C/c4csc5c(N)ncnc45)c3)cc(C(F)(F)F)c2)CC1

Procedure:
The procedure of Step 5 of Example 1 was repeated except for using (E)-3-(2-(4-aminothieno[3,2-d]pyrimidine-7-yl)vinyl)-4-methylbenzoic acid and 3-(4-ethylpiperazine-1-yl)-5-(trifluoromethyl)aniline to obtain the title compound (see Table 1).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=1.[OH:12][C@:13]1([CH3:20])[C@H:17]([CH3:18])[NH:16][C:15](=[O:19])[CH2:14]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:12][C@@:13]1([CH3:20])[CH2:14][C:15](=[O:19])[N:16]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=2)[C@H:17]1[CH3:18]
Reactant: COc1cc(Br)ccc1C#N
Reactant: C[C@@H]1NC(=O)C[C@]1(C)O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1cc(N2C(=O)C[C@](C)(O)[C@@H]2C)ccc1C#N

Procedure:
Using 4-bromo-2-methoxybenzonitrile (684 mg), (4S,5S)-4-hydroxy-4,5-dimethylpyrrolidin-2-one (500 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (286 mg), tris(dibenzylideneacetone)dipalladium(0) (148 mg) and cesium carbonate (1.55 g), and in the same manner as in Example 62, the title compound was obtained as a colorless amorphous solid (yield: 410 mg, 48%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7]([OH:13])=[C:6]([OH:14])[C:5]2=[O:15].[H-].[Na+].Br[CH2:19][CH2:20]Br>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7]1[O:13][CH2:19][CH2:20][O:14][C:6]=1[C:5]2=[O:15]
Reactant: BrCCBr
Reactant: O=C1C(O)=C(O)C(=O)c2cc(Cl)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1C2=C(OCCO2)C(=O)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-Chloro-2,3-dihydroxy-1,4-naphthoquinone (11.25 g) dissolved in dry dimethylformamide (100 ml) is treated with washed sodium hydride (2.64 g) in small portions under a blanket of nitrogen. After stirring 1 hour at room temperature, 1,2-dibromoethane (4.3 ml) is added via a syringe over 1 hour. The resultant mixture is warmed to 60° C. overnight, then cooled and diluted with water (500 ml) to afford 6-chloro-2,3-ethylenedioxy-1,4-naphthoquinone.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[CH2:7]O)[CH3:2].S(Cl)([Cl:17])=O>C1(C)C=CC=CC=1.N1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[CH2:7][Cl:17])[CH3:2]
Reactant: CCOc1ccc(CO)cc1OCC
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOc1ccc(CCl)cc1OCC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To 3,4-diethoxybenzyl alcohol (736 mg) dissolved in toluene (10 ml) were added pyridine (one drop) and thionyl chloride (0.41 ml), and the resulting mixture was stirred at room temperature for 20 minutes. The reaction mixture was diluted with ethyl acetate and the resulting mixture was washed with water, an aqueous saturated solution of sodium hydrogen carbonate and an aqueous saturated solution of sodium chloride, and was dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent to obtain 3,4-diethoxybenzyl chloride (802 mg) as an oil.
Reaction SMILES: O.[NH2:2]N.C[N:5](/[CH:7]=[N:8]/[C:9]([C:11]1[C:19]2[N:18]=[C:17]([CH3:20])[N:16]([CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)[C:15]=2[CH:14]=[C:13]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:12]=1)=O)C.C([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[CH3:20][C:17]1[N:16]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[C:15]2[CH:14]=[C:13]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)[CH:12]=[C:11]([C:9]3[N:8]=[CH:7][NH:5][N:2]=3)[C:19]=2[N:18]=1
Reactant: NN
Reactant: Cc1nc2c(C(=O)/N=C/N(C)C)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc2c(-c3nc[nH]n3)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
Hydrazine hydrate (3 mL) was added to a solution of N-[(1E)-(dimethylamino)methylidene]-2-methyl-6-(4-morpholinyl)-1-(1-naphthalenylmethyl)-1H-benzimidazole-4-carboxamide (130 mg, 0.29 mmol) in acetic acid (10 mL) and stirred at 130° C. for 30 min. The reaction mixture was cooled to rt and poured into saturated Na2CO3 solution (20 mL). A filtration was performed, and the filter cake was purified by silica gel chromatography eluted with EtOAc to give the product (88 mg, 72%), as a white solid. 1H NMR (300 MHz, DMSO-d6): δ ppm 2.50 (s, 3H), 3.09 (s, 4H), 3.71 (s, 4H), 6.06 (s, 2H), 6.37 (d, 1H, J=7.8 Hz), 7.20 (s, 1H), 7.34 (t, 1H, J=7.8 Hz), 7.54 (s, 1H), 7.61-7.72 (m, 2H,), 7.86 (d, 1H, J=8.4 Hz), 8.02 (d, 1H, J=7.8 Hz), 8.09 (s, 1H), 8.25 (d, 1H, J=8.4 Hz), 13.85 (s, 1H); LC-MS: m/e=425 [M+1]+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15](Br)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[Cl:28][CH2:29][CH2:30][CH2:31][C:32](=[O:34])[CH3:33]>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([C:32]([OH:34])([CH3:33])[CH2:31][CH2:30][CH2:29][Cl:28])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)CCCCl
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(Br)nc3N21
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(C(C)(O)CCCCl)nc3N21
Reaction time: 0.25 h
Yield: 50.9 %

Procedure:
A solution of 0.30 g (0.81 mmol) (4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 20 ml diethyl ether was cooled to −100 deg C. and treated dropwise with 65 μl (0.97 mmol) tert-butyllithium (1.5 M solution in n-pentane). After 15 min, 0.12 g (0.11 ml, 0.98 mmol) 5-chloro-2-pentanone was added, the temperature was allowed to rise to −75 deg C. and after an additional 15 min, the reaction was quenched with 10%. aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The solvent was removed on a rotary evaporator and the residue was chromatographed on silica gel (0.032–0.063 mm) with ethyl acetate:n-hexane (1:2) as eluant to afford the compound as a colorless oil (50.9%).