Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=3[Cl:26])=[C:16]([C:27](OCC)=[O:28])[CH:15]=[N:14][C:13]=12)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=3[Cl:26])=[C:16]([C:27]([N:42]3[CH2:43][CH2:44][CH:39]([C:36]4[CH:35]=[CH:34][C:33]([F:32])=[CH:38][CH:37]=4)[CH2:40][CH2:41]3)=[O:28])[CH:15]=[N:14][C:13]=12)(=[O:7])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1cnc2c(S(=O)(=O)NC(C)(C)C)cnn2c1Nc1ccc(C)cc1Cl
Reactant: Fc1ccc(C2CCNCC2)cc1
Product: Cc1ccc(Nc2c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc3c(S(=O)(=O)NC(C)(C)C)cnn23)c(Cl)c1
Yield: 57.9 %

Procedure:
Using ethyl 3-(N-tert-butylsulfamoyl)-7-(2-chloro-4-methylphenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylate (11.17 g, 24.0 mmol) obtained in step 3 and 4-(4-fluorophenyl)piperidine (5.93 g, 33.09 mmol) instead of 4-phenylpiperidine, and in the same manner as in Example 1 step 4, the title compound (8.33 g, 63%) was obtained.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[N-:11]=[N+:12]=[N-:13].[Na+].C(OCC)(=O)C>CN(C)C=O>[N:11]([CH2:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6])=[N+:12]=[N-:13]
Reactant: N#Cc1ccccc1CBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccccc1CN=[N+]=[N-]

Procedure:
A solution of 2-bromomethyl-benzonitrile (1.0 g, 5.1 mmol) and sodium azide (0.40 g, 6.1 mmol) in dimethylformamide (10 ml) was stirred at room temperature for 2 h. Ethyl acetate was added and the reaction mixture was washed with water and brine. Drying and solvent evaporation gave 2-azidomethyl-benzonitrile; 1H NMR (CDCl3, 400 MHz) δ7.71 (d, 1H, J=7.7 Hz), 7.64 (m, 1H), 7.53 (d, 1H, J=7.8 Hz), 7.47 (t, 1H, J=7.6 Hz), 4.62 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8](C(Cl)(Cl)Cl)[N:7]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[N:15]=3)[C:6]=2[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:28]([OH:33])[CH:29]([OH:32])[CH2:30][OH:31]>CN(C)C=O>[NH2:20][C:16]1[N:15]=[C:14]([N:7]2[C:6]3[CH:21]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[N:9]=[C:8]2[O:33][CH2:28][CH:29]([OH:32])[CH2:30][OH:31])[CH:19]=[CH:18][N:17]=1
Reactant: Nc1nccc(-n2c(C(Cl)(Cl)Cl)nc3ccc(Br)cc32)n1
Reactant: OCC(O)CO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1nccc(-n2c(OCC(O)CO)nc3ccc(Br)cc32)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 19.2 %

Procedure:
A mixture of 4-[6-bromo-2-(trichloromethyl)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (500 mg, 1.23 mmol), cesium carbonate (3.2 g, 9.82 mmol) and propane-1,2,3-triol (565 mg, 6.14 mmol) in N,N-dimethylformamide (3 mL) was stirred for 12 h at room temperature. The reaction mixture was filtered through a frit filter to remove any solid material and the filtrate was purified by Flash-Preparative HPLC to give 90 mg (19%) of 3-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]propane-1,2-diol as a yellow solid. 1H NMR (400 MHz, DMSO) delta 8.46 (s, 1H), 8.37 (d, J=5.2 Hz, 1H), 7.44-7.38 (m, 2H), 7.13-7.09 (m, 3H), 5.18 (d, J=5.2 Hz, 1H), 4.80 (d, J=6.0 Hz, 1H), 4.68-4.64 (m, 1H), 4.52-4.48 (m, 1H), 3.93 (d, J=4.8 Hz, 1H), 3.52-3.46 (m, 2H); LC-MS: m/z=+380 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4](I)[CH:3]=1.[C-:10]#[N:11].[Na+]>N1C=CC=CC=1>[C:10]([C:4]1[CH:3]=[C:2]([F:1])[CH:8]=[CH:7][C:5]=1[NH2:6])#[N:11]
Reactant: Nc1ccc(F)cc1I
Reactant: [C-]#N
Agent: [Na+]
Solvent: c1ccncc1
Product: N#Cc1cc(F)ccc1N

Procedure:
Fifteen grams of cuprous cyanide and 14 g. of dry pyridine are heated to a homogeneous melt. After adding 25.0 g. of 4-fluoro-2-iodoaniline, the mixture is heated at about 160°-170° C. for two hours. To the cooled mixture, concentrated sodium cyanide solution is added. The solid material is filtered off and extracted with benzene. The benzene extracts are concentrated and fractionally distilled to give 2-cyano-4-fluoroaniline.
Reaction SMILES: C([Li])CCC.O1CCCC1.[Cl:11][C:12]1[CH:29]=[CH:28][C:15]2[S:16][CH:17]=[C:18]([CH2:19][N:20]([CH2:22][CH:23]([O:26][CH3:27])[O:24][CH3:25])[CH3:21])[C:14]=2[CH:13]=1.[C:30](=[O:32])=[O:31]>CO>[Cl:11][C:12]1[CH:29]=[CH:28][C:15]2[S:16][C:17]([C:30]([OH:32])=[O:31])=[C:18]([CH2:19][N:20]([CH2:22][CH:23]([O:24][CH3:25])[O:26][CH3:27])[CH3:21])[C:14]=2[CH:13]=1
Reactant: O=C=O
Reactant: COC(CN(C)Cc1csc2ccc(Cl)cc12)OC
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Product: COC(CN(C)Cc1c(C(=O)O)sc2ccc(Cl)cc12)OC
Temperature: -30 °C
Yield: 54 %

Procedure:
Butyllithium in tetrahydrofuran (2.6M, 0.04 mol) was added slowly to a solution of 5-chloro-3-[N-(2,2-dimethoxyethyl)-N-methyl(aminomethyl)]benzo[b]thiophene (10 g, 0.033 mol) in freshly distilled tetrahydrofuran (100 ml) stirred at -30° C. under argon. The mixture was stirred for 30 minutes, treated with dry carbon dioxide for 5 minutes and allowed to warm to 25° C. The mixture was treated with methanol, poured into ice water and extracted with ethyl ether. The aqueous phase was adjusted to pH 7.5 and extracted with methylene chloride. The organic phase was washed with water, dried with magnesium sulfate and concentrated to give 6.0 g (54%) of 5-chloro-3-[N-(2,2-dimethoxyethyl)-N-methyl(aminomethyl)]benzo[b]thiophene-2-carboxylic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([NH:8][NH2:9])=[O:7])([O-:3])=[O:2].[C:14](Cl)(Cl)=[O:15].C1C=CC=CC=1>C(N(CC)CC)C>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]1[O:7][C:14](=[O:15])[NH:9][N:8]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)Cl
Reactant: NNC(=O)c1ccccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=c1[nH]nc(-c2ccccc2[N+](=O)[O-])o1

Procedure:
The reactions of Equation 37 above can be run according to similar procedures described in U.S. Pat. No. 4,259,104; Golfier and Milcent, J. Heterocycl. Chem., 10, 989 (1973); and R. Madhavan and V. Srinivasan, Indian J. Chem., 7, 760 (1969). Thus, in reaction 37a, a 2-nitrobenzhydrazide XLVIII is reacted with phosgene in an aprotic solvent such as benzene at ambient temperature for about 10 hours, followed by addition of two mole equivalents of triethylamine and heating at reflux for about 2 hours to form 2-(2-nitrophenyl)-1,3,4-oxadiazolin-5-one of Formula (LI). In reaction 37b, LI is reacted with phosphorus pentachloride in phosphorus oxychloride or with phosphorus pentabromide in phosphorus oxybromide at 25° to 80° C. for about 5 hours to form (Xk"'). And in reaction 37c, Xk"' is reacted with sodium methoxide or sodium ethoxide in a solvent such as methanol or tetrahydrofuran at 0° to 30° C. for about 0.5 to 5 hours to form Xk"".
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[O:4][C:5]([CH3:11])([CH2:9][CH3:10])[C:6]([OH:8])=O.CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.[CH2:34]([O:36][C:37](=[O:45])[CH2:38][C:39]1[N:40]=[C:41]([NH2:44])[S:42][CH:43]=1)[CH3:35].CCN=C=NCCCN(C)C>C(Cl)Cl>[CH2:34]([O:36][C:37](=[O:45])[CH2:38][C:39]1[N:40]=[C:41]([NH:44][C:6](=[O:8])[C:5]([O:4][C:3]2[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:2]=2[F:1])([CH3:11])[CH2:9][CH3:10])[S:42][CH:43]=1)[CH3:35]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: CCC(C)(Oc1ccc(F)cc1F)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCOC(=O)Cc1csc(NC(=O)C(C)(CC)Oc2ccc(F)cc2F)n1
Reaction time: 0.08 h
Yield: 57.7 %

Procedure:
To a solution of 2-(2,4-Difluoro-phenoxy)-2-methyl-butyric acid (0.2 g, 0.87 mmol) in DCM (5 ml) added N-Methyl morpholine (0.6 ml, 5.2 mmol) and HOBt (0.2 g, 1.3 mmol) at 0° C. After stirring at this temperature for 5 min. added (2-Amino-thiazol-4-yl)-acetic acid ethyl ester (0.17 g, 0.92 mmol) and followed by EDCI (0.217 g, 1.3 mmol). The resulting solution was stirred for 12 h. then quenched with sat NH4Cl solution (15 ml). The aqueous phase was extracted with CH2Cl2 (3×50 ml). The organic phase were successively washed with 2% HCl (50 ml), brine (50 ml) and dried over Na2SO4. After evaporation, the residue was purified by flash chromatography to give {2-[2-(2,4-Difluoro-phenoxy)-2-methyl-butyrylamino]-thiazol-4-yl}-acetic acid ethyl ester (0.2 g, 59%). 1H NMR (400 MHz, CDCl3): 1.03 (t, J=7.2 Hz, 3H), 1.28 (t, J=7.6 Hz, 3H), 1.43 (s, 3H), 1.83-1.89 (m, 1H), 2.04-2.1 (m, 1H), 3.73 (s, 2H), 4.2 (q, J=6.8 Hz, 2H), 6.8-6.93 (m, 3H), 7.0-7.04 (m, 1H); MS (EI) m/z: 399 (M+1).
Reaction SMILES: CN(C)[N:3]=[CH:4]/[CH:5]=[CH:6]/[CH3:7].Br[C:10]1[C:11](=[O:21])[C:12]2[C:17]([C:18](=[O:20])[CH:19]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2>C1(C)C(C)=CC=CC=1>[CH3:7][C:6]1[CH:5]=[CH:4][N:3]=[C:19]2[C:18](=[O:20])[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11](=[O:21])[C:10]=12
Reactant: C/C=C/C=NN(C)C
Reactant: O=C1C=C(Br)C(=O)c2ccccc21
Solvent: Cc1ccccc1C
Product: Cc1ccnc2c1C(=O)c1ccccc1C2=O
Yield: 57.3 %

Procedure:
(E)-2-Butenal N,N-dimethylhydrazone, (3.70 g, 0.033 mol) in dry xylene (10 mL, Fisher) was added to a xylene solution (50 mL) of 2-bromo-1,4-naphthoquinone, (6.00 g, 0.025 mol) in a 200-mL, round-bottomed flask fitted with a condensor. The dark mixture was then heated at reflux for 6 h under a nitrogen atmosphere before decanting the solution into a 500-mL separatory funnel. The solids coating the wall of the flask were washed thoroughly with ethyl acetate (6×25 mL) and these washings added to the separatory funnel. The combined organic solutions were extracted with 2N sulfuric acid solution (1×100 mL followed by 2×75 mL). The acid layers were then combined, chilled in ice, and made basic (~pH 10 test paper) with sodium hydroxide before extracting with ethyl acetate (4×100 mL). The latter organic layers were dried over potassium carbonate and concentrated to dryness on a rotary evaporator. This material was applied to a 4×70 cm column of Silica gel (Merck 230-400 mesh) and the product eluted with ethyl acetate. Concentration of the appropriate column fractions yielded pure cleistopholine (3.20 g, 57%); mp 202°-204° C. (lit. mp 198°-201° C.). IR (KBr) 1680, 1660, 1590, 1300, 980, 720 cm-1 ; 1H NMR (CDCl3) δ 8.86 (d,J=4.9 Hz, 1H), 8.34-8.30 (m, 1H), 8.24-8.19 (m, 1H), 7.82-7.76 (m, 2H), 7.47 (dd,J=4.9,0.7 Hz, 1H), 2.88 (br s, 3H); 13C NMR (CDCl3) 184.7 (0), 181.9 (0), 153.4 (1), 151.5 (0), 150.0 (0), 134.5 (1), 134.1 (1), 133.8 (0), 132.5 (0), 131.2 (1), 129.1 (0), 127.3 (1), 127.1 (1), 2.28 (3) ppm.
Reaction SMILES: [CH2:1]([O:5][N:6]=[C:7]([C:13](=O)[CH2:14]Cl)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:2][CH2:3][CH3:4].[NH2:17][C:18]([NH2:20])=[S:19].C([O-])(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[NH2:20][C:18]1[S:19][CH:14]=[C:13]([C:7](=[N:6][O:5][CH2:1][CH2:2][CH2:3][CH3:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:17]=1
Reactant: CCCCON=C(C(=O)CCl)C(=O)OCC
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCON=C(C(=O)OCC)c1csc(N)n1
Reaction time: 0.33 h
Yield: 63.8 %

Procedure:
A solution of ethyl 2-n-butoxyimino-4-chloro-3-oxobutyrate (syn isomer, 52.1 g.), thiourea (15.9 g.), sodium acetate 3 hydrate (18.4 g.), water (130 ml.) and ethanol (180 ml.) was stirred at 40° C. for 1.25 hours. The resultant solution was adjusted to pH 6.5 with an aqueous solution of sodium carbonate under ice cooling, and stirred for 20 minutes under ice cooling. The precipitates were collected by filtration, and washed with water and diisopropyl ether in turn to give ethyl 2-(2-aminothiazol-4-yl)-2-n-butoxyiminoacetate (syn isomer, 36.1 g.), mp 126° to 128° C.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.[CH3:25][N:26]([CH3:39])[CH2:27][CH2:28][NH:29][S:30]([C:33]1[S:34][C:35](Br)=[CH:36][CH:37]=1)(=[O:32])=[O:31]>>[CH3:25][N:26]([CH3:39])[CH2:27][CH2:28][NH:29][S:30]([C:33]1[S:34][C:35]([C:13]#[C:12][C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:24])=[CH:4][C:5]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=4)=[N:6][C:7]=23)=[CH:36][CH:37]=1)(=[O:32])=[O:31]
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CN(C)CCNS(=O)(=O)c1ccc(Br)s1
Product: CN(C)CCNS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (169 mg, 0.5 mmol) and 5-bromo-thiophene-2-sulfonic acid (2-dimethylamino-ethyl)-amide (example B.49) (157 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (170 mg, 60%). MS (ISP) 570.2 [(M+H)+]; mp 132° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[OH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:14]([N:11]1[C:6]2=[N:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:2][NH:1][C:36](=[O:37])[C:35]3[CH:34]=[CH:33][C:32]([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][OH:23])=[CH:40][CH:39]=3)[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:5]2[CH:13]=[N:12]1)[CH3:15]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: O=C(O)c1ccc(CCCCCCCCO)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(CCCCCCCCO)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 154 %

Procedure:
A solution of Intermediate 7 (182 mg, 0.6 mmol), 4-(8-hydroxyoctyl)benzoic acid (100 mg, 0.4 mmol, e.g. preparable according to K. Fukai JP11174621), (1H-1,2,3-benzotriazol-1-yloxy)(tri-1-pyrrolidinyl)phosphonium hexafluorophosphate (PyBOP, 208 mg, 0.4 mmol, e.g. available from Aldrich) and N,N-diisopropylethylamine (0.276 ml, 1.6 mmol) in dry N,N-dimethylformamide (3 ml) was allowed to stir at room temperature for 4 hours. The solvent was evaporated and the residue partitioned between chloroform (10 ml) and saturated aqueous sodium bicarbonate solution (10 ml); the organic fraction was collected by passing through a hydrophobic frit and evaporated. The residue was dissolved in chloroform (20 ml), and the solution passed through a 10 g aminopropyl SPE cartridge under gravity. The cartridge was further eluted with 10% methanol in chloroform, and product containing fractions evaporated to give the title compound (330 mg). LCMS showed MH+=536; TRET=2.92 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[C@@H:14]([CH:15]=[CH:16][C:17](=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][CH2:12][C:11]1=[O:24].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:37](O)[CH2:38][OH:39]>CCOCC>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[C@@H:14]([CH:15]=[CH:16][CH:17]([OH:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][CH:12]2[O:39][CH2:38][CH2:37][O:24][CH:11]12
Reactant: OCCO
Reactant: CCCCCC(=O)C=C[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: CCCCCC(O)C=C[C@H]1CC2OCCOC2[C@@H]1CCCCCCC(=O)OC
Reaction time: 0.5 h

Procedure:
A mixture if 9,15-dioxoprost-13-enoic acid methyl ester (2.0 g) benzene (50 ml), p-toluenesulfonic acid (37 mg) and ethylene glycol (372 mg) is refluxed for 2.5 hours, diluted with ether, washed neutral with water, dried over magnesium sulfate, and evaporated under reduced pressure. The residue containing 9-ethylenedioxy-15-oxoprost-13-enoic acid methyl ester is taken up in methanol (20 ml) and treated with sodium borohydride (300 mg) in small portions with stirring which is continued for 30 minutes. The solvent is evaporated under reduced pressure, the residue taken up in ether, washed to neutrality with water, dried over magnesium sulfate, and the solvent evaporated under reduced pressure. The residue is chromatographed on silica gel (140 g) and eluted with 40% ether in hexane to yield 9-ethylenedioxy-15-hydroxyprost-13-enoic acid methyl ester, γmaxFilm 3460, 1740, 1037, 975, 950 cm-1.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[C:22]([O:26][C:27](=[O:55])[NH:28][C@@H:29]1[CH2:35][CH2:34][C@@H:33]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:37]=2[F:43])[CH2:32][NH:31]/[C:30]/1=[N:44]\[CH2:45][CH:46](O)[C:47]1([C:50]([F:53])([F:52])[F:51])[CH2:49][CH2:48]1)([CH3:25])([CH3:24])[CH3:23]>C(#N)C>[C:22]([O:26][C:27](=[O:55])[NH:28][C@@H:29]1[CH2:35][CH2:34][C@@H:33]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:37]=2[F:43])[CH2:32][N:31]2[C:46]([C:47]3([C:50]([F:53])([F:52])[F:51])[CH2:49][CH2:48]3)=[CH:45][N:44]=[C:30]12)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN/C1=N\CC(O)C1(C(F)(F)F)CC1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C3(C(F)(F)F)CC3)cnc21
Reaction time: 70 h

Procedure:
Pyridinium dichromate (765 mg, 2.035 mmol) was added to a solution of crude tert-butyl [(2Z,3R,6S)-6-(2,3-difluorophenyl)-2-({2-hydroxy-2-[1-(trifluoromethyl)cyclopropyl]ethyl}imino)azepan-3-yl]carbamate from Step A (200 mg, 0.407 mmol) in acetonitrile (5 mL). After 70 h at ambient temperature, the mixture was filtered and concentrated. Saturated aqueous NaHCO3 was added and the mixture was extracted with CH2Cl2 (3×). The combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound. MS: m/z=472 (M+1).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:6]([F:15])[CH:5]=1.[Cl:16][C:17]1[C:22]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:21][CH:20]=[C:19]([C:28]([F:31])([F:30])[F:29])[N:18]=1>>[Cl:16][C:17]1[C:22]([CH:23]=[CH:24][C:25]([NH:2][CH2:3][C:4]2[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:6]([F:15])[CH:5]=2)=[O:26])=[CH:21][CH:20]=[C:19]([C:28]([F:29])([F:30])[F:31])[N:18]=1
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)nc1Cl
Agent: Cl
Product: CS(=O)(=O)Nc1ccc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2Cl)cc1F
Yield: 97.7 %

Procedure:
N-(4-Aminomethyl-2-fluoro-phenyl)-methanesulfonamide HCl salt (467 mg, 1.84 mmol) was reacted with 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (420 mg, 1.67 mmol) to give the title compound (737 mg, 98%).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH3:12])[C:5](=O)[NH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:16]>>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH3:12])[C:5]([Cl:16])=[N:4][CH:3]=1
Reactant: Cc1cccc2c(=O)[nH]cc(Br)c12
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cccc2c(Cl)ncc(Br)c12
Temperature: 0 °C
Yield: 92 %

Procedure:
A stirred solution of 4-bromo-5-methylisoquinolin-1(2H)-one (Intermediate-4) (10 g, 42 mmol) in POCl3 (50 mL) was heated to 100° C. for 30 min. The reaction mixture was then poured into ice-water, extracted with CH2Cl2 (3×200 mL), washed with water (2×200 mL), dried over Na2SO4, filtered and concentrated to obtain desired compound (10 g, 92%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C1C=C(Cl)C=C(C(OO)=[O:17])C=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N+:3]=1[O-:17]
Reactant: Cc1cccc(C)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1cccc(C)[n+]1[O-]
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.4 %

Procedure:
To a 0° C. solution of 2,6-dimethylpyridine (1.0 g, 0.009 mol) in CHCl3 (25 mL) was added mCPBA (3.17 g, 0.01 mol). The reaction mixture was then stirred for 12 h at RT, quenched with a saturated Na2CO3 solution. The organic layer was separated, dried over Na2SO4 and concentrated in vacuo to afford 2,6-dimethylpyridine 1-oxide (980 mg, 85%) as a solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:6][N:5](C(OC(C)(C)C)=O)[CH:4]([C:14]([O:16]C(C)(C)C)=[O:15])[CH2:3]1.[C:22]([OH:28])([C:24]([F:27])([F:26])[F:25])=[O:23]>C(Cl)Cl>[CH3:1][C:2]1([CH3:21])[CH2:6][NH:5][CH:4]([C:14]([OH:16])=[O:15])[CH2:3]1.[C:22]([OH:28])([C:24]([F:27])([F:26])[F:25])=[O:23]
Reactant: CC1(C)CC(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CNC(C(=O)O)C1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A mixture of 137e (27 g, 90 mmol) and TFA (100 mL) in DCM (200 mL) was stirred at 20° C. for 16 h. See FIG. 1. The reaction solution was concentrated under reduced pressure to give 4,4-dimethylpyrrolidine-2-carboxylic acid 137f as a brown oil (27 g, TFA salt). 1H NMR (400 MHz, CDCl3): δ 12.08 (br s, 2H), 9.56 (br s, 1H), 7.77 (br s, 1H), 4.52 (s, 1H), 3.20 (s, 2H), 2.30-2.24 (m, 1H), 2.00-1.94 (m, 1H), 1.17 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:3]=1[NH:4][C:5]1[S:9][C:8]2[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:7]=2[C:6]=1[C:16](OCC)=O.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C1(OC)C=CC=CC=1>[Ti](Cl)(Cl)(Cl)Cl>[F:25][C:22]1[CH:23]=[CH:24][C:2]2[N:1]=[C:16]([N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)[C:6]3[C:7]4[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:8]=4[S:9][C:5]=3[NH:4][C:3]=2[CH:21]=1
Reactant: CCOC(=O)c1c(Nc2cc(F)ccc2N)sc2cc(OC)ccc12
Reactant: CN1CCNCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: COc1ccccc1
Product: COc1ccc2c3c(sc2c1)Nc1cc(F)ccc1N=C3N1CCN(C)CC1

Procedure:
In the same manner as in Example 1 and using ethyl 2-(2-amino-5-fluoroanilino)-6-methoxybenzo[b]thiophene-3-carboxylate, 1-methylpiperazine, anisole and titanium tetrachloride, 8-fluoro-3-methoxy-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine is obtained.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][CH2:29][O:30][C:23]=3[CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][CH2:29][O:30][C:23]=4[CH:22]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=[N+]([O-])c1cc2c(NCc3ccc4c(c3)OCCO4)nc(Cl)nc2s1
Reactant: c1c[nH]cn1
Product: O=[N+]([O-])c1cc2c(NCc3ccc4c(c3)OCCO4)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-nitro-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-nitro-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([P:12](=[O:21])([O:17][CH2:18][CH2:19][CH3:20])[O:13][CH2:14][CH2:15][CH3:16])[P:2](=[O:11])([O:7][CH2:8][CH2:9][CH3:10])[O:3][CH2:4][CH2:5][CH3:6].C=O.[CH2:24](NCC)C>CO>[C:1]([P:2](=[O:11])([O:7][CH2:8][CH2:9][CH3:10])[O:3][CH2:4][CH2:5][CH3:6])([P:12](=[O:21])([O:13][CH2:14][CH2:15][CH3:16])[O:17][CH2:18][CH2:19][CH3:20])=[CH2:24]
Reactant: CCNCC
Reactant: CCCOP(=O)(CP(=O)(OCCC)OCCC)OCCC
Agent: C=O
Solvent: CO
Product: C=C(P(=O)(OCCC)OCCC)P(=O)(OCCC)OCCC
Yield: 71.9 %

Procedure:
5.97 g (17.4 mmol) of tetra-n-propyl methylenebisphosphonate, 2.61 g (86.8 mmol) of paraformaldehyde and 1.27 g (17.4 mmol) of diethylamine are combined with the same reactants and the same conditions as described above in Example I. This mixture is then refluxed for 46 hours. After the methanol is eliminated as described above in Example I, 4.46 g of tetra-n-propyl ethenylidenebisphosphonate is produced as a clear oil.