Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[CH:9].[C:16](=[O:18])=[O:17]>ClCCl.CO>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[C:9][C:16]([OH:18])=[O:17]
Reactant: C#Cc1ccc(-c2ccccc2)cc1Br
Reactant: O=C=O
Solvent: ClCCl
Solvent: CO
Product: O=C(O)C#Cc1ccc(-c2ccccc2)cc1Br

Procedure:
Prepared analogously to Example 4.3.a. from 3-bromo-4-ethynylbiphenyl and carbon dioxide. Yield: 2.5 g (89% of theory); C15H9BrO2 (M=301.13); calc.: molecular ion peak (M+H)+: 301/303 (Br); found: molecular ion peak (M+H)+: 301/303 (Br); Rf value: 0.3 (silica gel, dichloromethane/methanol (90:10)).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[C:11]3=[C:12]4[CH:18]=[CH:17][NH:16][C:13]4=[N:14][CH:15]=[C:10]3[NH:9][N:8]=2)[CH2:2]1.Cl[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1.CCN(C(C)C)C(C)C>CCO>[F:27][C:26]([F:29])([F:28])[C:23]1[CH:24]=[CH:25][C:20]([N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([C:7]3[C:11]4=[C:12]5[CH:18]=[CH:17][NH:16][C:13]5=[N:14][CH:15]=[C:10]4[NH:9][N:8]=3)[CH2:2]2)=[N:21][CH:22]=1
Reactant: c1cc2c(ncc3[nH]nc(C4CCCNC4)c32)[nH]1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: FC(F)(F)c1ccc(N2CCCC(c3n[nH]c4cnc5[nH]ccc5c34)C2)nc1
Temperature: 130 °C
Yield: 24.4 %

Procedure:
A mixture of 1-(piperidin-3-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine (0.16 g, 0.65 mmol, Example #26, Step E) and 2-chloro-5-(trifluoromethyl)pyridine (0.031 g, 0.17 mmol) with DIEA (0.09 mL, 0.51 mmol) in EtOH (2 mL) was heated at about 130° C. for about 1 h in a microwave reactor (250 psi maximum pressure, 1 min ramp, 300 max watts). The crude material was purified by silica gel chromatography eluting with a 5-100% EtOAc in heptane gradient to give 1-(1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine (0.016 g, 24%): LC/MS (Table 2, Method a) Rt=2.32 min; m/z: 387 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([N:22]2[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]2)=[O:21])[CH2:3][CH2:2]1.Cl.[OH:30][CH2:31][C@@H:32]1[C@H:36]([NH:37][C:38](=[O:40])[CH3:39])[CH2:35][CH2:34][NH:33]1>>[CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([N:22]2[CH2:27][CH2:26][CH:25]([N:33]3[CH2:34][CH2:35][C@@H:36]([NH:37][C:38](=[O:40])[CH3:39])[C@H:32]3[CH2:31][OH:30])[CH2:24][CH2:23]2)=[O:21])[CH2:3][CH2:2]1
Reactant: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)N1CCC(=O)CC1
Reactant: CC(=O)N[C@@H]1CCN[C@@H]1CO
Agent: Cl
Product: CC(=O)N[C@@H]1CCN(C2CCN(C(=O)c3c(C)nn(-c4cccc(C(F)(F)F)c4)c3C3CC3)CC2)[C@@H]1CO

Procedure:
The title compound was prepared from 1-[5-Cyclopropyl-3-methyl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carbonyl]-piperidin-4-one (Example 181B) and N-((2S,3R)-2-hydroxymethyl-pyrrolidin-3-yl)-acetamide hydrochloride in direct analogy to the general procedure used in example 129. MS: 534.2 (MH+).
Reaction SMILES: Cl[C:2]1[N:11]([CH3:12])[C:10](=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:14][CH3:15])[N:3]=1.[CH2:16]([NH:19][CH2:20][CH2:21][CH3:22])[CH2:17][CH3:18]>O1CCCC1.O>[CH2:16]([N:19]([CH2:20][CH2:21][CH3:22])[C:2]1[N:11]([CH3:12])[C:10](=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:14][CH3:15])[N:3]=1)[CH2:17][CH3:18]
Reactant: COc1cccc2nc(Cl)n(C)c(=O)c12
Reactant: CCCNCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCN(CCC)c1nc2cccc(OC)c2c(=O)n1C
Temperature: 80 °C
Reaction time: 60 h
Yield: 45.5 %

Procedure:
A mixture of 2-chloro-5-methoxy-3-methylquinazolin-4(3H)-one (75 mg, 0.334 mmol) and dipropylamine (0.137 ml, 1.00 mmol) in tetrahydrofuran (1 ml) was stirred at 80° C. for 60 h and diluted with water. The aqueous solution was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography eluting with 50% ethyl acetate/n-hexane to afford 44 mg (45%) of the title compound.
Reaction SMILES: [Si]([O:8][C@@H:9]([C@H:11]1[C:39](=[O:40])[N:13]2[C:14]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[C:15]([C:18]3[S:22][C:21]4=[CH:23][N:24]=[CH:25][N:20]4[CH:19]=3)[C@H:16]([CH3:17])[C@H:12]12)[CH3:10])(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>C1COCC1.C(OCC)(=O)C>[OH:8][C@@H:9]([C@H:11]1[C:39](=[O:40])[N:13]2[C:14]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=3)=[O:27])=[C:15]([C:18]3[S:22][C:21]4=[CH:23][N:24]=[CH:25][N:20]4[CH:19]=3)[C@H:16]([CH3:17])[C@H:12]12)[CH3:10]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cncc4s3)[C@H](C)[C@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cncc4s3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 20 h
Yield: 64.2 %

Procedure:
To a solution of 111 mg of 4-nitrobenzyl (1S,5R,6S)-6-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate in 3 ml of anhydrous THF were added 0.164 ml of acetic acid and 0.954 ml of a 1 M solution of tetra-n-butylammonium fluoride/THF, and the mixture was stirred at room temperature under the atmosphere of argon at 20 hours. The reaction mixture was diluted with ethyl acetate, and washed with a mixed solvent of semi-saturated aqueous saline and saturated aqueous sodium hydrogen carbonate (pH 8.0), and semi-saturated aqueous saline in this sequence. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by distillation. The residue thus obtained was purified by column chromatography on Sephadex LH-20 (chloroform:methanol=1:1) to give 57.3 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:15]C4(CCN(C)CC4)[CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH2:28]1[C@H:32]2CNC[CH2:36][N:31]2[C:30](=[O:37])[O:29]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:15][CH2:36][N:31]4[C:30](=[O:37])[O:29][CH2:28][C@H:32]4[CH2:13]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CN1CCC2(CC1)CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)C2
Reactant: O=C1OC[C@H]2CNCCN12
Product: O=C1OC[C@H]2CN(Cc3cc4nc(Cl)nc(N5CCOCC5)c4s3)CCN12

Procedure:
Prepared according to the method used in the preparation of 2-chloro-6-(7-methyl-2,7-diaza-spiro[3.5]non-2-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine using (R)-hexahydro-oxazolo[3,4-a]pyrazin-3-one in place of 7-methyl-2,7-diaza-spiro[3.5]nonane. The title compound was obtained as a white solid (71 mg, 50%).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[H-].[Na+].O.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Cl>O1CCCC1>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:10])[CH3:1]
Reactant: COc1ccccc1CCl
Reactant: CN(C)CCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1COCCCCCCN(C)C
Reaction time: 0.75 h

Procedure:
6-(Dimethylamino)hexanol (8.80 g, 60.6 mmol) was dissolved in an anhydrous 2:1 mixture of tetrahydrofuran and dimethylfornamide (150 mL) and the solution was cooled in an ice bath. Sodium hydride (60% in oil, 3.23 g, 80.8 mmol) was added in portions and after 5 min. the water bath was removed. After 45 min., 2-methoxybenzyl chloride (6.28 g, 40.4 mmol) was added. After 4 h, the reaction mixture was quenched with 1 M sodium thiosulfate and tetrahydrofuran was removed in vacuo. The reaction mixture was washed with ethyl acetate and the aqueous phase was basified with 3 M sodium hydroxide, followed by extraction with ether. The ether layer was dried over potassium carbonate, filtered and acidified with 4 M hydrochloric acid in dioxane. The reaction mixture was concentrated in vacuo and the residue was crystallized form ethanol/ether to give O-(2-methoxybenzyl)-6-dimethylaminohexanol as the hydrochloride salt (10.4 g, 85%). MS (M-Cl)+266.3.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:23](=O)([O:27]CC)[O:24][CH2:25][CH3:26]>C1COCC1>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([C:23]([O:24][CH2:25][CH3:26])=[O:27])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][CH:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)Cc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)c1ccc(OCc2ccccc2)cc1
Temperature: 30 °C
Reaction time: 18 h
Yield: 78.9 %

Procedure:
To a suspension of NaH (54 gm, 1.11 moles) in dry THF (500 ml) a solution of ethyl 2-(4-(benzyloxy)phenyl)acetate (100 gm, 0.37 moles) in dry THF (100 ml) was added at 0° C. To this was added diethyl carbonate (180 ml, 1.48 mole) dropwise over a period of one hour maintaining the reaction temperature at below 5° C. The reaction mixture was then stirred for 18 hours at 30° C. The contents of the reaction mixture were poured into ice cold water and extracted with ethyl acetate. The organic extract was successively washed with water & brine, dried over sodium sulfate and evaporated under reduced pressure to yield 100 gm of product as white solid.
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[O:10][CH:9]=[CH:8][C:7]=2[CH:6]=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1.[C@H:15]12[CH2:21][C@H:18]([NH:19][CH2:20]1)[CH2:17][N:16]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>>[N+:12]([C:5]1[CH:4]=[C:3]([CH2:2][N:19]2[CH2:20][C@@H:15]3[CH2:21][C@H:18]2[CH2:17][N:16]3[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:11]2[O:10][CH:9]=[CH:8][C:7]=2[CH:6]=1)([O-:14])=[O:13]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: O=[N+]([O-])c1cc(CBr)c2occc2c1
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2Cc1cc([N+](=O)[O-])cc2ccoc12
Yield: 79 %

Procedure:
The title compound was prepared according to the procedure of Example 112, Step 1, starting from 7-(bromomethyl)-5-nitro-1-benzofuran (120 mg, 70 mol %, 0.39 mmol; Intermediate 64) and tert-butyl (1S,4S)-(−)-2,5-diazabicyclo-(2.2.1)heptane-2-carboxylate (93 mg, 0.47 mmol). The title compound (115 mg, 79%) was obtained as a light yellow sticky oil. HPLC 99%, RT=2.34 min (System A; 5-60% MeCN over 3 min), 99%, RT=2.15 min (System B; 5-60% MeCN over 3 min). MS (ESI+) for C19H23N3O5 m/z 374 (M+H)+.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][CH2:9][CH2:10][N:11]1[C:15]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)[N:17]=2)=[CH:14][N:13]=[CH:12]1.N>N1C=CC=CC=1.CCOC(C)=O>[Cl:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[NH:22][C:18]1[N:17]=[C:16]([C:15]2[N:11]([CH2:10][CH2:9][NH:8][C:5](=[O:7])[CH3:6])[CH:12]=[N:13][CH:14]=2)[CH:21]=[CH:20][N:19]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCCn1cncc1-c1ccnc(Nc2cccc(Cl)c2)n1
Agent: N
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NCCn1cncc1-c1ccnc(Nc2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.1 %

Procedure:
Acetic anhydride (0.58 μl, 1.0 mmol) was added to solution of 2-(3-chloroanilino)-4-[1-(2-aminoethyl)imidazol-5-yl]pyrimidine (Example 13; 0.30 g, 0.63 mmol) in pyridine (2 ml) at 0° C. The mixture was allowed to warm to ambient temperature and stirred for 2 hours. 7M Methanolic ammonia (0.5 ml) was added and the mixture diluted with EtOAc (10 ml). The precipitate was removed by filtration and the filtrate pre-absorbed on to silica gel and purified by column chromatography on silica gel eluting with DCM/2% methanolic ammonia (11:1) to give the title compound (88 mg, 39%) as a white solid. NMR 9.68 (s, 1H), 8.43 (d, 1H), 8.03-7.96 (m, 2H), 7.81 (s, 1H), 7.79 (s, 1H), 7.60 (dd, 1H), 7.33 (t, 1H), 7.12 (d, 1H), 6.98 (dd, 1H), 4.56-4.46 (m, 2H), 3.44-3.37 (m, 2H), 1.80 (s, 3H); m/z 357.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10])=[N+:2]=[N-:3].[C:11](O)(=[O:15])[C:12]([CH3:14])=[CH2:13].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:11]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][N:1]=[N+:2]=[N-:3])(=[O:15])[C:12]([CH3:14])=[CH2:13]
Reactant: C=C(C)C(=O)O
Reactant: [N-]=[N+]=NCCCCCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=C(C)C(=O)OCCCCCCN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a 500 mL round bottom flask, a solution of 1-azido-6-hydroxyhexane (14.3 g, 100 mmol), methacrylic acid (7.74 g, 90 mmol), and 4-dimethylaminopyridine (DMAP) (3.67 g, 30 mmol) in 100 mL of methylene chloride was cooled to 0° C. Dicyclohexylcarbodiimide (DCC) (20.63 g, 100 mmol) was dissolved in 50 mL methylene chloride and added slowly to the solution. The resulting mixture was warmed to room temperature and stirred overnight. The precipitate was removed by filtration. After removal of the solvent and silica gel column chromatography (10:1 mixture of hexane and ethyl acetate), the product was obtained as a colorless liquid (yield: 16.1 g, 85%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N+:14]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([CH3:16])[CH3:15].[Cl-].[CH3:25][C:26]([N-:28][S:29]([C:32]1[CH:33]=[CH:34][C:35]([NH2:38])=[CH:36][CH:37]=1)(=[O:31])=[O:30])=[O:27].[Na+].C(Cl)(Cl)Cl.CS(C)=O>O>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N+:14]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([CH3:16])[CH3:15].[CH3:25][C:26]([NH:28][S:29]([C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1)(=[O:31])=[O:30])=[O:27]
Reactant: CC(=O)[N-]S(=O)(=O)c1ccc(N)cc1
Agent: CCCCCCCCCCCCC[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)NS(=O)(=O)c1ccc(N)cc1
Temperature: 25 °C

Procedure:
Benzalkonium chloride (0.001 mol) was dissolved in 60 mL of distilled water by gentle heating and stirring. Sodium sulfacetamide (0.001 mol) was dissolved in 60 mL of distilled water by gentle heating and stirring. The two solutions were combined and the reaction mixture was heated and stirred for 30 minutes. The reaction mixture cooled to room temperature and then 60 mL of chloroform was added. The reaction mixture was stirred for an additional 30 minutes. The two phases were separated and the chloroform phase was washed several times with cool distilled water to remove any inorganic salt. The presence of chloride anions was monitored by silver nitrate test. A rotary evaporator removed the chloroform and a yellowish gel was obtained in 76.99% yield. 1H and 13C NMR (DMSO) were obtained. Melting point (hot plate apparatus)=35-40° C. Thermal data determined by thermalgravimetric analysis (TGA): Tonset5%=164° C. and Tonset=181° C.
Reaction SMILES: [C:1]([CH2:3][C:4](O)=[O:5])#[N:2].[CH2:7]([O:9][C:10]([C:12]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH:25]=[CH2:26])=[CH:19][CH:18]=2)=[C:15]([CH3:27])[S:14][C:13]=1[NH2:28])=[O:11])[CH3:8].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:7]([O:9][C:10]([C:12]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH:25]=[CH2:26])=[CH:19][CH:18]=2)=[C:15]([CH3:27])[S:14][C:13]=1[NH:28][C:4](=[O:5])[CH2:3][C:1]#[N:2])=[O:11])[CH3:8]
Reactant: C=CCOc1ccc(-c2c(C)sc(N)c2C(=O)OCC)cc1
Reactant: N#CCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C=CCOc1ccc(-c2c(C)sc(NC(=O)CC#N)c2C(=O)OCC)cc1
Temperature: 25 °C
Yield: 100.7 %

Procedure:
To PCl15 (854 g, 4.1 mol) in 10 mL anhydrous CH2Cl2 was added cyanoacetic acid (348 g, 4.1 mmol). The reaction mixture was refluxed for 0.5 h, and then 4-(4-Allyloxyphenyl)-2-amino-5-methyl-thiophene-3-carboxylic acid ethyl ester from Example 29B (1.0 g, 3.1 mmol) in 5 ml anhydrous CH2Cl2 was added dropwise at room temperature. The reaction mixture was refluxed for 1 h and cooled to room temperature, and then saturated aq. Na2CO3 was added until pH=7. The organic layer was washed with brine, dried over MgSO4, concentrated in vacuo to give the titled compound (1.2 g, 100% yield) as a pale yellow oil which was pure enough to used in next step. 1H NMR (300 MHz, DMSO-d6) δ 11.15 (s, 1H), 7.07 (d, 2H, J=9.0 Hz), 6.97 (d, 2H, J=9.0 Hz), 6.05 (m, 1H), 5.44, 5.38, 5.28, 5.25 (4d, 2H, J=3.0 Hz), 4.60 (d, 2H, J=6.0 Hz), 4.25 (s, 2H), 3.97 (q, 2H, J=6.0 Hz), 2.12 (s, 3H), 0.84 (t, 3H, J=6.0 Hz). MS (ESI) m/e 385 (M+H)+, 383 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Br:17])[CH:15]=3)[C:10]([CH2:18]O)=[N:9]2)[CH:5]=[CH:4][N:3]=1.C(N(S(F)(F)[F:26])CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:17][C:14]1[CH:15]=[C:16]2[C:11]([C:10]([CH2:18][F:26])=[N:9][N:8]2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[N:7]=2)=[CH:12][CH:13]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: Nc1nccc(-n2nc(CO)c3ccc(Br)cc32)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Nc1nccc(-n2nc(CF)c3ccc(Br)cc32)n1
Reaction time: 16 h

Procedure:
To a solution of [1-(2-aminopyrimidin-4-yl)-6-bromo-1H-indazol-3-yl]methanol (200 mg, 0.47 mmol) in dry DCM (10 mL) at RT under an atmosphere of nitrogen was introduced (diethylamino)sulphur trifluoride (0.08 mL, 0.63 mmol). After 16 hr at this temperature, the reaction mixture was treated with sodium bicarbonate (25 mL of saturated aq NaHCO3) and extracted with DCM (2×20 mL extractions). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (Biotage, heptane/EtOAc gradient) to furnish the title compound as a colorless solid: 1H NMR (500 MHz, DMSO) delta 5.86 (2H, d, J=48.24 Hz), 7.06 (1H, d, J=5.04 Hz), 7.14 (2H, br. s.), 7.58 (1H, dd, J=8.04, 2.05 Hz), 7.92 (1H, d, J=8.98 Hz), 8.31 (1H, d, J=6.31 Hz), 9.17 (1H, d, J=1.42 Hz); LC-MS: m/z=+321.90/323.90 (M+H)+.
Reaction SMILES: [Na].[C:2]1([NH:8][CH2:9][C:10]([OH:12])=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C=CC(O)=CC=1)O.[C:21]([O:26][CH2:27][CH:28]1[O:30][CH2:29]1)(=[O:25])[C:22]([CH3:24])=[CH2:23].Cl>O.CO>[OH:30][CH:28]([CH2:27][O:26][C:21](=[O:25])[C:22]([CH3:24])=[CH2:23])[CH2:29][N:8]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]([OH:12])=[O:11]
Reactant: C=C(C)C(=O)OCC1CO1
Reactant: O=C(O)CNc1ccccc1
Agent: Cl
Agent: Oc1ccc(O)cc1
Agent: [Na]
Solvent: CO
Solvent: O
Product: C=C(C)C(=O)OCC(O)CN(CC(=O)O)c1ccccc1

Procedure:
A sodium salt of N-phenylglycine of 50 g (0.29 mol) was dissolved in water of 50 g and methanol of 50 g and then hydroquinone of 18 mg were added to the resulting solution. This solution was heated up to temperatures of 45° to 50° C. and glycidyl methacrylate of 41 g (0.29 mol) was added dropwise for 20 minutes with stirring followed by stirring for further 2 hours. Water of 200 g was added to the resulting solution and acidified with hydrochloric acid followed by filtering and drying the resulting crystals. N-(2-hydroxy-3-methacryloxypropyl)-N-phenylglycine (hereinafter called GMA-NPG for short) of 45 g was obtained. Then GMA-NPG of 2.0 g, MMA (methyl methacrylate) of 14.0 g, EA (ethyl acrylate) of 2.4 g and MAA (methacrylic acid) of 1.6 g were dissolved in dimethylformamide of 80 g. 20 g of a 1 wt %-solution of benzoyl peroxide in dimethylformamide was added dropwise to the above described solution under an atmosphere of nitrogen at 70° C. followed by stirring for further 6 hours. After cooling, hexane of about 10 times in weight was added to dilute the solution, the resulting polymer being settled and collected, the collected polymer being dissolved in methalethylketone and settled again in hexane, and the settled material being fltered and dried in a vacuum. A white powdery polymer was obtained. The number mean molecular weight of the obtained polymer was 25,000 and its acid value was 75. In addition, it was confirmed from the existence of an absorption having a peak at 300 nm in the UV absorption spectrum of this polymer that GMA was copolymerized with NPG.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][C:14]#[N:15])([O-:3])=[O:2].O>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10]([NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][NH2:15])=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: N#CCc1c[nH]c2ccc([N+](=O)[O-])cc12
Solvent: C1CCOC1
Solvent: O
Product: NCCc1c[nH]c2ccc([N+](=O)[O-])cc12
Reaction time: 8 h

Procedure:
Dissolve (5-nitro-1H-indol-3-yl)-acetonitrile (9 g, 44.7 mmol) in 250 mL dry THF and treat with 90 mL 1 M BH3 in THF at ambient temperature. Stir overnight and quench the reaction cautiously by the dropwise addition of 10 mL water. Concentrate to dryness under vacuum and partition the residuc between 5 N HCl and EtOAc. Extract the aqueous layer with EtOAc and combine with the original EtOAc layer. Treat the aqueous layer with 5 N NaOH and extract 3 times with 10% MeOH in EtOAc. Purify by flushing the extracts through a pad of 100 g SCX ion exchange resin, rinsing with 2 liters of MeOH which was discarded, and then eluting with the 2 M NH3 in MeOH and concentrating to give the title compound as a dark solid: ISMS 206 (M+1); Analysis for C20H18F6N2O2 0.3H2O 0.1C7H8: calcd: C, 57.34; H, 5.74; N, 19.29. found: C, 57.30; H, 5.38; N, 19.08. 1H NMR (DMSO-d6) 11.9-11.2 (bs, 1H), 8.50-8.49 (d, 1H), 7.95-7.92 (m, 1H), 7.47-7.45 (m, 1H), 7.38 (s, 1H), 2.79 (s, 4H), 2.2-1.3 (bs, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C>ClCCl>[CH2:22]([O:21][C:19]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)/[C:6](=[CH:12]/[CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17]2)/[C:7]1=[O:11])=[O:20])[CH3:23]
Reactant: CCOC(=O)Cl
Reactant: O=C1Nc2cc(Cl)ccc2/C1=C/C1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1C(=O)/C(=C\C2CCCC2)c2ccc(Cl)cc21
Yield: 58.6 %

Procedure:
In a manner similar to the method described in example 4b, E/Z-6-chloro-3-cyclopentylmethylene-1,3-dihydro-indol-2-one (0.8 g, 3.2 mmol) was reacted with ethyl chloroformate (0.46 mL, 4.9 mmol) and triethylamine (0.9 mL, 6.4 mmol) in dichloromethane to give E/Z-6-chloro-3-cyclopentylmethylene-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester as brown oil (Yield 0.6 g, 58%).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=2)=[O:7])=[CH:4][C:3]=1[N+:18]([O-])=O>[Ni].C1COCC1>[NH2:18][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:2]=1[NH2:1])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1)=[O:7]
Reactant: Nc1ccc(C(=O)Nc2ccc(Br)cn2)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)Nc2ccc(Br)cn2)cc1N

Procedure:
Prepared analogously to example 14b by hydrogenation of 4-amino-N-(5-bromo-pyridin-2-yl)-3-nitro-benzamide using Raney nickel in THF.
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([CH3:25])[CH:16]=2)[CH:4]=1.[S:27]([C:31]1[CH:32]=[C:33]([NH2:37])[CH:34]=[CH:35][CH:36]=1)(=[O:30])(=[O:29])[NH2:28]>>[S:27]([C:31]1[CH:32]=[C:33]([NH:37][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:26])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([CH3:25])[CH:16]=4)=[N:6][C:7]=23)=[O:14])[CH:34]=[CH:35][CH:36]=1)(=[O:29])(=[O:30])[NH2:28]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: Cc1cc(-c2cc(C(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Product: Cc1cc(-c2cc(C(F)F)n3ncc(C(=O)Nc4cccc(S(N)(=O)=O)c4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(3-methyl-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.5) and 3-sulfamoyl-phenylamine [commercially available] according to general procedure II. Yellow solid. MS (ISP) 524.0 [(M−H)−]; mp 252° C.