Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[CH:9]=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH:11]([CH3:13])[CH3:12])[CH:3]=1.[Li]CCCC.[Br:19][C:20]1[C:21]([O:32][CH2:33][CH3:34])=[N:22][CH:23]=[C:24]([CH:31]=1)[C:25](N(OC)C)=[O:26]>C(OCC)C.CCCCCC>[Br:19][C:20]1[CH:31]=[C:24]([C:25]([C:2]2[C:10]3[CH:9]=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH:11]([CH3:13])[CH3:12])[CH:3]=2)=[O:26])[CH:23]=[N:22][C:21]=1[O:32][CH2:33][CH3:34]
Reactant: CCOc1ncc(C(=O)N(C)OC)cc1Br
Reactant: CC(C)n1cc(I)c2cncnc21
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CCOc1ncc(C(=O)c2cn(C(C)C)c3ncncc23)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
A solution of 5-Iodo-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine (Preparation 93, 530 mg, 1.85 mmol) in anhydrous diethyl ether (8 mL) was cooled to −78° C. under nitrogen and n-BuLi (1 mL of a 2.03M solution in Hexane, 2.03 mmol) was added drop wise over a period of 10 min. Just after the completion of addition of n-BuLi, a solution of 5-Bromo-6-ethoxy-N-methoxy-N-methyl-nicotinamide (Preparation 240) in anhydrous diethyl ether (7 mL) was added slowly to the mixture and it was stirred at the same temperature for another 1 hour. The reaction mixture was warmed to room temperature and allowed to stir for another hour before being quenched with sat. aq. NH4Cl (15 mL). The mixture was extracted with EtOAc (3×15 mL), washed with water (20 mL), brine (15 mL), dried (Na2SO4) and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (EtOAc:petroleum ether 2:10) to afford the title compound as a yellow gum in 49% yield, 350 mg.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].[CH:13]([O:16][CH2:17][CH3:18])=[CH:14][CH3:15]>ClC(Cl)C.CC(C)(C)/C(/O)=C/C(C(C(C(F)(F)F)(F)F)(F)F)=O.CC(C)(C)/C(/O)=C/C(C(C(C(F)(F)F)(F)F)(F)F)=O.CC(C)(C)/C(/O)=C/C(C(C(C(F)(F)F)(F)F)(F)F)=O.[Yb]>[CH2:17]([O:16][CH:13]1[CH:14]([CH3:15])[CH2:1][C:2]2[CH2:11][CH2:10][C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[C:3]=2[O:12]1)[CH3:18]
Reactant: C=C1CCc2ccccc2C1=O
Reactant: CC=COCC
Agent: CC(C)(C)/C(O)=C/C(=O)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Yb]
Solvent: CC(Cl)Cl
Product: CCOC1OC2=C(CCc3ccccc32)CC1C
Reaction time: 20 h
Yield: 203.2 %

Procedure:
A solution of 2-methylene-3,4-dihydronaphthalen-1-one (44.9 g, 282 mmol), tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionato)ytterbium [Yb(fod)3, 15.0 g, 14.2 mmo], and ethyl propenyl ether (300 g, 390 mL, 3.5 mol) in 830 mL of dichloroethane was heated at reflux under nitrogen with stirring for 20 hours. Evaporation of the solvent left 200 g of a brown liquid that was purified on a silica gel column with 15/85 ethylacetate/hexane as the eluent, yielding 140 g of product, which was used without further purification.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:8]([CH3:34])=[C:9]([C:21]([NH:23][CH2:24][C:25]3[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=3[CH3:31])=[O:22])[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=3)[CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:35][NH:36][CH3:37].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH:1]1([NH:6][C:7]2[C:8]([CH3:34])=[C:9]([C:21]([NH:23][CH2:24][C:25]3[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=3[CH3:31])=[O:22])[CH:10]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([CH2:19][N:36]([CH3:37])[CH3:35])=[CH:17][CH:18]=3)[CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)cc3)cc(NC3CCCC3)c2C)c(=O)[nH]1
Reactant: CNC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN(C)C)cc3)cc(NC3CCCC3)c2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 5-(cyclopentylamino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4′-formyl-4-methyl-[1,1′-biphenyl]-3-carboxamide (0.11 g, 0.24 mmol) and N,N-dimethylamine (0.044 g, 1.2 mmol) in methanol (3 mL) was added acetic acid (0.014 g, 0.24 mmol) and the solution stirred at room temperature for 3 h. Then sodium cyanoborohydride (0.030 g, 0.48 mmol) was added and the solution stirred overnight. The solvent was removed under reduced pressure and the residue purified by column chromatography over silica gel to afford desired 5-(cyclopentylamino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4′-((dimethylamino)methyl)-4-methyl-[1,1′-biphenyl]-3-carboxamide
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>C(Cl)(Cl)Cl.[Cu]Cl>[Br:17][C:18]1[CH:24]=[CH:23][C:21]([N:22]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][CH:9]=[C:10]2[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:20][CH:19]=1
Reactant: Nc1ccc(Br)cc1
Reactant: C(C#Cc1ccccc1)#Cc1ccccc1
Agent: Cl[Cu]
Solvent: ClC(Cl)Cl
Product: Brc1ccc(-n2c(-c3ccccc3)ccc2-c2ccccc2)cc1
Temperature: 25 °C
Yield: 73.7 %

Procedure:
Under an argon atmosphere, 15 g (74 mmol) of 1,4-di-phenylbutadiyne, 12.76 g (74 mmol) of p-bromoaniline and 1.84 g (18 mmol) copper(I) chloride were put into 500 ml round-bottomed flask, and the resulting mixture was reacted at 150° C. for 5 hours while stirring. After the reaction was completed, the reaction mixture was cooled down to room temperature, dissolved in chloroform and then washed with 5% hydrochloric acid several times. The combined organic extract was washed with water several times and then dried with anhydrous magnesium sulfate. The solvent was removed to obtain solid, which was recrystallized from ethyl acetate to give 20.4 g (73.5%) white solid having a melting point of 218-219° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:17]2[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]3[CH:30]=[C:31]([C:34](OC)=[O:35])[CH:32]=[CH:33][C:19]=3[N:18]=2)[C:5](=[O:16])[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[N:7]=1>ClCCl.C1(C)C=CC=CC=1.[O-2].[Mn+4].[O-2].[O-2].[Mn+2]>[Cl:1][C:2]1[CH:3]=[C:4]([C:17]2[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:28])[CH3:29])[C:20]3[CH:30]=[C:31]([CH:34]=[O:35])[CH:32]=[CH:33][C:19]=3[N:18]=2)[C:5](=[O:16])[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[N:7]=1
Reactant: COC(=O)c1ccc2nc(-c3cc(Cl)nn(COCC[Si](C)(C)C)c3=O)n(COCC[Si](C)(C)C)c2c1
Agent: [Mn+2]
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOCn1nc(Cl)cc(-c2nc3ccc(C=O)cc3n2COCC[Si](C)(C)C)c1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
6-Chloro-4-(6-methoxycarbonyl-1-(2-trimethylsilanylethoxymethyl)-1H-benzimidazol-2-yl]-2-(2-trimethylsilanylethoxymethyl)-2H-pyridazin-3-one (3.0 g, 5.3 mmol) is dissolved in dichloromethane, and the solution is cooled to 0° C. 15% DIBA1H in toluene is added dropwise, and the reaction mixture is stirred at room temperature for 1 hour. A further 15% DIBA1H in toluene is then added dropwise at 0° C. and stirred at room temperature for 1 hour. Manganese(IV) oxide is then added directly and the reaction solution is heated to reflux for 3 hours. Additional manganese oxide is added every 3 hours until the conversion is complete according to LC-MS. The reaction solution is filtered through kieselguhr, the residue is washed several times with dichloromethane, and the solvent is removed in a rotary evaporator.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=1.Br[CH2:13][CH2:14][CH2:15][Cl:16].C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[Cl:16][CH2:15][CH2:14][CH2:13][N:7]1[C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=[C:3]1[S:2][CH3:1]
Reactant: ClCCCBr
Reactant: CSc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: CSc1nc2ccccc2n1CCCCl
Yield: 50 %

Procedure:
A mixture of 8.2 parts of 2-(methylthio)-1H-benzimidazole, 16 parts of 1-bromo-3-chloropropane, 5.3 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred and refluxed for 44 hours. After cooling, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is stirred in 2,2'-oxybispropane. The unreacted starting material is filtered off and the filtrate is evaporated, yielding 6 parts (50%) of 1-(3-chloropropyl)-2-(methylthio)-1H-benzimidazole as an oily residue.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:13]1([CH3:22])[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH2:21])=[CH:15][CH:14]=1.[BH4-].[Na+]>CO.Cl>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:21][CH2:20][CH2:19][C:16]2[CH:17]=[CH:18][C:13]([CH3:22])=[CH:14][CH:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(CCN)cc1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(CCNCc2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
0.39 ml of 4-tert-butylbenzaldehyde (2.25 mmol) and 0.22 ml 2-p-tolyl-ethylamine (1.5 mmol) were dissolved in 4.5 ml methanol and after stirring for 30 min at rt, were refluxed for 2.5 h. After cooling down to rt, 85 mg (2.25 mmol) sodium borohydride were added and after stirring for 5 min at rt, the reaction mixture was then refluxed for 2.5 h. After cooling down to rt, the reaction mixture was treated with 4 drops 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:1) to give 480 mg light yellow viscous oil (100%). MS (ISP) 282.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=1.[CH3:17][O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[NH2:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([C:14]([NH:21][C:20]([CH3:23])([CH3:22])[C:19]([O:18][CH3:17])=[O:24])=[O:16])[CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)C(C)(C)N
Reactant: O=C(O)c1cccc(-c2ccccc2Cl)n1
Product: COC(=O)C(C)(C)NC(=O)c1cccc(-c2ccccc2Cl)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(2-chlorophenyl)-2-pyridinecarboxylic acid (CAN 887982-21-0) and 2-methyl-alanine methyl ester as starting materials, MS (LC/MS): 333.1 (M+H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]2[N:10]=[C:11]([NH:13][C:14]3[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[C:18](Br)[CH:19]=3)[CH:12]=[C:6]2[CH2:5]1)(=[O:3])[CH3:2].[C:23]([O:26][CH2:27][C:28]1[C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=[CH:30][C:29]=1[N:43]1[CH2:55][CH2:54][N:46]2[C:47]3[CH2:48][CH2:49][CH2:50][CH2:51][C:52]=3[CH:53]=[C:45]2[C:44]1=[O:56])(=[O:25])[CH3:24].COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO.CCOCC.O.C(OCC)(=O)C>[C:23]([O:26][CH2:27][C:28]1[C:29]([N:43]2[CH2:55][CH2:54][N:46]3[C:47]4[CH2:48][CH2:49][CH2:50][CH2:51][C:52]=4[CH:53]=[C:45]3[C:44]2=[O:56])=[CH:30][CH:31]=[CH:32][C:33]=1[C:18]1[CH:19]=[C:14]([NH:13][C:11]2[CH:12]=[C:6]3[CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:9][CH2:8][N:7]3[N:10]=2)[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: CC(=O)N1CCn2nc(Nc3cc(Br)cn(C)c3=O)cc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCN(C(C)=O)C4)c(=O)n(C)c2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 130 °C
Yield: 36.9 %

Procedure:
A microwave tube equipped with a magnetic stirrer was charged with 3-(5-acetyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-5-bromo-1-methylpyridin-2(1H)-one 108d (120 mg, 0.3 mmol), 2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 114a (200 mg, 0.4 mmol), DME (4 mL) and 1M aqueous sodium carbonate (1 mL). After bubbling nitrogen for 15 min, Pd(PPh3)4 (19 mg, 0.02 mmol) was added. The mixture was heated in a microwave to 130° C. for 15 min. After this time, ethyl acetate (5 mL) and water (5 mL) were added. The separated aqueous layer was extracted with EtOAc (2×5 mL). The combined organics were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography eluting with a gradient of CH2Cl2-60:35:5 CH2Cl2:Et2O:MeOH to afford a 33% yield (69 mg) of 2-(5-(5-acetyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzyl acetate 108e.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=3)[C@@H:13]([CH2:33][N:34]([CH:39]([CH3:41])[CH3:40])[S:35]([CH3:38])(=[O:37])=[O:36])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[NH4+:43]>CCO>[NH2:43][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=3)[C@@H:13]([CH2:33][N:34]([CH:39]([CH3:41])[CH3:40])[S:35]([CH3:38])(=[O:37])=[O:36])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: CC(C)N(C[C@H]1CN(S(=O)(=O)c2ccc(Cl)nc2)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1)S(C)(=O)=O
Agent: [OH-]
Solvent: CCO
Product: CC(C)N(C[C@H]1CN(S(=O)(=O)c2ccc(N)nc2)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1)S(C)(=O)=O
Temperature: 140 °C
Yield: 55.8 %

Procedure:
A 5-mL microwave reaction vial charged with N-(((2R)-4-((6-chloro-3-pyridinyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-N-(1-methylethyl)methanesulfonamide (0.161 g, 0.246 mmol), concentrated ammonium hydroxide (0.65 mL, 5.0 mmol) and EtOH (2 mL). The vial was heated in an Initiator microwave reactor (Biotage AB, Inc., Uppsala, Sweden) at 140° C. for 2.5 h. The mixture was allowed to cool to room temperature and then concentrated in vacuo. The crude product was purified by column chromatography (25 g of silica gel, 30 to 100% EtOAc in hexanes) to afford N-(((2R)-4-((6-amino-3-pyridinyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-N-(1-methylethyl)methanesulfonamide (0.0873 g) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([O-:6])=[C:3]1[OH:4].[NH2:13][C:14]1[C:19]2[C:20]([C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=4)=[O:31])=[CH:25][CH:24]=3)=[CH:21][S:22][C:18]=2[C:17]([C:40]2[CH:41]=[N:42][N:43]([CH2:45][CH2:46][OH:47])[CH:44]=2)=[CH:16][N:15]=1.O1CCCC1>O>[NH2:13][C:14]1[C:19]2[C:20]([C:23]3[CH:24]=[CH:25][C:26]([NH:29][C:30]([NH:32][C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=4)=[O:31])=[CH:27][CH:28]=3)=[CH:21][S:22][C:18]=2[C:17]([C:40]2[CH:41]=[N:42][N:43]([CH2:45][CH2:46][OH:47])[CH:44]=2)=[CH:16][N:15]=1.[O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4]
Reactant: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: Nc1ncc(-c2cnn(CCO)c2)c2scc(-c3ccc(NC(=O)Nc4cccc(F)c4)cc3)c12
Solvent: C1CCOC1
Solvent: O
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O

Procedure:
There is further provided a process for preparing N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl}phenyl)-N′-(3-fluorophenyl)urea ascorbate in a solid crystalline form, wherein the crystalline form is Form VII, comprising: a) providing a mixture comprising (i) N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl}phenyl)-N′-(3-fluorophenyl)urea free base solid, tetrahydrofuran, water, and ascorbic acid; b) causing N-(4-{4-amino-7-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl}phenyl)-N′-(3-fluorophenyl)urea ascorbate crystalline Form VII to exist in the mixture.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20]([NH:22][C@@H:23]([CH2:31][CH2:32][CH2:33][OH:34])[C:24]([O:26]C(C)(C)C)=O)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1C=CC=CC=1.C(OCC)(=O)C>[CH2:12]([O:19][C:20]([NH:22][C@H:23]1[CH2:31][CH2:32][CH2:33][O:34][C:24]1=[O:26])=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)[C@H](CCCO)NC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(N[C@H]1CCCOC1=O)OCc1ccccc1
Yield: 51 %

Procedure:
In benzene (100 ml) was dissolved tert-butyl (S)-2-(N-benzyloxycarbonylamino)-5-hydroxyvalerate [synthesized by the method described in the Journal of Organic Chemistry, 55, 1711 (1990)](5.1 g) and following addition of p-toluenesulfonic acid (0.05 g), the mixture was stirred under reflux for 1 hour. This reaction mixture was diluted with ethyl acetate (100 ml) and washed with water, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride in the order mentioned. After drying (MgSO4), the solvent was distilled off. The residue was chromatographed on a silica gel column and elution was carried out with ethyl acetate-hexane (1:2, v/v). From the eluate was obtained (S)-3-(N-benzyloxycarbonylamino)-2-oxotetrahydropyran (2.0 g, 51%) as an oil. NMR (δ ppm in CDCl3): 1.54-1.74 (1H, m), 1.96-2.10 (2H, m), 2.55-2.72 (1H, m), 4.36 (2H, t, J=6.2 Hz), 4.37-4.50 (1H, m), 5.13 (2H, s), 5.62 (1H, broad), 7.34-7.40 (5H, m). Optical rotation [α]D +51.5° (C=0.98, CHCl3)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](I)=[CH:5][CH:4]=1.[OH-:10].[Cs+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(I)cc1
Reactant: [OH-]
Agent: [Cs+]
Product: COc1ccc(O)cc1
Yield: 90 %

Procedure:
Following general operating mode A, 4-methoxyiodobenzene (246 mg, 1.0 mmol) is caused to react with cesium hydroxide to give the expected product in the form of a white solid with a yield of 90% (eluent: ethyl acetate/heptanes 20:80).
Reaction SMILES: CC1(C)COB([C:8]2[CH:9]=[CH:10][C:11]([N+:21]([O-:23])=[O:22])=[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]3)[CH:13]=2)OC1.[S:25]1[CH2:30][CH:29]=[C:28](OS(C(F)(F)F)(=O)=O)[CH2:27][CH2:26]1.[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O>[S:25]1[CH2:26][CH:27]=[C:28]([C:8]2[CH:9]=[CH:10][C:11]([N+:21]([O-:23])=[O:22])=[C:12]([N:14]3[CH2:15][CH2:16][CH:17]([CH3:20])[CH2:18][CH2:19]3)[CH:13]=2)[CH2:29][CH2:30]1
Reactant: O=S(=O)(OC1=CCSCC1)C(F)(F)F
Reactant: CC1CCN(c2cc(B3OCC(C)(C)CO3)ccc2[N+](=O)[O-])CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC1CCN(c2cc(C3=CCSCC3)ccc2[N+](=O)[O-])CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a mixture of 1-[5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2-nitro-phenyl]-4-methyl-piperidine (as prepared in Example 33, step (b), 60 mg, 0.18 mmol), trifluoromethanesulfonic acid 3,6-dihydro-2H-thiopyran-4-yl ester (as prepared in the previous step, 54 mg, 0.22 mmol), Pd(PPh3)4 (31 mg, 0.027 mmol) and LiCl (15 mg, 0.36 mmol) in 1 mL of 1,4-dioxane was added 2.0 M Na2CO3 aq solution (80 μL, 0.16 mmol). The resulting mixture was stirred at 80° C. for 1 h, and then cooled to RT. Treated with 50 mL of EtOAc, the mixture was washed with H2O, brine and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (1% EtOAc/hexane) gave 56 mg (97%) of the title compound as a brown oil: 1H-NMR (CDCl3; 400 MHz): δ 7.77 (d, 1H, J=8.6 Hz), 7.01 (d, 1H, J=1.8 Hz), 6.88 (dd, 1H, J=8.6, 1.8 Hz), 6.24 (m, 1H), 3.34-3.37 (m, 2H), 3.26 (d, 2H, J=12.4 Hz), 2.89 (t, 2H, J=5.7 Hz), 2.82 (td, 2H, J=12.0, 1.6 Hz), 2.64-2.69 (m, 2H), 1.70 (dd, 2H, J=12.4, 2.1 Hz), 1.52 (m, 1H), 1.36-1.47 (m, 2H), 0.99 (d, 3H, J=6.2 Hz). Mass spectrum (ESI, m/z): Calcd. for C17H22N2O2S, 319.1 (M+H), found 319.1.
Reaction SMILES: Cl.C[O:3][C:4](=[O:16])[C@@H:5]([NH2:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[Cl:14].[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([NH:27][S:28]([C:31]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=2[F:38])(=[O:30])=[O:29])[CH:19]=1>>[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:15][CH:5]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[Cl:14])[C:4]([OH:3])=[O:16])=[O:23])=[C:20]([NH:27][S:28]([C:31]2[C:32]([F:38])=[CH:33][CH:34]=[CH:35][C:36]=2[F:37])(=[O:30])=[O:29])[CH:19]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(Cl)cc1Cl
Reactant: O=C(O)c1ccc(Br)cc1NS(=O)(=O)c1c(F)cccc1F
Agent: Cl
Product: O=C(NC(Cc1ccc(Cl)cc1Cl)C(=O)O)c1ccc(Br)cc1NS(=O)(=O)c1c(F)cccc1F

Procedure:
(S)-2-Amino-3-(2,4-dichloro-phenyl)-propionic acid was treated as in EXAMPLE 2, Part A, to produce (S)-2-amino-3-(2,4-dichloro-phenyl)-propionic acid methyl ester hydrochloride as a white solid. This ester was coupled with 4-bromo-2-(2,6-difluoro-benzenesulfonylamino)-benzoic acid as in EXAMPLE 1, Part C. The resulting methyl ester was hydrolyzed as in EXAMPLE 2, Part E, to afford title compound. HPLC: RT=10.26 min. MS (ESI−): mass calcd. for C22H15BrCl2F2N2O5S, 608.2; m/z found, 607 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.36 (s, 1H), 7.87 (d, J=1.8, 1H), 7.52-7.44 (m, 1H), 7.39 (d, J=1.6, 1H), 7.27-7.25 (m, 1H), 7.25-7.22 (m, 1H), 7.18-7.15 (m, 1H), 6.97 (t, J=8.7, 2H), 6.79 (d, J=7.7, 1H), 5.05-5.00 (m, 1H), 3.50 (dd, J=14.2, 5.5, 1H), 3.29 (dd, J=14.2, 8.1, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([NH2:18])=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:28]12([C:38](Cl)=[O:39])[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([NH:18][C:38]([C:28]34[CH2:37][CH:32]5[CH2:31][CH:30]([CH2:36][CH:34]([CH2:33]5)[CH2:35]3)[CH2:29]4)=[O:39])=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncnc2c1CCN(Cc1ccccc1)C2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ncnc2c1CCN(Cc1ccccc1)C2)C12CC3CC(CC(C3)C1)C2
Temperature: 160 °C
Yield: 41.8 %

Procedure:
In a 20 ml microwave vessel was added 7-benzyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-ylamine (1.5 g, 6.3 mmole) in 7.0 ml of chloroform, diisopropylethylarnine (2.2 ml, 12.6 mmole) and 1-adamantane carbonylchloride (2.51 g, 12.6 mmole). The reaction was heated at 160° C. for 7.0 minutes in a microwave. After completion the solvent was evaporated and the residue was dissolved in EtOAc and washed with sat. NaHCO3, washed with brine and dried over sodium sulphate. The solvents were removed under reduced pressure and the residue was chromatographed using chloroform (100%) to give the desired product as a white solid (1.06 g).