Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Al](C)C.[CH3:5][C:6]1[S:10][C:9]([NH2:11])=[N:8][CH:7]=1.[Si:12]([O:19][CH:20]1[CH2:23][N:22]([CH2:24][C@H:25]([OH:30])[C:26](OC)=[O:27])[CH2:21]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>C(Cl)Cl>[Si:12]([O:19][CH:20]1[CH2:23][N:22]([CH2:24][C@H:25]([OH:30])[C:26]([NH:11][C:9]2[S:10][C:6]([CH3:5])=[CH:7][N:8]=2)=[O:27])[CH2:21]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: Cc1cnc(N)s1
Reactant: COC(=O)[C@@H](O)CN1CC(O[Si](C)(C)C(C)(C)C)C1
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cnc(NC(=O)[C@@H](O)CN2CC(O[Si](C)(C)C(C)(C)C)C2)s1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 23.4 %

Procedure:
Trimethylaluminium (1M in heptane) (3.97 mL, 3.97 mmol) was added to 5-methylthiazol-2-amine (0.434 g, 3.80 mmol) in DCM (40 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes. (S)-Methyl 3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-hydroxypropanoate (Intermediate AD3) (1 g, 3.45 mmol) in DCM (10 mL) was added and the reaction was allowed to warm to room temperature and then heated at reflux for 2 hours, then left to cool to room temperature overnight. Rochelle solution (20%; 50 mL) was added and the resulting mixture was stirred vigorously for 90 mins. The mixture was diluted with DCM (50 mL) and the layers separated. The organics were dried (MgSO4) and evaporated (733 mg). The residue was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in EtOAc to afford the product (0.300 g, 23.37%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:12][N:13]([O:16]C2CCCCO2)[CH:14]=[O:15])[C:5]([F:30])=[C:4]([NH:31][CH2:32][C:33]2[CH:37]=[CH:36][S:35][CH:34]=2)[N:3]=1>C(O)(=O)C.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)[CH2:12][N:13]([OH:16])[CH:14]=[O:15])[C:5]([F:30])=[C:4]([NH:31][CH2:32][C:33]2[CH:37]=[CH:36][S:35][CH:34]=2)[N:3]=1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)NNc1nc(Cl)nc(NCc2ccsc2)c1F)OC1CCCCO1
Solvent: O
Solvent: CC(=O)O
Product: O=CN(O)C[C@@H](CC1CCCC1)C(=O)NNc1nc(Cl)nc(NCc2ccsc2)c1F
Reaction time: 8 h
Yield: 38.1 %

Procedure:
[(2R)-3-(2-{2-Chloro-5-fluoro-6-[(3-thienylmethyl)amino]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (0.7045 g, 1.272 mmol) was dissolved in acetic acid (8 mL) and water (2 mL). The reaction mixture was stirred overnight. The volatiles were evaporated, and the resulting residue was purified by RP-HPLC to provide [(2R)-3-(2-{2-chloro-5-fluoro-6-[(3-thienylmethyl)amino]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl]hydroxyformamide as a beige solid (0.2284 g, 38%). LCMS: (M+H)+=471.0.
Reaction SMILES: [O:1]=[C:2]([C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([F:13])[CH:7]=1)[C:3]([OH:5])=[O:4].[CH3:14][Mg]Cl>C(OCC)C>[F:13][C:8]1[CH:7]=[C:6]([C:2]([OH:1])([CH3:14])[C:3]([OH:5])=[O:4])[CH:11]=[C:10]([F:12])[CH:9]=1
Reactant: O=C(O)C(=O)c1cc(F)cc(F)c1
Reactant: C[Mg]Cl
Solvent: CCOCC
Product: CC(O)(C(=O)O)c1cc(F)cc(F)c1
Reaction time: 1.5 h

Procedure:
The compound was prepared according to the general procedure of Stiller et al., J. Med. Chem., 15:1029 (1972). A solution of alpha-keto-3,5-difluorophenylacetic acid (prepared according to Middleton et al., J. Org Chem., 45:2883 (1980)) in diethyl ether was cooled to 0° C. Methylmagnesium chloride (4.7 eq., 3.0 M solution in THF) was added dropwise via syringe pump at a rate of 10 ml/min so that the internal temperature did not exceed 5.5° C. The cooling bath was removed and stirring continued at ambient for 1.5 hours. After approximately 30 minutes, the clumps of solid dissolved. The mixture was poured onto ice and acidified with 1N HCl. The aqueous layer was extracted thrice with ethyl acetate. The combined organics were washed with 5% NaHSO3, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to a yellowish solid. The solid was recrystallized from dichloromethane, giving a white crystalline solid having a melting point of 102.5-103.2 C. C9H8F2O3 (MW 202.17); mass spectroscopy found (M−H) 201.2. Anal calcd for C9H8F2O3: C, 53.47, H, 3.99. Found: C, 53.76; H, 3.82.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)(=O)C.O=[Pt]=O>[N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1cncc(CN2CCCC2)c1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: C1CNCC(CN2CCCC2)C1

Procedure:
The educt 3-(1-pyrrolidinylmethyl)-pyridine (24.6 g) is taken up in 250 ml glacial acetic acid and hydrogenated with 2 g of PtO2 under 3 bar H2 at ambient temperature. The solution filtered off is evaporated down, combined with ice and made alkaline with solid KOH while cooling. Afer extracting three times with 250 ml of diethylether the crude product is dried with MgSO4. After the MgSO4 has been filtered off the solvent is eliminated and the amine is distillled in a water jet vacuum at a boiling point of 123° C.
Reaction SMILES: [F:1][C:2]1([F:41])[CH2:3][CH2:4][N:5]([C:18](=[O:40])[C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:39])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:21][CH:20]=2)[C:6]2[CH:17]=[CH:16][CH:15]=[CH:14][C:7]=2/[C:8]/1=[CH:9]/[C:10]([O:12]C)=[O:11].O.[OH-].[Li+]>CO>[F:41][C:2]1([F:1])[CH2:3][CH2:4][N:5]([C:18](=[O:40])[C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:39])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:21][CH:20]=2)[C:6]2[CH:17]=[CH:16][CH:15]=[CH:14][C:7]=2/[C:8]/1=[CH:9]/[C:10]([OH:12])=[O:11]
Reactant: COC(=O)/C=C1/c2ccccc2N(C(=O)c2ccc(NC(=O)c3ccccc3-c3ccccc3)cc2)CCC1(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)/C=C1/c2ccccc2N(C(=O)c2ccc(NC(=O)c3ccccc3-c3ccccc3)cc2)CCC1(F)F
Temperature: 25 °C
Reaction time: 7 h
Yield: 75.8 %

Procedure:
Methyl (Z)-[4,4-difluoro-1-[4-(2phenylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ylidene]acetate (857 mg) was dissolved in 10 ml of methanol, 2 ml of aqueous solution containing 195 mg of lithium hydroxide monohydrate was added dropwise to the above solution under ice-cooling, and the mixture was stirred at room temperature for 7 hours. After evaporating the solvent under a reduced pressure, 1N hydrochloric acid aqueous solution was added, and the mixture was extracted with chloroform and dried over anhydrous magnesium sulfate. After evaporation of the solvent under a reduced pressure, the resulting residue was recrystallized from ethyl acetatehexane to obtain 633 mg of (Z)-[4,4-difluoro-1-[4-(2-phenylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ylidene]acetic acid.
Reaction SMILES: C(O[C:4]1[C:5](=[O:16])[C:6](=[O:15])[C:7]=1[NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)C.[Cl:17][C:18]1[CH:32]=[CH:31][C:21]([O:22][C:23]2[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=2)[CH2:26][NH2:27])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:32]=[CH:31][C:21]([O:22][C:23]2[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=2)[CH2:26][NH:27][C:4]2[C:5](=[O:16])[C:6](=[O:15])[C:7]=2[NH:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:20][CH:19]=1
Reactant: CCOc1c(Nc2cccnc2)c(=O)c1=O
Reactant: NCc1cccc(Oc2ccc(Cl)cc2)c1
Product: O=c1c(NCc2cccc(Oc3ccc(Cl)cc3)c2)c(Nc2cccnc2)c1=O
Yield: 84 %

Procedure:
The title compound was prepared according to the procedure described in example 1B starting from 3-ethoxy-4-(pyridin-3-yl-amino)-3-cyclobutene-1,2-dione prepared according to example 1A and 3-(4-chlorophenoxy)-benzylamine.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.Cl[CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:21]([CH3:23])=[C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3cc(OC)ccc3OCC3CC3)ncnc12
Product: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3cc(OC)ccc3OCC3CC3)ncnc12

Procedure:
Starting from ethyl 4-(2-cyclopropylmethoxy-5-methoxy-phenyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example D.a6) and commercially available (2-chloromethoxy-ethyl)-trimethyl-silane the title compound is obtained as yellow viscous oil.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([O:14][CH3:15])[C:8]([CH2:12][OH:13])=[CH:9]2)=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].CC(C)=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([O:14][CH3:15])[C:8]([CH:12]=[O:13])=[CH:9]2)=[CH:4][CH:3]=1
Reactant: COc1cc2ccc(Br)cc2cc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Product: COc1cc2ccc(Br)cc2cc1C=O

Procedure:
In a 500 ml three-necked bottle, 34.1 g of 7-bromo-3-methoxy-2-naphthylcarbinol (0.128 mol) and 350 ml of acetone were added, and the mixture was stirred vigorously to form a solution. 167 g of active manganese dioxide (1.92 mol) was added to the solution, and the mixture was stirred at room temperature for 48 h to complete the reaction. The mixture was filtered, and the manganese dioxide filter cake was washed with ethyl acetate (200 ml*6). The filtrates were combined, and dried under vacuum in a rotary dryer to obtain a crude product as a yellow solid, which was recrystallized from methanol to obtain 29.3 g with a yield of the two steps of 86%.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([OH:35])[C:31]([F:34])([F:33])[F:32])=[C:26]([F:36])[CH:25]=1.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])=[C:26]([F:36])[CH:25]=1
Reactant: OC(c1ccc(Br)cc1F)C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccc(Br)cc1F)C(F)(F)F
Yield: 30.2 %

Procedure:
Dess-Martin periodinane (16.57 g, 39.06 mmol) was added to a solution consisting of 1-(4-bromo-2-fluoro-phenyl)-2,2,2-trifluoro-ethanol (10.66 g, 39.06 mmol) and DCM (100 mL) and the resultant mixture was stirred at rt for 1.5 h. Na2S2O3 (10% aq., 100 mL) was added and the resulting mixture extracted with CH2Cl2 (100 mL). The organic layer was washed with Na2S2O3 (50 mL×2), NaHCO3 (satd. aq., 100 mL×2), and brine (100 mL×2). The organic layer was dried (Na2SO4) and concentrated. The crude material was purified (FCC) to yield the title compound (3.20 g, 30%).
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[C:8]([NH2:9])=[C:7]([Cl:10])[CH:6]=[CH:5][C:4]=1[OH:11].[K+].[Br-].[CH3:14][C:15]([CH3:17])=O>>[ClH:2].[Cl:1][CH:5]1[C:6](=[C:15]([CH3:17])[CH3:14])[C:7]([Cl:10])=[C:8]([NH2:9])[CH:3]=[C:4]1[OH:11]
Reactant: CC(C)=O
Reactant: Nc1c(Cl)ccc(O)c1Cl
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: CC(C)=C1C(Cl)=C(N)C=C(O)C1Cl

Procedure:
Corresponding to the procedure and data in Example 1, 2,4-dichloro-3-aminophenol hydrochloride was reacted with acetone. The reaction product obtained according to this example of this invention had the following characteristic data: IR-spectrum (KBr) cm-1 1652, 1598, 1570, 1480, 1438, 1370, 1315, 1260, 1238, 1225, 1218, 1176, 1112, 1085, 1010, 980, 930, 870, 835, 805, 762, 730, 710, 675, 655.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].C(N(CC)CC)C.[CH3:13][C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([O:24][CH2:25][CH3:26])([CH3:23])[CH3:22])[C:15]=1[NH2:16]>C(Cl)Cl>[CH3:13][C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([O:24][CH2:25][CH3:26])([CH3:23])[CH3:22])[C:15]=1[NH:16][C:3](=[O:4])[CH2:2][Cl:1]
Reactant: O=C(Cl)CCl
Reactant: CCOC(C)(C)c1cccc(C)c1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(C)(C)c1cccc(C)c1NC(=O)CCl
Reaction time: 8 h

Procedure:
In this example 1.45 g (1.03 ml) of chloroacetyl chloride was added dropwise to a solution containing 1.44 g (2 ml) of triethylamine and 0.0129 mole of 2-methyl-6-(1-ethoxy-1-methylethyl)aniline in methylene chloride at about but below 20° C. The mixture was then refluxed and then allowed to stand overnight at room temperature. Another 0.51 ml of chloroacetyl chloride and 1 ml of triethylamine was then added dropwise. The mixture was then again refluxed and allowed to stand overnight at room temperature. The mixture was then washed with saturated aqueous sodium bicarbonate, dried and evaporated affording the title compound as a brown oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>C1COCC1.[OH-].[Na+]>[C:12]([N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CNc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C(=O)c1ccccc1)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a mixture of 4-(methylamino)benzoic acid (1.50 g) in THF (30 mL) and 1 mol/L aqueous sodium hydroxide solution (30 mL) was added dropwise benzoyl chloride (1.20 mL) under ice-cooling, and the mixture was stirred at room temperature for 14 hr. The reaction mixture was adjusted to pH=1-2 by the addition of dilute hydrochloric acid, and extracted with ethyl acetate (50 mL×2). The organic layer was washed with saturated brine and concentrated under reduced pressure. The residue was washed with a chloroform/hexane mixture and collected by filtration to give the title compound (1.81 g) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][NH2:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:20]([O:23][CH2:24][C:25](Cl)=[O:26])(=[O:22])[CH3:21].O>ClCCl>[CH2:1]([O:8][C:9]([NH:11][NH:12][C:25](=[O:26])[CH2:24][O:23][C:20](=[O:22])[CH3:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OCC(=O)Cl
Reactant: NNC(=O)OCc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCC(=O)NNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2.04 g of hydrazine carboxylic acid benzyl ester in 40 mL of dichloromethane was added 2.57 mL of triethylamine. Under ice cooling, a solution of 1.32 mL of acetoxyacetylchloride in 20 mL of dichloromethane was added dropwise over 25 minutes, and stirred at room temperature for 1 hour. The reaction solution was added with water, extracted with ethyl acetate, and the resultant organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and then dried over magnesium sulfate. The solvent was evaporated, and the resulting solid product was washed with diethyl ether and collected by filtration, to give 1.92 g of the title compound as white crystals.
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([O:18][CH:19]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:29])([F:28])[F:27])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.[Cl:38]C1C=CC=CC=1C(OC1CNC1)C1C=CC(Cl)=CC=1>>[ClH:38].[F:29][C:26]([F:27])([F:28])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH:19]([O:18][CH:16]1[CH2:17][NH:14][CH2:15]1)[C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1
Reactant: Clc1ccc(C(OC2CNC2)c2ccccc2Cl)cc1
Reactant: Cc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccccc2C(F)(F)F)cc1
Agent: Cl
Product: Cc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Yield: 54 %

Procedure:
This material was prepared from 1-benzhydryl-3-[2-(trifluoromethyl)-4′-methylbenzyloxy]azetidine (150) (7.5 mmol) using the procedure described for compound (9). Crystallisation from DIPE-MeOH afforded the product as a white solid (1.39 g, 54%).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[N:6]=1.C([Li])CCC.[Cl:13][C:14]1[N:19]=[CH:18][CH:17]=[CH:16][N:15]=1.O.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[OH-].[Na+]>C(OCC)C.C1COCC1>[Br:7][C:5]1[N:6]=[C:2]([C:16]2[CH:17]=[CH:18][N:19]=[C:14]([Cl:13])[N:15]=2)[S:3][CH:4]=1
Reactant: Clc1ncccn1
Reactant: Brc1csc(Br)n1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: Clc1nccc(-c2nc(Br)cs2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a cooled (−78° C.) solution of 2,4-dibromothiazole (1.22 g, 5.0 mmol) in anhydrous diethyl ether (15 ml) was added n-Butyllithium (2.2 ml of 2.5 M solution in Hexanes, 5.5 mmol) in a dropwise fashion. The mixture was maintained at this temperature, with stirring, for 1 hour before a suspension of 2-chloropyrimidine (0.85 g, 7.5 mmol) in anhydrous diethylether (15 ml) was added slowly and the resulting solution allowed to slowly warm up to room temperature. The misture was then allowed to stir at room temperature for 1 hr before being quenched with water (0.113 ml, 5.0 mmol) in THF (1.25 ml) and treated with DDQ (1.25 g, 5.4 mmol) in THF (6.25 ml). The mixture was then stirred at 25° C. for 15 minutes, cooled to 0° C., treated with hexanes (4.16 ml) then cold 2M NaOH (6.25 ml, 12.5 mmol). The organic extract was removed and remaing aqueous fraction extracted further with CH2Cl2 (3×20 ml). The organic extracts were combined, dried (MgSO4), filtered and concentrated in vacuo to give a sticky brown residue which was purified by flash chromatography (SiO2) (1:1—CH2Cl2:Hexanes going to 7:3—CH2Cl2:Hexanes) to give a white solid (1.38 g, 47.1%) corresponding to the title compound in analytically pure form. m/z (LC-MSW, ESP):278.0 [M+H]+, R/T=3.90 mins
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][CH:7]=[CH:6][CH2:5][N:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]1=[O:17].[Cl:18][C:19]1[CH:35]=[CH:34][C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[CH:21][CH:20]=1>N1C=CC=CC=1>[CH2:10]([O:9][N:4]1[CH2:5][CH:6]=[CH:7][CH2:8][C@@H:2]([NH:1][S:30]([C:27]2[CH:28]=[CH:29][C:24]([O:23][C:22]3[CH:34]=[CH:35][C:19]([Cl:18])=[CH:20][CH:21]=3)=[CH:25][CH:26]=2)(=[O:31])=[O:32])[C:3]1=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N[C@@H]1CC=CCN(OCc2ccccc2)C1=O
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: c1ccncc1
Product: O=C1[C@H](NS(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CC=CCN1OCc1ccccc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 57.9 %

Procedure:
To a solution of 3.69 g of 3-(R)-amino-1-benzyloxy-1,3,4,7-tetrahydro-azepin-2-one from Step D in 30 mL of pyridine was added 6.28 g of 4-(4-chloro-phenoxy)-benzene sulfonyl chloride. The reaction was stirred at room temperature for 5 days. The reaction was extracted with ethyl acetate, and washed with 5% HCl (aq.) twice, NaHCO3 (aq.) twice, and NaCl (aq.) once. The aqueous layers were re-extracted with ethyl acetate, and the organic layers combined and dried over Na2SO4(s). The reaction mixture was filtered and the solvent removed. The mixture was dissolved in dichloromethane, and filtered over silica gel. The dichloromethane layer was discarded. The silica gel was eluted with ethyl acetate, and the solvent removed under vacuum. Next, ethyl ether was added, and the solids collected under vacuum. The solids were washed with ethyl ether, and dried. Obtained 4.59 g of a white solid. MS: 521 (M+Na), 499 (M+H).
Reaction SMILES: Br.[CH3:2][C:3]1([CH3:9])[NH:7][C:6]([NH2:8])=[N:5][CH2:4]1.[N:10]1[CH:15]=[CH:14][C:13]([C:16](=O)[CH2:17][C:18](OCC)=[O:19])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:2][C:3]1([CH3:9])[CH2:4][N:5]2[C:18](=[O:19])[CH:17]=[C:16]([C:13]3[CH:14]=[CH:15][N:10]=[CH:11][CH:12]=3)[N:8]=[C:6]2[NH:7]1
Reactant: CCOC(=O)CC(=O)c1ccncc1
Reactant: CC1(C)CN=C(N)N1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC1(C)Cn2c(nc(-c3ccncc3)cc2=O)N1

Procedure:
A suspension of 4.5 g (23.2 mmol) of 5,5-dimethyl-4,5-dihydro-1H-imidazol-2-ylamine hydrobromide, 2.99 g (15.46 mmol) of ethyl 3-(pyridin-4-yl)-3-oxopropionate and 4.27 g (30.89 mmol) of potassium carbonate in 100 ml of ethanol was heated at reflux temperature for 18 h.
Reaction SMILES: [CH3:1][N:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[C:21]3[C:20]([NH:22][C@H:23]([C:25]4[N:30]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[C:29](=[O:37])[C:28]5=[C:38]([CH3:41])[CH:39]=[CH:40][N:27]5[N:26]=4)[CH3:24])=[N:19][CH:18]=[N:17][C:16]=3[N:15](COCC[Si](C)(C)C)[CH:14]=2)[CH:8]=1)[S:3]([CH3:6])(=[O:5])=[O:4].FC(F)(F)C(O)=O.N>>[CH3:1][N:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[C:21]3[C:20]([NH:22][C@H:23]([C:25]4[N:30]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)[C:29](=[O:37])[C:28]5=[C:38]([CH3:41])[CH:39]=[CH:40][N:27]5[N:26]=4)[CH3:24])=[N:19][CH:18]=[N:17][C:16]=3[NH:15][CH:14]=2)[CH:8]=1)[S:3]([CH3:6])(=[O:4])=[O:5]
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cccc(N(C)S(C)(=O)=O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cccc(N(C)S(C)(=O)=O)c5)c34)n(-c3ccccc3)c(=O)c12
Yield: 90.6 %

Procedure:
(S)—N-Methyl-N-(3-(4-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)methanesulfonamide (143 mg, 0.20 mmol) was treated with trifluoroacetic acid (3.8 ml, 49 mmol) and a solution of ammonia (7N in methanol, 3.8 ml, 27 mmol) according to the method described in Example 27 to give 103 mg (86% yield) of the title compound. Purity 96%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[N+:15]([O-])=O.Cl.C(=O)(O)[O-].[K+]>C(Cl)(Cl)Cl>[NH2:15][C:3]1[CH:4]=[CH:5][C:6]([S:8][C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1cc(Sc2ncccn2)ccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: Nc1ccc(Sc2ncccn2)cc1N

Procedure:
3.5 G. of 2-amino-1-nitro-4-(pyrimidin-2-ylthio)benzene is treated with 16 g. stannous chloride in 16 ml. concentrated hydrochloric acid on the steam bath for 30 minutes. The mixture is cooled, treated with an excess of potassium bicarbonate, chloroform, and filtered. The chloroform layer is dried and stripped yielding 1,2-diamino-4-(pyrimidin-2-ylthio)benzene which may be recrystallized from benzene.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=O)[CH2:7][C:8]32[CH2:12][CH2:11]3)=[CH:4][CH:3]=1.Cl.[NH2:15][OH:16].CC([O-])=O.[Na+]>CO>[Br:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[N:15]/[OH:16])/[CH2:7][C:8]32[CH2:12][CH2:11]3)=[CH:4][CH:3]=1
Reactant: O=C1CC2(CC2)c2cc(Br)ccc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O/N=C1\CC2(CC2)c2cc(Br)ccc21
Yield: 99.8 %

Procedure:
A solution of 6′-bromospiro[cyclopropane-1,1′-inden]-3′(2′H)-one (2.1 g, 8.86 mmol), hydroxylamine HCl (1.23 g, 17.7 mmol) and NaOAc (4.32 g, 53.1 mmol) in MeOH (160 mL) was stirred overnight at room temperature. The reaction was concentrated, slurried water (40 mL), then sonicated and filtered. The precipitate was dried under high vacuum to give (E)-6′-bromospiro[cyclopropane-1,1′-inden]-3′(2′H)-one oxime (2.23 g, 100% yield) as a white solid. MS (EI) m/z=253.1[M+1]+.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[C-:11]#[N:12].[K+]>C(#N)C.C(OCC)C.C1OCCOCCOCCOCCOCCOC1>[F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:11]#[N:12]
Reactant: [C-]#N
Reactant: Fc1cccc(CBr)c1F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: N#CCc1cccc(F)c1F
Yield: 100.1 %

Procedure:
2,3-Difluorobenzyl bromide (5 g, 24.2 mmol) in acetonitrile (20 mL) was treated with 18-crown-6 (638 mg, 2.4 mmol) and potassium cyanide (5 g, 77 mmol). The reaction was heated at reflux for 5.5 hours. The reaction was diluted with diethyl ether (100 mL). The resulting organic solution was washed with 1 N NaOH (3×25 mL), dried over anhydrous MgSO4, filtered, and concentrated to afford 3.71 g of crude 2,3-difluorobenzyl cyanide.