Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:9]1(=[O:16])[CH:14]=[CH:13][C:12](=[O:15])[CH:11]=[CH:10]1.Cl.C(OCC)(=O)C>C1COCC1>[CH2:7]([O:6][C:4](=[O:5])[CH2:3][C:9]1([OH:16])[CH:14]=[CH:13][C:12](=[O:15])[CH:11]=[CH:10]1)[CH3:8]
Reactant: CCOC(=O)C[Zn]Br
Reactant: O=C1C=CC(=O)C=C1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1(O)C=CC(=O)C=C1
Yield: 70 %

Procedure:
Under nitrogen atmosphere, 6 mL of THF was added to 1.22 g (2 mmol, 0.6 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 0.36 g (3.33 mmol) of p-benzoquinone in 2.5 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 20˜25° C. for 1 hour. 5 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 25 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of water, 5 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. After concentration under reduced pressure, purification with silica gel column (developing solvent; ethyl acetate/n-hexane=1/3, 1/2) afforded 0.46 g of the desired product (yield 70%).
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[CH:4][N:3]=[CH:2]1.[Li]CCCC.[C:17](Cl)(=[O:33])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C1COCC1.CCOC(C)=O.[Cl-].[Cl-].[Zn+2]>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:5]1[O:1][C:2]([C:17](=[O:33])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[N:3][CH:4]=1
Reactant: c1ccc(-c2cnco2)nc1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCC(=O)c1ncc(-c2ccccn2)o1
Reaction time: 0.33 h
Yield: 41.5 %

Procedure:
(183) A solution of 2-(oxazol-5-yl)pyridine (95 mg, 0.65 mmol) in anhydrous THF (5 mL) cooled to −75° C. under N2 was treated with n-BuLi (2.5 M in hexanes, 1.1 equiv, 0.72 mmol, 0.29 mL), and stirred for 20 min. ZnCl2 (0.5 M in THF, 2.0 equiv, 1.30 mmol, 2.6 mL) was added at −75° C., and stirred for 45 min at 0° C. Cul (1.0 equiv, 0.65 mmol, 124 mg) was added, and the solution was stirred for 10 min at 0° C. Palmitoyl chloride (2 equiv, 1.3 mmol, 357 mg, 0.39 mL) was added and the solution was stirred for 1 h at 0° C. The reaction was diluted with EtOAc (10 mL), and washed with 15% aqueous NH4OH (1×10 mL), H2O (1×10 mL), and saturated aqueous NaCl (1×10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. Flash chromatography (SiO2, 2.5 cm×17.5 cm, 20% EtOAc-hexanes) afforded 1-(5-(pyridin-2-yl)oxazol-2-yl)hexadecan-1-one (183) (103 mg, 0.27 mmol, 42% yield) as an off-white powder: mp 78-80° C.; 1H NMR (CDCl3, 250 MHz) d 8.66 (br d, J=5.1 Hz, 1H), 7.88-7.76 (m, 3H), 7.34-7.27 (m, 1H), 3.10 (t, J =7.3 Hz, 2H), 1.83-1.70 (m, 2H), 1.24 (br s, 24H), 0.87 (br t, J=6.9 Hz, 3H); 13C NMR (CDCl3, 62.5 MHz) d 188.6, 157.4, 153.2, 150.1, 146.3, 137.0, 126.8, 124.1, 120.4, 39.2, 31.9, 29.6 (2C), 29.6 (2C), 29.4 (2C), 29.3 (3C), 29.2 24.0, 22.7, 14.1; IR (KBr) umax 2935, 2847, 1699, 1605, 1425, 1381 cm−1; MALDI-FTMS (DHB) m/z 385.2841 (C24H36N2O2+H+ requires 385.2849).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[ClH:9].[C:10]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:13])[NH:11][NH2:12]>C(O)C>[ClH:9].[N:1]1[CH:2]=[CH:3][C:4]([CH:7]=[N:12][NH:11][C:10]([O:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:13])=[CH:5][CH:6]=1
Reactant: NNC(=O)Oc1ccccc1
Reactant: O=Cc1ccncc1
Agent: Cl
Solvent: CCO
Product: O=C(NN=Cc1ccncc1)Oc1ccccc1
Temperature: 25 °C
Yield: 66 %

Procedure:
A solution of 6.43 gm (0.06 mole) of 4-pyridinecarboxaldehyde, 11.31 gm (0.06 mole) of phenyl carbazate hydrochloride and 300 ml of 95% ethanol is refluxed 4 hr. The reaction mixture is evaporated to dryness. The crude product is suspended in 200 ml of boiling absolute ethanol and sufficient methanol added to give a solution. The hot solution is filtered, the filtrate cooled to room temperature and then chilled in the freezer. The crystals are collected, washed with Skellysolve B and dried to yield 11.0 gm (66%) of the title compound having a melting point of 224.4° C. (decomp).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:10]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>>[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:28][CH2:29][N:30]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:31][CH2:32]2)[N:10]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: CS(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N

Procedure:
The same procedure as described in Example 60 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 59, and methanesulfonyl chloride (Aldrich), to give [4-amino-2-( 1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone. MS (M+H)+, 424.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]([CH3:14])[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]=1[CH3:15])([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:13]=[C:12]([CH3:14])[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]=1[CH3:15]
Reactant: [H][H]
Reactant: Cc1cc([N+](=O)[O-])c(C)c2c1OCCO2
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N)c(C)c2c1OCCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
A mixture of 3.10 g of 6-nitro-5,8-dimethyl-1,4-benzodioxane and 0.30 g of 10% palladium on carbon in 75 mL of ethanol is placed under a 50 psi hydrogen atmosphere. The mixture is shaken for three hours at room temperature. The reaction mixture is filtered through Celite to yield a brownish solution. Concentration under reduced pressure affords 2.6 g of 6-amino-5,8-dimethyl-1,4-benzodioxane.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:4]#[N:5].[CH2:12]([O:16][C:17]1[C:18]2[C:23]([C:24]([O:35][CH2:36][CH2:37][CH2:38][CH3:39])=[C:25]3[C:30]=1[CH:29]=[C:28]([S:31](Cl)(=[O:33])=[O:32])[CH:27]=[CH:26]3)=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:14][CH3:15].ClCCl>C(N(CC)CC)C>[CH2:12]([O:16][C:17]1[C:18]2[C:23]([C:24]([O:35][CH2:36][CH2:37][CH2:38][CH3:39])=[C:25]3[C:30]=1[CH:29]=[C:28]([S:31]([O:1][N:2]=[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:4]#[N:5])(=[O:32])=[O:33])[CH:27]=[CH:26]3)=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCOc1c2ccccc2c(OCCCC)c2cc(S(=O)(=O)Cl)ccc12
Reactant: N#CC(=NO)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOc1c2ccccc2c(OCCCC)c2cc(S(=O)(=O)ON=C(C#N)c3ccccc3)ccc12

Procedure:
A mixture of 0.50 g of 2-hydroxyimino-2-phenylacetonitrile, 1.43 g of 9,10-dibutoxyanthracene-2-sulfonyl chloride and 20 ml of dichloromethane was stirred on an ice bath, and 0.34 g of triethylamine was added.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:5][C:6]1([C:29]([NH:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[O:30])[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][C:24]([CH3:26])=[N:23][CH:22]=4)=[C:17]([O:27][CH3:28])[CH:16]=3)=[N:13][N:14]=[C:7]12.[H-].[Na+].[CH3:43]I>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:5][C:6]1([C:29]([N:31]([CH3:43])[CH2:32][C:33]([F:36])([F:34])[F:35])=[O:30])[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][C:24]([CH3:26])=[N:23][CH:22]=4)=[C:17]([O:27][CH3:28])[CH:16]=3)=[N:13][N:14]=[C:7]12
Reactant: COc1cc(-c2nnc3n2CCCC3(Cc2ccc(F)c(F)c2)C(=O)NCC(F)(F)F)ccc1-c1cnc(C)o1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(-c2nnc3n2CCCC3(Cc2ccc(F)c(F)c2)C(=O)N(C)CC(F)(F)F)ccc1-c1cnc(C)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 8-(3,4-difluorobenzyl)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-N-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxamide (200 mg) in DMF (2 mL) was added sodium hydride (60%, 7.8 mg) at 0° C., and the mixture was stirred at room temperature for 1 hr. Methyl iodide (0.012 mL) was added to the reaction mixture at 0° C., and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, the mixture was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and further recrystallized from ethyl acetate/methanol to give the title compound (25.3 mg).
Reaction SMILES: [C:1]([O:5][CH2:6][C@H:7]([CH3:10])[CH2:8]O)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:30]N1C(=O)CCC1=O>C(Cl)Cl>[C:1]([O:5][CH2:6][C@H:7]([CH3:10])[CH2:8][Br:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](CO)COC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@H](CBr)COC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 25.8 g. (0.176 mole) of (R)-(+)-3-tert. butoxy-2-methyl-1-propanol and 50.5 g. (0.193 mole) of triphenylphosphine in 105 ml. of CH2Cl2 was stirred while 32.8 g. (0.184 mole) of N-bromosuccinimide was added in portions, keeping the temperature below 30° C. with occasional ice bath cooling. The resulting solution was stirred at room temperature for one hour then most of the solvent was distilled under a water aspirator pressure using a Vigreaux column. The product was distilled from the residue using a short distilling head giving 0.7 g. of forerun b.p. 58°-62° C. (23 mm Hg) and then the main fraction (31.1 g.) b.p. 62°-69° C. (14-18 mm Hg). The total distillate (31.8 g.) was chromatographed on 450 g. of silica gel. Elution with 19:1 parts by volume and 9:1 parts by volume hexane-ether yielded the pure (S)-(+)-3-tert. butoxy-2 -methyl-1-bromopropane which was distilled giving 26 g. (70.6%) of colorless liquid, b.p. 71° C. (16 mm Hg); [α]25D + 23.32° (c 4.23, C6H6).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[NH2:26][CH2:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=1.C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:26][CH2:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=1)=[O:20]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Reactant: NCc1ccc2ccccc2c1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc2ccccc2c1)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.4 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (0.800 g, 2.20 mmol), 2-aminomethylnaphthalene (0.380 g, 2.42 mmol), triethylamine (0.240 g, 2.37 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'(2-naphthylmethyl)-3,4,5,6-tetrahydrophthalamide as white crystals (0.200 g, 17.5% yield).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][C:16]=1[F:24])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[C:26]1[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=1>COCCOC.O.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>[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:26]2[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:17][C:16]=1[F:24])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Nc1ncccc1Br
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
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: COCCOC
Solvent: O
Product: Nc1ncccc1-c1ccc(OCc2ccccc2)c(F)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of sodium carbonate (7.18 g), tetrakis(triphenylphosphine)palladium(0) (1.957 g), 4-(benzyloxy)-3-fluorophenylboronic acid (10 g), and 3-bromopyridin-2-amine (5.86 g) in DME (120 mL) and water (24 mL) was stirred at 80° C. overnight. The mixture was added with silica gel, concentrated in vacuo, and purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (9.97 g) as a pale yellow solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[NH:5]1[C:9]2=[C:10]([NH:14][C:15]([CH:17]3[CH2:19][CH2:18]3)=[O:16])[N:11]=[CH:12][CH:13]=[C:8]2[CH:7]=[CH:6]1.[Br:20][C:21]1[CH:29]=[C:28]([Cl:30])[C:24]([C:25](Cl)=[O:26])=[C:23]([Cl:31])[CH:22]=1.CO>ClCCl>[Br:20][C:21]1[CH:22]=[C:23]([Cl:31])[C:24]([C:25]([C:7]2[C:8]3[C:9](=[C:10]([NH:14][C:15]([CH:17]4[CH2:18][CH2:19]4)=[O:16])[N:11]=[CH:12][CH:13]=3)[NH:5][CH:6]=2)=[O:26])=[C:28]([Cl:30])[CH:29]=1
Reactant: O=C(Cl)c1c(Cl)cc(Br)cc1Cl
Reactant: O=C(Nc1nccc2cc[nH]c12)C1CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: ClCCl
Product: O=C(c1c(Cl)cc(Br)cc1Cl)c1c[nH]c2c(NC(=O)C3CC3)nccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.2 %

Procedure:
Aluminium chloride (4.3 g, 32.2 mmol) was added to a solution of N-(1H-pyrrolo[2,3-c]pyridin-7-yl)cyclopropanecarboxamide (0.65 g, 3.2 mmol) in dichloromethane (100 mL) under Argon atmosphere. The mixture was stirred at room temperature under inert atmosphere for about 1 hour, followed by drop wise addition of 4-bromo-2,6-dichlorobenzoyl chloride (4.6 g, 15.9 mmol) in dichloromethane (20 mL). After complete addition the reaction mixture was stirred at room temperature for about 16 hours. Methanol (100 mL) was poured in the reaction mixture and stirred well. Solvent was evaporated under vacuum, water (250 mL) was added and extracted with ethyl acetate (3×200 mL). The organic layer was washed with aqueous sodium bicarbonate (10%) solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by silica gel (100-200 mesh) column chromatography using 2% methanol in dichloromethane as an eluant to afford N-[3-(4-bromo-2,6-dichlorobenzoyl)-1H-pyrrolo[2,3-c]pyridin-7-yl]cyclopropanecarboxamide (0.8 g, 54%).
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[CH2:4][CH2:5][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[S:12][C:11]=2[C:10]([CH2:22][NH:23][CH3:24])=[CH:9][CH:8]=1)[CH3:2].C(N(CC)CC)C.[CH2:34]([S:36](Cl)(=[O:38])=[O:37])[CH3:35]>C(Cl)Cl>[CH2:25]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[S:12][C:11]=2[C:10]([CH2:22][N:23]([CH3:24])[S:36]([CH2:34][CH3:35])(=[O:38])=[O:37])=[CH:9][CH:8]=1)[CH3:26]
Reactant: CCN(CC)CCNc1ccc(CNC)c2sc3ccccc3c(=O)c12
Reactant: CCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)CCNc1ccc(CN(C)S(=O)(=O)CC)c2sc3ccccc3c(=O)c12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 95.9 %

Procedure:
A solution of 2.03 g (5.49 mmol) of 1-[[2-(diethylamino)ethyl]amino]-4-[(methylamino)methyl]thioxanthen-9-one (prepared by the method described in Example 5) and triethylamine in 45 mL of methylene chloride was cooled to 0° C. and treated with ethanesulfonyl chloride (0.74 g, 5.76 mmol). After 15 min at 0° C., the reaction mixture was stirred at room temperature for 72 h. The mixture was concentrated in vacuo, the residue dissolved in chloroform and purified by passing through a pad of silica gel (chloroform; then 1% triethylamine/chloroform) affording 2.43 g (96%) of N-[[1-[[2-(diethylamino)ethyl]amino]-9-oxothioxanthen-4-yl]methyl]-N-methylethanesulfonamide. The sulfonamide was recrystallized from ethyl acetate and treated with methanesulfonic acid in isopropanol to afford the product as the methanesulfonate salt, m.p. 159°-161° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][C@H:10]([NH:19][C:20]([C:22]2([CH2:27][CH:28]([CH2:32][C:33]([NH:35][CH:36]([CH3:38])[CH3:37])=[O:34])[C:29]([OH:31])=[O:30])[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])[C:9]1=[O:39])([CH3:4])([CH3:3])[CH3:2].[CH3:41][O:42][CH2:43][CH2:44][O:45][CH2:46]Cl.C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[CH3:41][O:42][CH2:43][CH2:44][O:45][CH2:46][C:28]([CH2:27][C:22]1([C:20]([NH:19][C@H:10]2[CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:8]([CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:40])[C:9]2=[O:39])=[O:21])[CH2:26][CH2:25][CH2:24][CH2:23]1)([CH2:32][C:33]([NH:35][CH:36]([CH3:37])[CH3:38])=[O:34])[C:29]([OH:31])=[O:30]
Reactant: CC(C)NC(=O)CC(CC1(C(=O)N[C@H]2CCc3ccccc3N(CC(=O)OC(C)(C)C)C2=O)CCCC1)C(=O)O
Reactant: COCCOCCl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCOCC(CC(=O)NC(C)C)(CC1(C(=O)N[C@H]2CCc3ccccc3N(CC(=O)OC(C)(C)C)C2=O)CCCC1)C(=O)O
Reaction time: 8 h

Procedure:
300 mg 2-{[1-({[(3S)-1-(2-tert. butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}-carbonyl)cyclopentyl]methyl}-4-(isopropylamino)-4-oxobutyric acid (for preparation see Example 12) was dissolved in 5 ml dichloromethane. 33 mg DMAP, 74 μl methoxyethoxymethyl chloride and 90 μl triethylamine were added to this receiving solution. The reaction mixture was stirred overnight, then diluted with 5 ml dichloromethane and the organic phase was washed in succession once each with 3 ml dilute aqueous KHSO4 solution and saturated aqueous common salt solution. The organic phase was dried over magnesium sulfate, the solvent was largely evaporated at reduced pressure and the remaining residue was chromatographed on silica gel (mobile phase: EA/cyclohexane 2:1 v/v). Drying the product fractions in an oil pump vacuum yielded 191 g of the title compound, MS: [M+H]+: 646; m/z: 590, 540, 484, 425.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:7][CH:8]=[CH:9][CH:10]=1)=O.[BH4-].[Na+].II.CO>C1COCC1>[CH3:1][NH:2][CH2:3][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][CH:12]=1
Reactant: CNC(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CNCc1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 24.3 %

Procedure:
At 0° C. a solution of 4′-(trifluoromethyl)biphenyl-2-carboxylic acid methylamide (8.50 g, 36.44 mmol) in THF (100 ml) was added to a suspension of sodium borohydride (2.8 g, 73.05 mmol) in THF (50 ml). The reaction mixture was stirred for 20 min at 0° C. A solution of iodine (7.70 g, 36.44 mmol) in THF (100 ml) was added dropwise. The reaction mixture was heated to reflux for 16 hours. It was cooled to 0° C. Methanol (200 ml) was added dropwise. The solvent was removed in vacuo. The residue was dissolved in tert-butyl methyl ether (150 ml) and a 20% aqueous solution of sodium hydroxide (150 ml). The phases were separated. The aqueous phase was extracted with tert-butyl methyl ether (2×80 ml). The combined organic layers were dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (400 g) using DCM/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 2.35 g of N-methyl-N-((4′-(trifluoromethyl)biphenyl-2-yl)methyl)amine.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[O:8][C:7]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:6][CH:5]1[CH:14]=[N:15][OH:16].[Cl:17]N1C(=O)CCC1=O>CN(C=O)C>[OH:16][N:15]=[C:14]([Cl:17])[C@H:5]1[C@H:4]([CH2:3][O:2][CH3:1])[O:8][C:7]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:6]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COCC1OC2(CCCCC2)OC1C=NO
Solvent: CN(C)C=O
Product: COC[C@@H]1OC2(CCCCC2)O[C@H]1C(Cl)=NO
Temperature: 25 °C
Yield: 93.1 %

Procedure:
3-(Methoxymethyl)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde oxime (33.2 g, 145 mmol) was dissolved in DMF (600 mL) and cooled in an ice bath. 1-Chloropyrrolidine-2,5-dione (19.3 g, 145 mmol) was added and the reaction allowed to slowly warm to ambient temperature overnight. Most of the DMF was removed under reduced pressure and the remaining material was partitioned between water and EtOAc. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated to afford (2R,3S)-N-hydroxy-3-(methoxymethyl)-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (35.6 g, 135 mmol, 93.2% yield) which was taken forward without further purification.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[F:19][C:20]([F:28])([F:27])[C:21]1([OH:26])[CH2:25][CH2:24][NH:23][CH2:22]1>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([N:23]3[CH2:24][CH2:25][C:21]([OH:26])([C:20]([F:28])([F:27])[F:19])[CH2:22]3)=[O:17])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: OC1(C(F)(F)F)CCNC1
Agent: Cl
Product: O=C(c1ccc(C2CC2)c(OCC2CC2)n1)N1CCC(O)(C(F)(F)F)C1
Yield: 47.3 %

Procedure:
In analogy to the procedure described in Example 127 e), 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3 c, 20 mg, 85.7 μmol) was reacted with 3-(trifluoromethyl)pyrrolidin-3-ol hydrochloride (CAN 1334147-81-7, 19.7 mg, 103 μmol) to obtain the title compound (15 mg, 47%) as colorless liquid, MS (EI): m/e=371.3 [MH+].
Reaction SMILES: C(O[C:6]([C:8]1[C:17]([NH2:18])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([O:28][CH3:29])=[C:13]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:14]=2)[CH:9]=1)=[O:7])(C)(C)C.[CH:30]([NH2:32])=O>C(Cl)Cl.CO>[CH3:29][O:28][C:12]1[C:13]([O:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:14][C:15]2[CH:16]=[C:17]3[C:8]([C:6](=[O:7])[NH:32][CH:30]=[N:18]3)=[CH:9][C:10]=2[CH:11]=1
Reactant: COc1cc2cc(C(=O)OC(C)(C)C)c(N)cc2cc1OCCN1CCOCC1
Reactant: NC=O
Solvent: CO
Solvent: ClCCl
Product: COc1cc2cc3c(=O)[nH]cnc3cc2cc1OCCN1CCOCC1
Temperature: 178 °C

Procedure:
A mixture of 3.5 g (8.6 mmol) of 3-amino-7-methoxy-6-(2-morpholin-4-yl-ethoxy)-naphthalene-2-carboxylic acid tert-butyl ester and 60 ml of formamide is heated at 178° C. for 2 hours, then cooled. To this is added 4:1 methylene chloride/methanol. The resulting solution is washed several times with brine, dried over anhydrous sodium sulfate and evaporated to yield an oil. The oil is purified by silica gel chromatography, utilizing a gradient of 99:1 to 88:12 methylene chloride/methanol to give sticky solid, which is triturated with ethyl acetate to yield 1.5 g of 7-methoxy-8-(2-morpholin-4-yl-ethoxy)-3H-benzo[g]quinazolin-4-one as a tan solid, mp 230-232° C.