Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:26](=[O:28])=[O:27]>C1COCC1.O>[C:1]1([N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]([C:26]([OH:28])=[O:27])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]2=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C=O
Reactant: c1ccc(N2c3ccccc3Cc3ccccc32)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1c2ccccc2N(c2ccccc2)c2ccccc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 20.8 %

Procedure:
A solution of N-phenylacridan (14.15 g, 55 mmol) in 200 mL of dry THF under inert atmosphere was cooled to −78° C. and 33.0 mL of 2.5 M n-butyllithium in hexanes (82.5 mmol) was added dropwise over 20 minutes. The solution was stirred at −78° C. for 30 minutes and then warmed to room temperature over 35 minutes. The reaction mixture was again cooled to −78° C. and 350 g of crushed dry ice was added causing a precipitate to form. The reaction was allowed to slowly warm to room temperature causing the reaction to become homogeneous. Stirring under argon was continued at room temperature. The resultant precipitate was collected by suction filtration. The solid was dissolved in 100 mL of water, which was acidified to pH 3 with 2N HCl and extracted with 4×200 mL of ethyl acetate. The combined organics were dried over sodium sulfate and concentrated to dryness to afford 8.72 g of crude product. The reaction mixture filtrate was also concentrated to dryness to afford a solid that was taken up in 300 mL of water. The aqueous solution was acidified, extracted with 3×200 mL of methylene chloride and the combined organics were dried over sodium sulfate and concentrated to afford a second crop of 3.44 g of N-phenylacridan-9-carboxylic acid (73.4%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH2:12][C:13](O)=O)=[CH:3]1.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.[CH3:36][S:37]([NH:40][C:41]1[CH:42]=[CH:43][C:44]2[O:49][CH2:48][CH:47]([CH2:50][NH2:51])[O:46][C:45]=2[CH:52]=1)(=[O:39])=[O:38]>CN(C=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH2:12][CH2:13][NH:51][CH2:50][CH:47]2[CH2:48][O:49][C:44]3[CH:43]=[CH:42][C:41]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:52][C:45]=3[O:46]2)=[CH:3]1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)OC(CN)CO2
Reactant: Cn1cc(CCC(=O)O)c2ccccc21
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(CCCNCC2COc3ccc(NS(C)(=O)=O)cc3O2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
1-Methylindole-3-propionic acid (1.2 g, 6.0 mmole), 1-hydroxybenzotriazole hydrate (0.97 g, 7.2 mmole) and 1,3-diisopropylcarbodiimide (1.1 ml, 7.2 mmole) were combined in 100 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 7-methylsulfonylamino-2,3-dihydro-1,4-benzodioxin-2-methanamine (1.9 g, 7.2 mmole) in 50 ml of DMF and the mixture was further stirred for 24 hours. The solvent was removed and the residue partitioned between dichloromethane and water. The separated dichloromethane layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on a silica gel column using ethyl acetate as the eluant. Fractions containing product were concentrated and washed with a minimum amount of THF to remove a by-product and to give 2.1 g (79%) of the desired product, (7-methylsulfonyl-2,3-dihydro-benzo[1,4]dioxin-2ylmethyl)-4-(1-methyl-1H-indol-3-yl)-propanamide, as a fluffy white solid.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[CH:25]=[N:24][C:23]([CH2:26][NH:27][CH3:28])=[CH:22][N:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(#N)C>[Br:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[N:21]=[CH:22][C:23]([CH2:26][N:27]([CH3:28])[S:38]([CH3:37])(=[O:40])=[O:39])=[N:24][CH:25]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CS(=O)(=O)Cl
Reactant: CNCc1cnc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)cn1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cnc(CN(C)S(C)(=O)=O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
To a suspension of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-({5-[(methylamino)methyl]pyrazin-2-yl}methyl)pyridin-2(1H)-one (0.16 g, 0.34 mmol) in acetonitrile at 0° C. was added triethylamine (0.043 g, 0.42 mmol), followed by the addition of methane sulfonylchloride (0.047 g, 0.41 mmol) and stirred at room temperature for 1 h under argon atmosphere. The solvents were removed in vacuo and the residue was triturated with water and filtered. It was washed with water an, acetonitrile and dried in vacuo to afford 0.11 g of material. 1H NMR (CD3OD/400 MHz) δ 8.62 (s, 1H), 8.55 (s, 1H), 7.61 (m, 1H), 7.0 (m, 2H), 6.53 (s, 1H), 5.47 (s, 2H), 5.29 (s, 2H), 4.49 (s, 2H), 2.95 (s, 3H), 2.85 (s, 3H), and 2.55 (s, 3H); 19F NMR (CD3OD/400 MHz) −111.70 (m) and −116.07 (m); ES-HRMS m/z 543.0515 (M+H calcd for C21H22BrF2N4O4S requires 543.0508).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[O:6][CH2:7][C:8]1[N:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:11][C:12]=1[CH3:13].[OH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31]([O:33][CH3:34])=[O:32].CN(C)C=O.[H-].[Na+]>O>[CH3:13][C:12]1[O:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:9][C:8]=1[CH2:7][O:6][C:5]1[CH:4]=[C:3]([CH:22]=[CH:21][CH:20]=1)[CH2:2][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31]([O:33][CH3:34])=[O:32]
Reactant: COC(=O)Cc1ccccc1O
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CCl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1ccccc1OCc1cccc(OCc2nc(-c3ccccc3)oc2C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 56.8 %

Procedure:
To a mixture of 4-(3-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (0.70 g), methyl 2-(2-hydroxyphenyl)acetate (0.33 g) and N,N-dimethylformamide (10 mL) was added sodium hydride (60%, oil, 0.09 g) under ice-cooling and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After concentration of the organic layer, the residue was subjected to silica gel column chromatography to give methyl 2-[2-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate as an oil (0.50 g, 56%) from a fraction eluted with ethyl acetate-hexane (1:4, v/v).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]2[CH:11]=[C:10]([CH3:12])[C:9](B(O)O)=[CH:8][CH:7]=2)=[CH:4][CH:3]=1.[C:18]([O-:21])(=[O:20])[CH3:19].[C:22]([O-:25])(=[O:24])[CH3:23].[C:26]([O-:29])(=[O:28])[CH3:27].C([O-])(=O)C.[Pb+4:34].CCCCCC.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[C:18]([O-:21])(=[O:20])[CH3:19].[C:22]([O-:25])(=[O:24])[CH3:23].[C:26]([O-:29])(=[O:28])[CH3:27].[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]2[CH:11]=[C:10]([CH3:12])[C:9]([Pb+3:34])=[CH:8][CH:7]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)ccc1B(O)O
Reactant: [Pb+4]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: Cc1cc(-c2ccc(Cl)cc2)ccc1[Pb+3]
Temperature: 25 °C
Yield: 55.5 %

Procedure:
4′-Chloro-3-methylbiphen-4-ylboronic acid (6.0 g, 0.024 mol) is added in one portion to a mixture of lead tetraacetate (13.0 g, 0.029 mol) and mercuric acetate (0.38 g, 5 mol %) in chloroform (50 ml) under an atmosphere of nitrogen. The reaction mixture is stirred at ambient temperature until dissolution is complete, and then heated at 40° C. for 4 hrs. The reaction mixture is cooled to ambient temperature, filtered through a plug of diatomaceous earth and the filtrate is concentrated under reduced pressure to give an orange colored solid. Trituration with hexane (50 ml) to afford a yellow solid which was dried under high vacuum. This solid is then dissolved in chloroform (100 ml), anhydrous potassium carbonate (42.5 g, 0.3 mol) is added and the suspension is stirred rapidly for 10 minutes. The mixture is filtered through a plug of diatomaceous earth, and the filtrate is concentrated under reduced pressure to give 4′-chloro-3-methylbiphen-4-yllead triacetate (7.8 g) as a cream colored solid.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C1(S(O[CH2:27][CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[NH:37][C:38](=[O:40])[CH3:39])(=O)=O)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].C(#N)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:27][CH2:28][CH2:29][O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[NH:37][C:38](=[O:40])[CH3:39])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(=O)Nc1ccccc1OCCCOS(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(=O)Nc1ccccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 45.6 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.4 g, 16 mmol), N-[2-(3-phenylsulfonyloxypropoxy)phenyl]acetamide (5.3 g, 16 mmol), K2CO3 (2.2 g), and acetonitrile (50 ml) was stirred and refluxed for 5 hours. The reaction was poured into water, and the aqueous suspension was extracted with ethyl acetate. The ethyl acetate was washed (water and brine), dried (MgSO) and the solvent was concentrated to afford 6.0 g of a thick, brown oil. The oil was chromatographed on a Waters Prep 500 LC on silica gel. Concentration of the appropriate fractions afforded 3.0 g of a beige solid. This was recrystallized from ethyl acetate to yield (with concentration of the mother liquors) 2.2 g (33%) of N-[2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)l-piperidinyllpropoxy]phenyl]acetamide as a beige solid, m.p.=118-120° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:14]4=[N:15][C:16]([CH:19]=[CH2:20])=[CH:17][CH:18]=[C:13]4[N:12]=[CH:11]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Cl:21][CH2:22][CH2:23][CH2:24][S:25](Cl)(=[O:27])=[O:26].C(N(CC)C(C)C)(C)C>ClCCl>[Cl:21][CH2:22][CH2:23][CH2:24][S:25]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:14]4=[N:15][C:16]([CH:19]=[CH2:20])=[CH:17][CH:18]=[C:13]4[N:12]=[CH:11]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)(=[O:27])=[O:26]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: C=Cc1ccc2ncn(-c3ccc4c(c3)CCN4)c2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=Cc1ccc2ncn(-c3ccc4c(c3)CCN4S(=O)(=O)CCCCl)c2n1

Procedure:
A solution of 3-(2,3-dihydro-1H-indol-5-yl)-5-vinyl-3H-imidazo[4,5-b]pyridine (270 mg, 1.03 mmol) (Intermediate 10.1), 3-chloropropanesulfonyl chloride (0.25 ml, 2.06 mmol), and N,N-diisopropylethylamine (1.08 ml, 6.18 mmol) in dichloromethane (15 ml) is stirred for 10 min at ambient temperature. The mixture is successively extracted with saturated aqueous ammonium chloride and saturated aqueous sodium bicarbonate. The organic layer is dried over sodium sulfate and concentrated in vacuo to render 351 mg (85%) of the respective sulfonamide. HPLC (over 10 min 10-85% MeCN/100 mM aq. NaOAc): 92% purity, tR 8.44 min (tR(SM) 6.59 min). MS (ESI) m/z (C19H19ClN4O2S) 403.0 (m, 100), 294.9 (65) Finnegan LCQ.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:11][CH2:12][NH:13][S:14]([C:17]1[C:18]2[CH:19]=[CH:20][N:21]=[CH:22][C:23]=2[CH:24]=[CH:25][CH:26]=1)(=[O:16])=[O:15])=O)(C)(C)C.C(OCC)C>FC(F)(F)C(O)=O>[NH2:8][CH2:9][CH:10]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:11][CH2:12][NH:13][S:14]([C:17]1[C:18]2[CH:19]=[CH:20][N:21]=[CH:22][C:23]=2[CH:24]=[CH:25][CH:26]=1)(=[O:16])=[O:15]
Reactant: CC(C)(C)OC(=O)NCC(CCNS(=O)(=O)c1cccc2cnccc12)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: NCC(CCNS(=O)(=O)c1cccc2cnccc12)c1ccccc1
Reaction time: 0.5 h
Yield: 97 %

Procedure:
In 30 ml of trifluoroacetic acid was dissolved 6.0 g of N-(4-t-butoxycarbonylamino-3-phenylbutyl)-5-isoquinolinesulfonamide, and left at a temperature of 20° C.~25° C. for 30 minutes. The mixrure was condensed under reduced pressure. To the reaction solution was added ethyl ether, and the crystals precipitated were separated by filtration. The crystals thus obtained were washed with ethylether to give 4.54 g of N-(4-amino-3-phenylbutyl)-5-isoquinolinesulfonamide in a yield of 97%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])([CH3:4])([CH3:3])[CH3:2].C([O:22][C:23](=O)[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[N:37][CH:36]=[C:35]([CH3:39])[N:34]=2)[CH:28]=1)=[O:26])(C)(C)C>>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:23](=[O:22])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[N:37][CH:36]=[C:35]([CH3:39])[N:34]=2)[CH:28]=1)=[O:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cncc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)n1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: Cc1cncc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(C)cc3NC(=O)OC(C)(C)C)c2)n1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (257 mg, 1.0 mmol) and 3-[3-(6-methyl-pyrazin-2-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K16) (312 mg, 1.0 mmol) according to the general procedure M. Obtained as a light brown foam (470 mg, 95%).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4F)[C:11](=[O:25])[N:10]([CH2:26][CH:27]4[CH2:29][CH2:28]4)[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>>[CH2:17]([N:12]1[C:13](=[O:16])[C:14]2[NH:15][C:7]([CH2:6][C:5]3[CH:30]=[CH:31][C:2]([NH:1][S:38]([C:35]4[CH:36]=[CH:37][C:32]([CH3:42])=[CH:33][CH:34]=4)(=[O:40])=[O:39])=[CH:3][CH:4]=3)=[N:8][C:9]=2[N:10]([CH2:26][CH2:27][CH2:29][CH3:28])[C:11]1=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Product: CCCCn1c(=O)n(Cc2ccccc2)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4ccc(C)cc4)cc3)nc21

Procedure:
8-(4-Amino-benzyl)-3-cyclopropylmethyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione was condensed with 4-toluenesulfonyl chloride under the conditions previously described to give the stated sulfonamide as an off white solid (59%); 1H NMR(DMSO-d6, 300 MHz) δ13.49 (s, 1H), 10.28 (s, 1H), 7.70 (d, J=8.1 Hz, 2H), 7.45–7.25 (m, 7H), 7.21 (d, J=8.4 Hz, 2H), 7.09 (d, J=8.4 Hz, 2H), 5.12 (s, 2H), 4.02 (s, 2H), 4.01 (t, J=7.0 Hz, 2H), 2.39 (s, 3H), 1.75–1.60 (m, 2H), 1.40–1.25 (m, 2H), 0.94 (t, J=7.5 Hz, 3H); EI-HRMS m/e calculated for C30H31N5O4S (M+) 557.2097, found 557.2090.
Reaction SMILES: [CH:1]([NH:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:13][CH:14]=2)[C:9]([NH:20][CH2:21][C:22](=[O:28])[NH:23][CH:24]2[CH2:27][NH:26][CH2:25]2)=[N:8]1)=[O:6])([CH3:3])[CH3:2].[CH:29]([CH:32]1[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1)([CH3:31])[CH3:30]>>[CH:1]([NH:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:18])([F:19])[F:17])=[CH:13][CH:14]=2)[C:9]([NH:20][CH2:21][C:22](=[O:28])[NH:23][CH:24]2[CH2:25][N:26]([CH:35]3[CH2:36][CH2:37][CH:32]([CH:29]([CH3:31])[CH3:30])[CH2:33][CH2:34]3)[CH2:27]2)=[N:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)n1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Reactant: CC(C)C1CCC(=O)CC1
Product: CC(C)NC(=O)n1nc(NCC(=O)NC2CN(C3CCC(C(C)C)CC3)C2)c2cc(C(F)(F)F)ccc21

Procedure:
The title compound was prepared as a white solid from reaction of 3-[(azetidin-3-ylcarbamoylmethyl)-amino]-5-trifluoromethyl-indazole-1-carboxylic acid isopropylamide (as prepared in Example 90, Step A) and 4-iso-propyl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH3:20])[CH2:9][CH:8]([OH:10])[O:7][CH:6]1[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:4].[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1([CH3:20])[CH2:9][CH:8]([O:10][C:21](=[O:23])[CH3:22])[O:7][CH:6]1[CH2:11][O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:4]
Reactant: COC(=O)C1(C)CC(O)OC1COCc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)C1(C)CC(OC(C)=O)OC1COCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 2-Benzyloxymethyl-5-hydroxy-3-methyl-tetrahydro-furan-3-carboxylic acid methyl ester (0.48 g, 1.7 mmol) prepared as previously described, in pyridine (5 mL), Acetic Anhydride (0.32 mL, 3.4 mmol) and DMAP (5 mg) were added and the reaction was stirred at room temperature. After 3 h stirring, the reaction mixture was diluted with ethyl acetate, washed with 0.5N HCl and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography (EA/Hexanes, 40:60). The product was isolated as a 2.8/1 anomeric mixture.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[CH:39][C:40](=[O:46])[N:41]([CH:43]([F:45])[F:44])[CH:42]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1>[F:44][CH:43]([F:45])[N:41]1[C:40](=[O:46])[CH:39]=[CH:38][C:37]([C:16]2[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:18][CH:17]=2)=[CH:42]1
Reactant: O=c1ccc(Br)cn1C(F)F
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C(F)F)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 110 °C
Yield: 50.6 %

Procedure:
A microwave vial equipped with a flea stirbar was charged with (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (20 mg, 0.047 mmol), 5-bromo-1-(difluoromethyl)pyridin-2(1H)-one (25 mg, 0.113 mmol), Cs2CO3 (27 mg, 0.083 mmol), H2O (0.1 mL) and dry dioxane (1 mL). The mixture was sparged with N2 for 10 min and heated at 110° C. in the microwave for 0.5 h. The mixture was diluted with glacial HOAc (0.1 mL) and MeOH (0.5 mL) and filtered. The filtrate was directly purified by prep HPLC to afford (S)-3-((S)-1-(4-(1-(difluoromethyl)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (11.8 mg, 57%) as an oil. LC-MS Method 1 tR=1.55 min, m/z=497, 248; 1H NMR (CDCl3) 1.13 (s, 3H), 1.19 (s, 3H), 1.56 (d, 3H), 2.15-2.35 (s, 4H), 2.42 (m, 2H), 2.88 (m, 1H), 5.71 (q, 1H), 6.64 (d, 1H), 7.04 (d, 2H), 7.18 (d, 2H), 7.30-7.40 (5H), 7.52 (1H), 7.60 (m, 1H), 7.75 (t, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[CH:9]([C:12]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:13]=1[NH2:14])([CH3:11])[CH3:10]>C(O)=O.CO>[CH:9]([C:12]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:13]=1[N:14]=[CH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)([CH3:11])[CH3:10]
Reactant: O=Cc1ccccn1
Reactant: Cc1cccc(C(C)C)c1N
Solvent: CO
Solvent: O=CO
Product: Cc1cccc(C(C)C)c1N=Cc1ccccn1
Reaction time: 5 h

Procedure:
A mixture of 2-pyridine-carboxaldehyde (8.5 ml, 0.052 mole), 2-iso-propyl-6-methylaniline (5 ml, 0.052 mole), 3 drops of formic acid and 30 ml methanol was stirred for five hours. The methanol was removed under vacuum. An oil-like residue was recrystallized from n-hexane. 2-(N-(2-iso-propyl-6-methylphenyl)-iminomethyl)-pyridine was isolated as yellow crystals. Yield: 10.25 g (82.8%). 1H NMR (200 MHz; CDCl3; δ, ppm; J, Hz): 1.18 d (6H, CH(CH3)2, J=6.9), 2.15 s (3H, CH3), 3.03 sept. (1H, CHMe2, J=6.9), 701-7.21 m (3H, C6H3), 7.41 d,d,d (1H, H(5) 3J4,5=7.5, 3J5,6=4.9, 4J3,5=1.3); 7.85 t,d,d (1H, H(4) 3J=7.7, 4J4,6=1.8, 5J=0.6); 8.28 d,t (1H, H(3) 3J3,4=7.9, J=1.1); 8.33 s (1H, HC═N); 8.73 d,d,d (1H, H(6) 3J5,6=4.9, 4J4,6=1.6, 5J3,6=1.0). 13C NMR, DEPT (50 MHz; CDCl3; δ, ppm): 18.6 (CH3), 23.3 (CH(CH3)2), 27.9 (CHMe2), 121.3 (C(3)H), 123.2 and 124.3 (C(3′)H and C(5′)H), 125.4 (C(5)H), 126.1 (C(6′)Me), 128.0 (C(4′)H), 136.7 (C(4)H), 137.9 (C(2′)i-Pr), 149.3 (C(1′)), 149.7 (C(6)H), 154.4 (C(2)), 163.4 (HC═N).
Reaction SMILES: N#N.[Si:3]([O:10][CH2:11][C:12]1[O:13][CH:14]=[C:15]([C:17]2([OH:20])[CH2:19][CH2:18]2)[N:16]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[C:21](Cl)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23].[NH4+].[Cl-]>N1C=CC=CC=1.CC(=O)OCC>[C:21]([O:20][C:17]1([C:15]2[N:16]=[C:12]([CH2:11][O:10][Si:3]([C:6]([CH3:9])([CH3:7])[CH3:8])([CH3:5])[CH3:4])[O:13][CH:14]=2)[CH2:18][CH2:19]1)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OCc1nc(C2(O)CC2)co1
Agent: N#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)OC1(c2coc(CO[Si](C)(C)C(C)(C)C)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-(2-(((tert-butyldimethylsilyl)oxy)methyl)oxazol-4-yl)cyclopropanol (509 mg, 1.89 mmol) in pyridine (2.0 mL) was treated with pivaloyl chloride (0.28 mL, 2.27 mmol) and the reaction mixture was stirred at rt overnight. Sat. aq. NH4Cl (10 mL) was added followed by EA (10 mL). The org. layer was washed with a CuSO4 sol. (2×15 mL) followed by brine (10 mL). The layers were separated and the org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (9:1 hept-EA) gave the title compound as a colorless oil: TLC: rf (9:1 hept-EA)=0.35. LC-MS-conditions 06: tR=1.19 min, [M+H]+=354.18.
Reaction SMILES: [CH3:1][S:2]([N:5]([CH3:29])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:20]2[C:15]([CH:16]=[N:17][C:18](OS(C(F)(F)F)(=O)=O)=[N:19]2)=[CH:14][CH:13]=1)(=[O:4])=[O:3].[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]2[N:42]([CH3:43])[CH2:41][CH2:40][N:39]([CH3:44])[C:38]2=[O:45])=[CH:33][CH:32]=1>>[CH3:43][N:42]1[CH2:41][CH2:40][N:39]([CH3:44])[C:38](=[O:45])[CH:37]1[C:34]1[CH:35]=[CH:36][C:31]([NH:30][C:18]2[N:17]=[CH:16][C:15]3=[CH:14][CH:13]=[C:12]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=4[N:5]([CH3:29])[S:2]([CH3:1])(=[O:4])=[O:3])[N:20]3[N:19]=2)=[CH:32][CH:33]=1
Reactant: CN(c1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12)S(C)(=O)=O
Reactant: CN1CCN(C)C(c2ccc(N)cc2)C1=O
Product: CN1CCN(C)C(c2ccc(Nc3ncc4ccc(-c5ccccc5N(C)S(C)(=O)=O)n4n3)cc2)C1=O

Procedure:
N-(2-{2-[4-(1,4-Dimethyl-3-oxo-piperazin-2-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-phenyl)-N-methyl-methanesulfonamide was prepared from trifluoro-methanesulfonic acid 7-[2-(methanesulfonyl-methyl-amino)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester and 3-(4-amino-phenyl)-1,4-dimethyl-piperazin-2-one in an analogous manner to Example 1061. Product isolated as an orange foam (80 mg, 53%). LCMS (m/e) 520 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.71 (s, 1H), 7.95-7.88 (m, 1H), 7.58-7.46 (m, 3H), 7.45 (d, 2H, J=8.4 Hz), 7.20 (d, 2H, J=8.4 Hz), 7.03 (d, 1H, J=4.7 Hz), 6.87 (d, 1H, J=4.7 Hz), 6.82 (bs, 1H), 3.77-3.67 (m, 1H), 3.64 (s, 1H), 3.24-3.17 (m, 1H), 3.11 (s, 3H), 3.05-2.96 (m, 1H), 2.98 (s, 3H), 2.70 (s, 3H), 2.69-2.61 (m, 1H), 2.16 (s, 3H).