Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:33]([O:35][C:36](=[O:46])[C:37]1[CH:42]=[CH:41][C:40]([N:43]=[C:44]=[O:45])=[CH:39][CH:38]=1)[CH3:34]>ClCCl>[CH2:33]([O:35][C:36](=[O:46])[C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:45])=[CH:39][CH:38]=1)[CH3:34]
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (0.15 g, 0.40 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (0.139 ul, 1.0 mmol) (Aldrich), followed by the addition of 4-isocyanato-benzoic acid ethyl ester (92.0 mg, 0.48 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give rac-4-({3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1Hindol-3-yl]-piperidine-1-carbonyl}-amino)-benzoic acid ethyl ester as a white solid. (Yield 0.14 g, 60.8%).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([SH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:13]([C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:24]=1)[CH2:20]Br)([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:13]([C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:24]=1)[CH2:20][S:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([S:12][CH2:20][C:19]2[CH:18]=[C:17]([C:13]([CH3:15])([CH3:14])[CH3:16])[CH:24]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:22]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1cc(CBr)cc(C(C)(C)C)c1
Reactant: COC(=O)c1cc(S)cc(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(SCc2cc(C(C)(C)C)cc(C(C)(C)C)c2)cc(SCc2cc(C(C)(C)C)cc(C(C)(C)C)c2)c1

Procedure:
Methyl 3,5-dimercaptobenzoate (20.0 g, 100.0 mmol), 3,5-di-tertiarybutylbenzyl bromide (molecular weight 283.25, 57.0 g, 201.2 mmol) and potassium carbonate (molecular weight 138.21, 28.0 g, 202.6 mmol) were dissolved in 350 ml of acetone and the mixture was heated under reflux for 12 hours. The acetone and salts were removed, and the residue was purified by means of chromatography with dichloromethane as the developing solvent, giving methyl 3,5-bis(3,5-di-tertiary-butylbenzylthio)benzoate as needles.
Reaction SMILES: [Si]([O:18][CH2:19][C@@H:20]([N:24]1[C@H:29]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[C@@H:28]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=2)[CH2:27][C@@:26]([C:45]2([C:48]([O:50][CH3:51])=[O:49])[CH2:47][CH2:46]2)([CH3:44])[C:25]1=[O:52])[CH:21]1[CH2:23][CH2:22]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:43][C:39]1[CH:38]=[C:37]([C@@H:28]2[C@@H:29]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[N:24]([C@@H:20]([CH:21]3[CH2:22][CH2:23]3)[CH2:19][OH:18])[C:25](=[O:52])[C@:26]([C:45]3([C:48]([O:50][CH3:51])=[O:49])[CH2:46][CH2:47]3)([CH3:44])[CH2:27]2)[CH:42]=[CH:41][CH:40]=1
Reactant: COC(=O)C1([C@@]2(C)C[C@H](c3cccc(Cl)c3)[C@@H](c3ccc(Cl)cc3)N([C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C3CC3)C2=O)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)C1([C@@]2(C)C[C@H](c3cccc(Cl)c3)[C@@H](c3ccc(Cl)cc3)N([C@H](CO)C3CC3)C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 143R,5R,6S)-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)cyclopropanecarboxylate (53 mg, 0.070 mmol; Example 270, Step C) in THF (0.70 mL) was added 1 M TBAF in THF (0.21 mL, 0.21 mmol) and the reaction was stirred at rt overnight. The reaction was quenched (sat. NH4Cl), extracted (2×EtOAc), and washed (brine). The combined organic layers were dried (Na2SO4) and concentrated under the reduced pressure. Purification of the residue by chromatography on silica gel (4 g SiO2, 10%, 45%, and 55% EtOAc/Hex) provided the title compound as a white foam
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[CH2:10][CH2:11][OH:12].[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C(Cl)(Cl)Cl>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH2:10][CH2:11][O:12][S:27]([C:24]1[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=1)(=[O:29])=[O:28]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccccc1C(CCO)c1ccccc1OC
Solvent: ClC(Cl)Cl
Product: COc1ccccc1C(CCOS(=O)(=O)c1ccc(C)cc1)c1ccccc1OC
Temperature: 0 °C

Procedure:
The propanol (XVII) of Example 3b) (35 g, 0.128 mol) in 100 ml chloroform containing 30 ml pyridine was cooled to about -10° and then treated with p-toluene sulphonyl chloride (29 g, 0.15 mol). After standing in the cooler (about +5° C.) overnight, the mixture was poured into ice-water, the organic phase was washed with water and cold 2N HCl, dried, and the solvent was distilled off at <50° C., giving a crude oil in quantitative yield. Recrystallization from IPE gave white crystals of low and indefinite m.p.
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([O:11][CH3:12])=[C:5]([Cl:13])[C:3]=1[NH2:4].[C:14](Cl)(Cl)=[O:15].C1(C)C=CC=CC=1.[CH3:25][O:26][CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]2[CH:42]=[C:41]([NH:43][CH3:44])[N:40]=[CH:39][N:38]=2)=[C:32]([N+:45]([O-:47])=[O:46])[CH:31]=1>O1CCOCC1.CCOC(C)=O>[Cl:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([O:11][CH3:12])=[C:5]([Cl:13])[C:3]=1[NH:4][C:14](=[O:15])[N:43]([C:41]1[CH:42]=[C:37]([NH:36][C:33]2[CH:34]=[CH:35][C:30]([O:29][CH2:28][CH2:27][O:26][CH3:25])=[CH:31][C:32]=2[N+:45]([O-:47])=[O:46])[N:38]=[CH:39][N:40]=1)[CH3:44]
Reactant: O=C(Cl)Cl
Reactant: CNc1cc(Nc2ccc(OCCOC)cc2[N+](=O)[O-])ncn1
Reactant: COc1cc(OC)c(Cl)c(N)c1Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COCCOc1ccc(Nc2cc(N(C)C(=O)Nc3c(Cl)c(OC)cc(OC)c3Cl)ncn2)c([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 6 h
Yield: 32 %

Procedure:
To a stirred solution of 2,6-dichloro-3,5-dimethoxyaniline (500 g, 2.252 mmol) in dioxane (10 mL) was added 20% phosgene in toluene (4.4 mL, 9.0 mmol) under argon atmosphere at 0° C. The resulting mixture was stirred for 6 h at 90° C., and then allowed to cool to room temperature. The solvents were removed and the residue was dissolved in toluene (10 mL). To this, was added N4-(4-(2-methoxyethoxy)-2-nitrophenyl)-N6-methylpyrimidine-4,6-diamine (0.718 g, 8.358 mmol, 1.0 eq). The resultant reaction mixture was then refluxed for 6 h. After completion of the reaction by TLC (Hexanes:EtOAc, 7:3), reaction mixture was cooled to room temperature, concentrated under vacuum to obtain a crude reaction mixture. The solid precipitated on addition of ethyl acetate to the crude reaction mixture was filtered, washed with ether and pentane to afford the title compound (0.285, yield: 32%) as a white solid. MS (ESI): 567.0 [M+H]+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[C:20]([C:22]#[N:23])[C:19]3[N:24]=[CH:25][N:26]([CH3:27])[C:18]=3[CH:17]=2)=[CH:12][C:11]=1[C:28]([F:31])([F:30])[F:29].C(N(C(C)C)CC)(C)C.O>CN1C(=O)CCC1>[CH3:1][S:2]([O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[C:20]([C:22]#[N:23])[C:19]3[N:24]=[CH:25][N:26]([CH3:27])[C:18]=3[CH:17]=2)=[CH:12][C:11]=1[C:28]([F:30])([F:29])[F:31])(=[O:4])=[O:3]
Reactant: Cn1cnc2c(C#N)nc(-c3ccc(OCCO)c(C(F)(F)F)c3)cc21
Reactant: CS(=O)(=O)Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cn1cnc2c(C#N)nc(-c3ccc(OCCOS(C)(=O)=O)c(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methanesulphonyl chloride (0.23 ml) was added dropwise to a solution of 6-(4-(2-hydroxyethoxy)-3-(trifluoromethyl)-phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (0.77 g) and diisopropylethylamine (1.2 ml) in NMP (6 ml). The mixture was stirred at room temperature for 3 hours. After adding cold water (20 ml), solid product was collected by filtration, washed with cold ethanol (20 ml) to give 2-(4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)ethyl methanesulfonate (0.89 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:4][CH:3]=1.[CH3:35][N:36]([CH3:46])[C:37](=[O:45])[CH2:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:42]3[CH2:41][CH2:40][N:39]([CH2:38][C:37]([N:36]([CH3:46])[CH3:35])=[O:45])[CH2:44][CH2:43]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:33])[CH3:34])=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C2=N[C@@H](c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)Cl)c(OC(C)C)c1
Reactant: CN(C)C(=O)CN1CCNCC1
Product: COc1ccc(C2=N[C@@H](c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)N2CCN(CC(=O)N(C)C)CC2)c(OC(C)C)c1

Procedure:
2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N,N-dimethyl-acetamide was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 6) and N,N-dimethyl-2-piperazin-1-yl-acetamide (Oakwood Chemicals) in an analogous manner as described in example 8. LR-MS: 652.3 [(M+H)+].
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[S:5].Cl[CH:17]([C:23]([CH3:25])=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(O)C>[CH2:21]([O:20][C:18]([C:17]1[S:5][C:4]([C:3]2[CH:7]=[CH:8][C:9]([C:12]([F:15])([F:14])[F:13])=[C:10]([F:11])[C:2]=2[F:1])=[N:6][C:23]=1[CH3:25])=[O:19])[CH3:22]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: NC(=S)c1ccc(C(F)(F)F)c(F)c1F
Solvent: CCO
Product: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)c(F)c2F)nc1C
Yield: 41.7 %

Procedure:
A solution of 2,3-difluoro-4-trifluoromethyl-thiobenzamide (1.15 g, 4.8 mmol) and ethyl 2-chloro-acetoacetate (0.67 ml, 4.8 mmol) in ethanol (70 ml) was heated at reflux temperature for 14 hours. The solvent was removed under reduced pressure and the residue partitioned between ice water and ethyl acetate. The layers were separated and the aqueous phase extracted two more times with ethyl acetate. The combined extracts were washed two times with ice water/brine 1/1 and dried over sodium sulfate. The solvent was removed under reduced pressure to give a yellow oil which was purified by column chromatography (silica gel, heptane/AcOEt) to yield 700 mg (2 mmol, 42%) of the title compound as yellow crystals.
Reaction SMILES: [S:1]([N:11]1[C:15]2[N:16]=[CH:17][N:18]=[C:19]([N:20]3[CH2:25][CH2:24][CH2:23][C:22](=O)[CH2:21]3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CC(O)=O.[BH3-]C#N.[Na+]>CO.O>[CH2:27]([NH:34][CH:22]1[CH2:23][CH2:24][CH2:25][N:20]([C:19]2[C:14]3[CH:13]=[CH:12][N:11]([S:1]([C:4]4[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=4)(=[O:3])=[O:2])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:21]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N4CCCC(=O)C4)ncnc32)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N4CCCC(NCc5ccccc5)C4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-one (75 mg, 0.2 mmol) and benzylamine (25 μL, 0.22 mmol) in MeOH (3 mL) was added AcOH (20 μL, 0.4 mmol) and NaBH3CN (32 mg, 0.5 mmol). The solution was stirred at rt for 16 hr after which time the solvent was removed in vacuo to afford a residue which was diluted with water and extracted with EtOAc. The organic phase was separated, washed with aq. NaHCO3 and water, dried (Na2SO4) and concentrated in vacuo to afford a residue which was purified by column chromatography (silica gel, gradient EtOAc in hexanes). EIMS (m/z): calcd. for C25H27N5O2S (M++1) 462.2. found 462.2.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][CH:11]1[CH2:16][CH2:15][CH:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:13][CH2:12]1.CS([C:25]1[N:30]=[C:29]([C:31]2[C:39]3[C:34](=[C:35]([O:40][CH2:41][CH2:42][CH2:43][S:44]([CH3:47])(=[O:46])=[O:45])[CH:36]=[CH:37][CH:38]=3)[NH:33][N:32]=2)[CH:28]=[CH:27][N:26]=1)=O.O>CN1C(=O)CCC1>[CH3:47][S:44]([CH2:43][CH2:42][CH2:41][O:40][C:35]1[CH:36]=[CH:37][CH:38]=[C:39]2[C:34]=1[NH:33][N:32]=[C:31]2[C:29]1[CH:28]=[CH:27][N:26]=[C:25]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:13][CH2:12]2)[N:30]=1)(=[O:46])=[O:45]
Reactant: CS(=O)(=O)NC1CCC(N)CC1
Reactant: CS(=O)c1nccc(-c2n[nH]c3c(OCCCS(C)(=O)=O)cccc23)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: CS(=O)(=O)CCCOc1cccc2c(-c3ccnc(NC4CCC(NS(C)(=O)=O)CC4)n3)n[nH]c12
Temperature: 130 °C
Reaction time: 2.5 h

Procedure:
DIEA (0.31 mL) and N-(4-aminocyclohexyl)-methanesulfonamide (348 mg) were stirred in NMP (1 mL) at RT for 1 hour. 3-(2-Methanesulfinyl-pyrimidin-4-yl)-7-(3-methane-sulfonyl-propoxy)-1H-indazole (200 mg, 0.5 mmol) was added to the mixture and stirred at 130° C. for 2.5 h. The reaction mixture was then poured into water and the precipitate purified on a silica column using flash chromatography, eluting with hexane:EtOAc:MeOH 5:4.5:0.5 to yield N-(-4-{4-[7-(3-methanesulfonyl-propoxy)-1H-indazol-3-yl]-pyrimidin-2-ylamino}-cyclo-hexyl)-methanesulfonamide (Compound 315).
Reaction SMILES: CO[C:3]([C:5]1[S:28][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[O:21][C@H:22]3[CH2:27][CH2:26][CH2:25][O:24][CH2:23]3)[C:7]=2[C:6]=1[CH3:29])=[O:4].[CH3:30][N:31]([CH3:36])[CH2:32][CH2:33][CH2:34][NH2:35]>>[CH3:30][N:31]([CH3:36])[CH2:32][CH2:33][CH2:34][NH:35][C:3]([C:5]1[S:28][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[O:21][C@H:22]3[CH2:27][CH2:26][CH2:25][O:24][CH2:23]3)[C:7]=2[C:6]=1[CH3:29])=[O:4]
Reactant: CN(C)CCCN
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCCOC3)c2c1C
Product: Cc1c(C(=O)NCCCN(C)C)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCCOC3)c12

Procedure:
Prepared analogously to example 10.4 from 4-{4-fluoro-2-[(S)-(tetrahydro-pyran-3-yl)oxy]-phenylamino}-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester and N,N-dimethyl-1,3-propanediamine.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2C=C[CH:17]=[CH:16][C:15]=2F)=[CH:10][C:9]=1[NH:21][C:22](=[O:37])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[CH:35]=[CH:34][N:33]=[N:32]2)[CH:26]=1)(C)(C)C.[C:39](O)([C:41]([F:44])(F)F)=O>C(Cl)Cl>[F:44][C:41]1[CH:39]=[CH:17][CH:16]=[CH:15][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:31]4[CH:35]=[CH:34][N:33]=[N:32]4)[CH:26]=3)[CH2:23][C:22](=[O:37])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3ccnn3)c2)=Nc2ccc(-c3ccccc3F)cc2N1

Procedure:
Prepared from {2′-fluoro-3-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K77) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (100 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.C(=O)([O-])[O-].[K+].[K+].[CH3:18][NH:19][CH2:20][CH2:21][OH:22]>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:19]([CH3:18])[CH2:20][CH2:21][OH:22]
Reactant: CNCCO
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN(CCO)c1ccc([N+](=O)[O-])cc1F
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 99 %

Procedure:
To a solution of 554 μL (5.0 mmol) of 3,4-difluoronitrobenzene in 10 mL of dimethyl sulfoxide were added 1.38 mg (10.0 mmol) of potassium carbonate and 803 μL (10.0 mmol) of 2-methylaminoetanol, and the mixture was stirred for 1.5 hours at 100° C. The reaction mixture was cooled to room temperature and extracted with ethyl acetate, then, the extract was washed with water and saturated saline solution. After dried over with anhydrous sodium sulfate, the solvent was removed under reduced pressure ant the residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=1/1) to give 1.06 g (99%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:36]=[CH:35][C:11]([CH2:12][NH:13][C:14]([C:16]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27]CC5C=CC=CC=5)[CH:22]=4)=[CH:19][NH:18][N:17]=3)=[O:15])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1>CO.[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:12][NH:13][C:14]([C:16]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=4)=[CH:19][NH:18][N:17]=3)=[O:15])=[CH:35][CH:36]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccc(CNC(=O)c3n[nH]cc3-c3cccc(OCc4ccccc4)c3)cc2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(c2ccc(CNC(=O)c3n[nH]cc3-c3cccc(O)c3)cc2)CC1
Yield: 40.9 %

Procedure:
A solution of 4-(3-benzyloxy-phenyl)-1H-pyrazole-3-carboxylic acid 4-(4-methyl-piperazin-1-yl)-benzylamide (25 mg; 0.05 mmol) in methanol (5 ml), was treated with 10% palladium on carbon (10 mg) then hydrogenated at room temperature and pressure overnight. The catalyst was removed by filtration through Celite and the filtrate evaporated. Purification by preparative LC/MS gave 8 mg of the required product as a cream solid. (LC/MS: Rt 1.67 [M+H]+ 392).
Reaction SMILES: [CH:1]1([Si:4]([CH:11]2[CH2:13][CH2:12]2)([C:6]([OH:10])([CH3:9])[CH2:7][CH3:8])[CH3:5])[CH2:3][CH2:2]1.[CH:14]1([SiH](C2CC2)C(=O)CCC)CC1.C([Li])C>>[CH:11]1([Si:4]([CH:1]2[CH2:3][CH2:2]2)([C:6]([CH2:9][CH3:14])([OH:10])[CH2:7][CH3:8])[CH3:5])[CH2:12][CH2:13]1
Reactant: CCC(C)(O)[Si](C)(C1CC1)C1CC1
Reactant: CCCC(=O)[SiH](C1CC1)C1CC1
Agent: [Li]CC
Product: CCC(O)(CC)[Si](C)(C1CC1)C1CC1

Procedure:
Under an atmosphere of argon, a 1.9 M solution of tert-butyl lithium in pentane (10.0 ml, 19.0 mmol) was added in one portion with stirring at −78° C. to a solution of (E/Z)-1-ethoxyprop-1-ene (1.61 g, 18.7 mmol) in pentane (20 ml). The reaction mixture was then allowed to warm to 0° C. within 30 min. Subsequently, TMEDA (5.39 g, 46.4 mmol) was added, and the reaction mixture was allowed to warm to room temp. After stirring for 1 h at room temp., the mixture was cooled to −78° C. and chloro(dicyclopropyl)-methylsilane (3.00 g, 18.7 mmol, prepared according to Example 1) was added dropwise over a period of 30 min. After a further 16 h stirring at room temp., the mixture was poured into water (50 ml). After 10 min. of stirring, the organic layer was separated, and the aqueous one extracted with Et2O (2×50 ml). The combined organic extracts were dried (Na2SO4), and concentrated under reduced pressure to afford crude dicyclopropyl(1-ethoxypropionyl)methylsilane, which was taken up in acetone/1 N HCl (2:1, 48 ml). The reaction mixture was stirred for 45 min. at room temp. followed by the addition of water/Et2O (1:1, 100 ml). The organic layer was separated, and the aqueous one extracted with Et2O (2×30 ml). The combined ethereal extracts were dried (Na2SO4) and concentrated under reduced pressure. Silica-gel chromatography (silica gel 40-63 μm, hexane/EtOAc, 9:1, relevant fractions were determined by GC) followed by bulb-to-bulb distillation (0.08 mbar, 40° C.) of the resulting residue provided 437 mg (13% over 2 steps) of dicyclopropyl(methyl)propionylsilane. Following the procedure for the preparation of dicyclopropyl(1-hydroxy-1-methylpropyl)methylsilane (see Example 5), dicyclopropyl(methyl)propionylsilane (470 mg, 2.58 mmol) was then reacted with ethyl lithium (1.7 M in n-Bu2O, 12.1 ml, 20.6 mmol) to provide after purification by silica-gel flash chromatography (silica gel 40-63 μm, hexane/EtOAc, 9:1) 360 mg (66%) of the odoriferous title compound.
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]3[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=3[N:8]=2)[CH2:3][CH2:2]1.Cl[C:14]1[N:15]=[C:16]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[C:17]2[N:23]=[C:22]([CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([C:31]([OH:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]3)[CH:21]=[CH:20][C:18]=2[N:19]=1>>[CH:1]1([C:4]2[N:5]([C:14]3[N:15]=[C:16]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[C:17]4[N:23]=[C:22]([CH2:24][N:25]5[CH2:30][CH2:29][CH:28]([C:31]([OH:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]5)[CH:21]=[CH:20][C:18]=4[N:19]=3)[C:6]3[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=3[N:8]=2)[CH2:3][CH2:2]1
Reactant: c1ccc2[nH]c(C3CC3)nc2c1
Reactant: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Product: CC(C)(O)C1CCN(Cc2ccc3nc(-n4c(C5CC5)nc5ccccc54)nc(N4CCOCC4)c3n2)CC1

Procedure:
Following General Procedure C, 2-cyclopropyl-benzimidazole and 2-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol from Example 8 were reacted to give 102. LCMS (MH+)=528.3. 1H-NMR (DMSO-d6): δ 8.19 (d, 1H), 8.03 (m, 1H), 7.89 (d, 1H), 7.44 (m, 1H), 7.23 (m, 2H), 4.56 (s, 4H), 4.01 (s, 1H), 3.83 (m, 4H), 3.74 (2, 2H), 2.94 (m, 3H), 1.99 (m, 2H), 1.67 (m, 2H), 1.29 (m, 2H), 1.16 (m, 3H), 1.08 (m, 2H), 1.04 (s, 6H)
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[CH3:10][C:11]1[N:16]=[C:15]([Cl:17])[N:14]=[C:13]([N:18]2[CH2:23][CH2:22][C:21]3[CH:24]=[CH:25][S:26][C:20]=3[CH:19]2[CH3:27])[CH:12]=1>CN(C)C=O>[ClH:17].[CH3:10][C:11]1[N:16]=[C:15]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][C:4]=2[CH3:9])[N:14]=[C:13]([N:18]2[CH2:23][CH2:22][C:21]3[CH:24]=[CH:25][S:26][C:20]=3[CH:19]2[CH3:27])[CH:12]=1
Reactant: Cc1cc(N2CCc3ccsc3C2C)nc(Cl)n1
Reactant: Cc1cc(F)ccc1N
Solvent: CN(C)C=O
Product: Cc1cc(N2CCc3ccsc3C2C)nc(Nc2ccc(F)cc2C)n1
Product: Cl
Yield: 44.5 %

Procedure:
After 4-fluoro-2-methylaniline(0.5 ml, 4.6 mmol) was added to a mixture solution of 6-methyl-4-(7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-yl)-2-chloropyrimidine(0.7 g, 2.5 mmol) and dimethylformamide(10 ml), 0.45 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1.