Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]#[N:21])[CH2:15][CH2:14]3)(=[O:12])=[O:11])[S:7][C:6]=2[CH:22]=1.C(N(C(C)C)CC)(C)C.[SH2:32]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:14][CH2:15][N:16]([CH2:19][C:20]([NH2:21])=[S:32])[CH2:17][CH2:18]3)(=[O:11])=[O:12])[S:7][C:6]=2[CH:22]=1
Reactant: N#CCN1CCN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CC1
Reactant: S
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: NC(=S)CN1CCN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CC1

Procedure:
A suspension of [4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-piperazin-1-yl]-acetonitrile (1.2 g, 3.2 mmol) is heated with diisopropylethylamine (0.65 g, 5.0 mmol) in a solution of ethanol saturated with hydrogen sulfide gas for 4 hours. The reaction is cooled, filtered and washed with cold ethanol to provide 2-[4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-piperazin-1-yl]-thioacetamide. 1H NMR (300 MHz, DMSO-d6) δ9.71 (bs, 1H), 9.01 (bs, 1H), 8.35 (d, 1H), 8.21 (s, 1H), 8.08 (d, 1H), 7.59 (dd, 1H), 4.15 (s, 2H), 3.73 (s, 2H), 3.43 (s, 4H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]2[CH2:24][CH2:23][CH2:22]2)[C:5]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[CH3:25][NH:26][C:27](=[O:43])[C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:29]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]2[CH2:24][CH2:23][CH2:22]2)[C:5]2[C:10]([C:31]3[CH:32]=[CH:33][C:28]([C:27]([NH:26][CH3:25])=[O:43])=[CH:29][CH:30]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: CNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(OC3CCC3)nc(Cl)nc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1ccc(-c2cn(COCC[Si](C)(C)C)c3nc(Cl)nc(OC4CCC4)c23)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 65.7 %

Procedure:
To a degassed mixture of 2-chloro-4-cyclobutoxy-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 equiv), N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (1.1 equiv) and tripotassium phosphate trihydrorate (3.0 equiv) in a 9:1 mixture of 1,4-dioxane and water (0.125 M) was added palladium 1,1-bis(diphenylphosphion)ferrocene dicholoride (0.1 equiv). The reaction mixture was stirred at 80° C. for 4 h. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (1% MeOH in DCM) to afford the desired product (65.7% yield) as a yellow solid. MS (ESI) m/z 487.2 [M+H]+.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](Cl)[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[C:5]1=[O:25])(=O)C.[CH3:26][N:27]([CH2:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[CH3:28].[OH-].[Na+]>CN(C=O)C.CO>[CH3:28][N:27]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([NH:34]/[C:16](=[C:6]2\[C:5](=[O:25])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[CH:35][CH:36]=1)[CH3:26]
Reactant: CN(C)Cc1ccc(N)cc1
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2cccc(Cl)c2)c2cc([N+](=O)[O-])ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C)Cc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2cccc(Cl)c2)cc1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-[1-chloro-1-(3-chlorophenyl)-methylidene)-5-nitro-2-indolinone and 4-dimethylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][O:4]1.[CH2:9]([NH:16][C:17]([C:19]1[S:23][C:22]([N:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][C:25]2=[O:31])=[N:21][C:20]=1[CH3:32])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([NH:16][C:17]([C:19]1[S:23][C:22]([N:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:2][CH:3]3[CH2:8][CH2:7][CH2:6][CH2:5][O:4]3)=[CH:26][C:25]2=[O:31])=[N:21][C:20]=1[CH3:32])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCC1CCCCO1
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccccc1
Product: Cc1nc(-n2ccc(OCC3CCCCO3)cc2=O)sc1C(=O)NCc1ccccc1
Yield: 66 %

Procedure:
Following the procedure as described in Example 21, making variation only as required to use 2-(bromomethyl)tetrahydro-2H-pyran in place of 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole to react with N-benzyl-2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 66% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.77 (t, J=5.9 Hz, 1H), 8.58 (d, J=8.1 Hz, 1H), 7.36-7.26 (m, 4H), 7.23-7.18 (m, 1H), 6.34 (dd, J=8.1, 2.7 Hz, 1H), 6.11 (d, J=2.6 Hz, 1H), 4.38 (d, J=5.9 Hz, 2H), 4.03-3.94 (m, 2H), 3.86-3.82 (m, 1H), 3.62-3.55 (m, 1H), 3.38-3.31 (m, 1H), 2.53 (s, 3H), 1.76-1.69 (m, 1H), 1.59-1.20 (m, 5H); MS (ES+) m/z 440.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[C:5]([N+:11]([O-])=O)=[CH:4][CH:3]=1.[Cl-].[NH4+]>CCO.O.[Fe]>[NH2:11][C:5]1[C:6]([C:8]([NH2:10])=[O:9])=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: NC(=O)c1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: NC(=O)c1nc(Cl)ccc1N
Temperature: 60 °C
Reaction time: 1 h

Procedure:
6-chloro-3-nitro-pyridine-2-carboxylic acid amide (10.43 g, 51.75 mmol) is taken up in EtOH (250 mL), combined with ammonium chloride (1.384 g, 25.87 mmol) in water (250 mL) and heated to 60° C. At this temperature iron powder (8.67 g, 155.23 mmol) is added batchwise and the mixture is stirred for 1 h at 60° C. After cooling it is concentrated by rotary evaporation, filtered through silica gel, washed with DCM/MeOH (90/10 to 80/20), the resulting filtrate is evaporated down using the rotary evaporator and 3-amino-6-chloro-pyridine-2-carboxylic acid amide (HPLC-MS: tRet.=0.90 min; MS (M+H)+=172) is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:7]=1[NH2:13])=[O:5])[CH3:2].[C:14]1(=[O:20])[O:19][C:17](=[O:18])[CH:16]=[CH:15]1>CCOCC>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:7]=1[NH:13][C:14](=[O:20])[CH:15]=[CH:16][C:17]([OH:19])=[O:18])=[O:5])[CH3:2]
Reactant: O=C1C=CC(=O)O1
Reactant: CCOC(=O)c1c(N)sc(C)c1C
Solvent: CCOCC
Product: CCOC(=O)c1c(NC(=O)C=CC(=O)O)sc(C)c1C
Temperature: 25 °C
Reaction time: 10 h
Yield: 72.1 %

Procedure:
A solution of 2-Amino-4,5-dimethyl-thiophene-3-carboxylic acid ethyl ester (5.53 g, 27.8 mmol) in 25 mL of anhydrous ether was added dropwise to a solution of maleic anhydride (2.72 g, 27.8 mmol) in 25 mL of anhydrous ether. The reaction mixture was stirred at room temperature for 10 h. A yellow precipitate was formed. 2-(3-Carboxy-acryloylamino)-4,5-dimethyl-thiophene-3-carboxylic acid ethyl ester (5.96 g, 72% yield) was obtained as a yellow solid by filtration.
Reaction SMILES: C[O-].[Na+].[CH:4]([O:6][CH3:7])=[O:5].[Cl:8][C:9]1[N:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][C:24](OC)=[O:25])[CH:12]=[CH:11][CH:10]=1.O>C1(C)C=CC=CC=1>[Cl:8][C:9]1[N:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2/[C:23](=[CH:24]\[OH:25])/[C:4]([O:6][CH3:7])=[O:5])[CH:12]=[CH:11][CH:10]=1
Reactant: COC=O
Reactant: COC(=O)Cc1ccccc1COc1cccc(Cl)n1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)/C(=C/O)c1ccccc1COc1cccc(Cl)n1
Yield: 98.6 %

Procedure:
Sodium methoxide (0.39 g, 6.9 mmol) and methyl formate (1 ml, 16 mmol) were added portionwise to a stirred solution of methyl 2-(6-chloropyrid-2-yloxymethyl)phenylacetate (1.0 g, 3.3 mmol) in dry toluene (15 ml) under a nitrogen atmosphere at room temperature. After 3 hours at room temperature the mixture was poured into water and extracted with ethyl acetate. The ethyl acetate extracts were washed with water, dried and the ethyl acetate removed to give (E)-methyl 2-[2-(6-chloropyrid-2-yloxymethyl)phenyl]-3-hydroxyacrylate (1.04 g, 95%) as a brown gum which was used in the final stage without further purification; 1H NMR(270 MHz)δ: 3.75(3H,s), 5.29(2H,s), 6.65(1H,d), 6,90(1H,d), 7.15-7.60(6H,m), 11.98(1H,d) ppm.
Reaction SMILES: [N:1]([C:4](=[CH:10][N:11]([CH3:13])[CH3:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:2]=[O:3].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[C:5]([C:4]([NH:1][C:2]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:3])=[CH:10][N:11]([CH3:12])[CH3:13])([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(=CN(C)C)N=C=O
Reactant: Nc1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CN(C)C)NC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of Ethyl 2-isocyanato-3-(dimethylamino)-propenoate (5.52 g) in toluene (250 mL) was added aniline (2.79 g). The reaction was stirred at room temperature for 30 min. The resulting solid was collected and dried to yield N-(1-Carboethoxy-2-dimethylaminovinyl)-N'-phenyl urea as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[CH2:16][C:17]([CH3:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1/[C:16](=[CH:22]/[N:23]([CH3:25])[CH3:24])/[C:17](=[O:18])[CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Cc1cc(Cl)ccc1OCc1ccccc1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CC(=O)/C(=C\N(C)C)c1cc(Cl)ccc1OCc1ccccc1
Temperature: 100 °C

Procedure:
A mixture of the product from step (ii) (5.72 g) and dimethylformamide dimethyl acetal (3.5 ml) in toluene (50 ml) were heated at 100° C. for 12 h. The solvent was evaporated under reduced pressure to give an oil, 6.37 g.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]2[CH:17]=[N:16][N:15]([CH2:18][CH3:19])[C:9]2=[N:10][C:11]=1[O:12][CH2:13][CH3:14])=[O:5])C.[CH2:20]([NH2:24])[CH2:21][CH2:22][CH3:23]>>[CH2:20]([NH:24][C:4]([C:6]1[N:7]=[C:8]2[CH:17]=[N:16][N:15]([CH2:18][CH3:19])[C:9]2=[N:10][C:11]=1[O:12][CH2:13][CH3:14])=[O:5])[CH2:21][CH2:22][CH3:23]
Reactant: CCCCN
Reactant: CCOC(=O)c1nc2cnn(CC)c2nc1OCC
Product: CCCCNC(=O)c1nc2cnn(CC)c2nc1OCC

Procedure:
18 g. of 6-ethoxy-1-ethyl- 1H-pyrazolo[3,4-b]pyrazine-5-carboxylic acid ethyl ester (0.068 mol.), prepared according to Example 1c, are heated with 180 ml. of butylamine in an autoclave at 70° for 5 hours. After vacuum removal of excess butylamine, the residual N-butyl- 6-ethoxy-1-ethyl-1H-pyrazolo-[3,4-b]pyrazine-5-carboxamide is recrystallized from acetonitrile, m.p. 115°-117°. The mother liquor contains N-butyl-6-butyl-amino-1-ethyl-1H-pyrazolo[3,4-b]pyrazine-5-carboxamide (m.p. 128°-129°) which is identical with the compound of Example 4.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:9]([OH:10])=[C:8]([C:11]([CH3:13])=[O:12])[CH:7]=[CH:6][C:5]=1[OH:14].Br[CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CCOCC>[C:11]([C:8]1[CH:7]=[CH:6][C:5]([O:14][CH2:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=2)=[C:4]([CH2:3][CH2:2][CH3:1])[C:9]=1[OH:10])(=[O:12])[CH3:13]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: CCCc1c(OCc2ccc(C(=O)OC)cc2)ccc(C(C)=O)c1O
Yield: 68.7 %

Procedure:
A solution of 1.0 g (5.15 mmoles) of 2,4-dihydroxy-3-propylacetophenone, see R. A. Appleton et al. in J. Med. Chem. 1977, 20, pages 371-379, and 1.77 g (7.7 mmoles) of methyl 4-bromomethylbenzoate in 20 ml of acetone was treated with 784 mg (5.66 mmoles) of K2CO3 and stirred at reflux for 15 hours. The reaction mixture was diluted with ether, washed with water and saturated aqueous NaHCO3 solution and dried with MgSO4. Evaporation of the solvent gave an oil which crystallized. This material was purified by chromatography on silica gel with 30% hexane/dichloromethane as eluent to provide 1.212 g (69% yield) of the title compound as a white powder mp 99.5°-100.5° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12]3[N:17]=[C:16]([C:18](=S)[NH2:19])[CH:15]=[CH:14][CH:13]=3)[CH:9]=[N:8]2)[CH:2]=1.[CH3:21][N:22]([CH:24]=O)[NH2:23]>>[CH3:24][N:22]1[CH:21]=[N:19][C:18]([C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([C:10]3[CH:9]=[N:8][N:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH:11]=3)[N:17]=2)=[N:23]1
Reactant: CN(N)C=O
Reactant: NC(=S)c1cccc(-c2cnn(-c3cccnc3)c2)n1
Product: Cn1cnc(-c2cccc(-c3cnn(-c4cccnc4)c3)n2)n1

Procedure:
0.57 g (2 mmol) of 6-(l-pyridin-3-yl-1H-pyrazol-4-yl)pyridine-2-carbothioamide and 2.5 ml (27 mmol) of 1-methyl-1-formylhydrazine were stirred at 145° C. for 6 h. After cooling, the mixture was purified by chromatography on silica gel (cyclohexane/acetone).
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[C:15]([O:17][CH:18]([CH3:20])[CH3:19])[C:14]([NH:21][C:22]3[N:27]=[C:26]4[NH:28][N:29]=[C:30]([CH3:31])[C:25]4=[C:24]([NH:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[S:39]([CH:42]([CH3:44])[CH3:43])(=[O:41])=[O:40])[N:23]=3)=[CH:13][C:12]=2[CH3:45])[CH2:7][CH2:6]1)=[O:4].[NH:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1>CN(C=O)C>[CH:18]([O:17][C:15]1[C:14]([NH:21][C:22]2[N:27]=[C:26]3[NH:28][N:29]=[C:30]([CH3:31])[C:25]3=[C:24]([NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[S:39]([CH:42]([CH3:43])[CH3:44])(=[O:41])=[O:40])[N:23]=2)=[CH:13][C:12]([CH3:45])=[C:11]([CH:8]2[CH2:7][CH2:6][N:5]([C:3](=[O:4])[CH2:2][N:46]3[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]3)[CH2:10][CH2:9]2)[CH:16]=1)([CH3:19])[CH3:20]
Reactant: C1CCNCC1
Reactant: Cc1cc(Nc2nc(Nc3ccccc3S(=O)(=O)C(C)C)c3c(C)n[nH]c3n2)c(OC(C)C)cc1C1CCN(C(=O)CBr)CC1
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(Nc3ccccc3S(=O)(=O)C(C)C)c3c(C)n[nH]c3n2)c(OC(C)C)cc1C1CCN(C(=O)CN2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-bromo-1-(4-(5-isopropoxy-4-(4-(2-(isopropylsulfonyl)phenylamino)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-2-methylphenyl)piperidin-1-yl)ethanone from Example 8 (10 mg, 0.014 mmol), and piperidine (3 uL, 0.031 mmol) in DMF was stirred at rt overnight. The crude mixture was directly purified by reverse phase HPLC to give 1-(4-(5-isopropoxy-4-(4-(2-(isopropylsulfonyl)phenylamino)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-2-methylphenyl)piperidin-1-yl)-2-(piperidin-1-yl)ethanone. MS: m/z=703.4 (M+1), 352.2 (M/2+1). 1H-NMR (400 MHz, CD3OD): δ=8.39 (brs, 1H), 7.98 (dd, 1H, J=1.6, 8.0 Hz), 7.70 (t, 1H, J=7.6 Hz), 7.53-7.49 (m, 2H), 6.88 (s, 1H), 4.73-4.69 (m, 1H), 4.62 (sept, 1H, J=6.0 Hz), 4.31 (d, 1H, J=16.4 Hz), 4.22 (d, 1H, J=16.4 Hz), 3.85-3.82 (m, 1H), 3.60 (t, 2H, J=12.0 Hz), 3.41-3.25 (m, 2H), 3.11-3.00 (m, 3H), 2.90-2.84 (m, 1H), 2.79 (s, 3H), 2.22 (s, 3H), 1.99-1.85 (m, 7H), 1.80-1.54 (m, 3H), 1.27 (d, 6H, J=6.0 Hz), 1.24 (d, 6H, J=6.8 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])[N:9]=[CH:8][CH:7]=[C:6]2[O:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[O:31])=[C:25]([F:40])[CH:24]=1)#[N:2].[OH-].[Na+].O.Cl>CO>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[N:9]=[CH:8][CH:7]=[C:6]2[O:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)=[O:31])=[C:25]([F:40])[CH:24]=1)#[N:2]
Reactant: CCOC(=O)CCCOc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)c(F)c3)c2cc1C#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)c(F)c3)ccnc2cc1OCCCC(=O)O
Temperature: 80 °C
Reaction time: 0.67 h
Yield: 30.3 %

Procedure:
N-(4-(6-Cyano-7-(3-(ethoxycarbonyl)propoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(4-fluorophenyl)urea (800 mg) was dissolved in methanol (45 ml), 2N NaOH water (15 ml) was added, and the mixture was heated and stirred for 40 minutes at 80° C. After completion of the reaction, the reaction solution was poured into ice water and neutralized with 1N HCl, and the precipitated solid was filtered out. The obtained solid was washed with water and dried to obtain 230 mg of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:22]=[CH:21][C:8]([CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:20])[C:17]([OH:19])=[O:18])[CH2:12][CH2:11]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].N[C:24]1C=CC2NC(=O)OC=2[CH:25]=1>>[CH2:24]([O:18][C:17](=[O:19])[C:16]([N:13]1[CH2:12][CH2:11][CH:10]([CH2:9][C:8]2[CH:21]=[CH:22][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=2)[CH2:15][CH2:14]1)=[O:20])[CH3:25]
Reactant: Nc1ccc2[nH]c(=O)oc2c1
Reactant: CC(C)(C)c1ccc(CC2CCN(C(=O)C(=O)O)CC2)cc1
Product: CCOC(=O)C(=O)N1CCC(Cc2ccc(C(C)(C)C)cc2)CC1

Procedure:
The title compound is prepared from [4-(4-tert-butyl-benzyl)-piperidin-1-yl]-oxo-acetic acid and 6-amino-3H-benzoxazol-2-one according to the method described in Example 2. The filtered crystals are purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and toluene:methanol=4:1 as eluent. Melting Point: 168° C. (diethylether-hexane-diisopropyl ether).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:21][CH2:20][CH2:19][C@H:18]3[CH2:22][OH:23])[CH2:13][CH2:12]2)=[O:10])=[C:4]([CH3:24])[CH:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[N:35][CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=2)O1>>[CH3:8][C:6]1[CH:7]=[C:2]([C:33]2[CH:34]=[N:35][CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=2)[CH:3]=[C:4]([CH3:24])[C:5]=1[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:21][CH2:20][CH2:19][C@H:18]2[CH2:22][OH:23])[CH2:13][CH2:12]1)=[O:10]
Reactant: CC1(C)OB(c2cncc(C(F)(F)F)c2)OC1(C)C
Reactant: Cc1cc(Br)cc(C)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1
Product: Cc1cc(-c2cncc(C(F)(F)F)c2)cc(C)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1

Procedure:
In analogy to the procedure described for example 1, (4-bromo-2,6-dimethyl-phenyl)-[4-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-piperidin-1-yl]-methanone (intermediate 4) was reacted with 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-pyridine (intermediate 6) to give the title compound as light yellow solid. MS: 462.4 (MH+).
Reaction SMILES: [CH:1]1([CH:4]([OH:18])[CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=2[O:16][CH3:17])[CH2:3][CH2:2]1.C(=O)=O.CC(O)C>CC#N.CC(O)C>[CH:1]1([C@@H:4]([OH:18])[CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=2[O:16][CH3:17])[CH2:3][CH2:2]1
Reactant: COc1cc([N+](=O)[O-])ccc1OCC(O)C1CC1
Agent: O=C=O
Solvent: CC#N
Solvent: CC(C)O
Product: COc1cc([N+](=O)[O-])ccc1OC[C@H](O)C1CC1

Procedure:
Racemic 1-cyclopropyl-2-(2-methoxy-4-nitrophenoxy)ethanol (45.1 g, mmol) in 2/1 MeCN/i-PrOH (451 mL) was resolved by chiral chromatography resolution using a CHIRALPAK® AD-H (3×25 cm, 5 μm) column under the Chiral-SFC conditions. The chromatographic conditions employed an 85/15 mixture of CO2/i-PrOH as the mobile solvent with a flow rate of 130 mL/min at 35° C. with the BPR pressure maintained at 100 bar and detector wavelength at 234 nM. Each 0.7 mL injection required a run time of 7 min. The chiral purity of the R enantiomer was determined to be greater than 99.9% at 234 nm based on SFC/UV area % using analytical SFC conditions. Concentration of the resultant eluant under vacuum using a rotary evaporator yielded (R)-1-cyclopropyl-2-(2-methoxy-4-nitrophenoxy)ethanol as yellow oil. Subsequent dissolution in 150 ml EtOH and reconcentration yielded the title compound in the form of a yellow oil which solidified to form a light yellow solid (20.9 g) upon drying under high vacuum overnight. M.P. 77° C. 1H NMR (400 MHz, CDCl3): δ 0.30-0.37 (m, 1H), 0.42-0.50 (m, 1H), 0.55-0.69 (m, 2H), 0.97-1.08 (m, 1H), 2.40-2.70 (bs, 1H), 3.41 (ddd, J=8.3, 8.3, 2.7 Hz, 1H), 3.93 (s, 3H), 4.10 (dd, J=9.3, 8.0 Hz, 1H), 4.23 (dd, J=9.3, 2.7 Hz, 1H), 6.95 (d, J=8.8 Hz, 1H), 7.74 (d, J=2.2 Hz, 1H), 7.89 (dd, J=8.8, 2.2 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 153.7, 149.2, 141.7, 117.6, 111.5, 106.7, 74.4, 73.5, 56.2, 13.4, 2.7, 2.0. HPLC: 6.26 min retention time, 98.7% API; ZORBAX® column SB C18 4.6×75 mm; flow rate 2.5 ml/min; Gradient solvent system: from 100% A:0% B to 0% A:100% B for 8 min (Solvent A: 10% MeOH 90% H2O=0.2% H3PO4; Solvent B: 90% MeOH−10% H2O+0.2% H3PO4) Detection at 220 run. LC/MS: m/e=254.3 (M+H).
Reaction SMILES: CN(C=O)C.[H-].[Na+].[Si:8]([O:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][NH:18]1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[CH2:23]([N:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]1[CH2:16][O:15][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCC1CCCCN1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC1CCCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
To a DMF (4 ml) solution of 60% sodium hydride (0.21 g, 5.2 mmol) was dropwise added a DMF (4 ml) solution of 2-(tert-butyldimethylsilyloxymethyl)piperidine (1.00 g, 4.4 mmol) at room temperature. The mixture was stirred at room temperature for 30 min., to which was then dropwise added a THF (1 ml) solution of benzyl bromide (0.75 g, 4.4 mmol). After stirring at room temperature for additional 30 min., a reaction solution was poured onto water followed by extraction with diethyl ether (30 ml). The extract was washed successively with water and saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 1.30 g of the title compound.
Reaction SMILES: Cl[CH2:2][C@H:3]([OH:18])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[CH:6]=1.[N-:19]=[N+:20]=[N-:21].[Na+]>>[N:19]([CH2:2][C@H:3]([OH:18])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[CH:6]=1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: CCC(CC)COc1cccc(C[C@@H](O)CCl)c1
Agent: [Na+]
Product: CCC(CC)COc1cccc(C[C@@H](O)CN=[N+]=[N-])c1

Procedure:
Treatment of (R)-1-chloro-3-(3-(2-ethylbutoxy)phenyl)propan-2-ol with sodium azide following the method used in Example 66 gave (R)-1-azido-3-(3-(2-ethylbutoxy)phenyl)propan-2-ol which was used without further purification.
Reaction SMILES: CN(C)S([N:6]1[C:10]([CH2:11][CH2:12][CH2:13][Cl:14])=[C:9]([Br:15])[C:8]([CH3:16])=[N:7]1)(=O)=O.Cl>CO>[Br:15][C:9]1[C:8]([CH3:16])=[N:7][NH:6][C:10]=1[CH2:11][CH2:12][CH2:13][Cl:14]
Reactant: Cc1nn(S(=O)(=O)N(C)C)c(CCCCl)c1Br
Agent: Cl
Solvent: CO
Product: Cc1n[nH]c(CCCCl)c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
To a solution of 4-bromo-5-(3-chloro-propyl)-3-methyl-pyrazole-1-sulfonic acid dimethylamide (3.85 g, 11.2 mmol) in MeOH (50 ml) at 0° C. was added 6 N HCl (50 mL). The reaction was warmed to room temperature and stirred overnight. The reaction was quenched by adding concentrated NH4OH until a pH of 8 was obtained. After concentrating to remove the MeOH, the remaining reaction solution was extracted with EtOAc and the organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified over normal phase silica starting with 10% EtOAc in heptane for 5 m and then increasing to 100% EtOAc over 40 m to give the desired product as a clear oil (2.42 g, 10.2 mmol). MS m/z 239.3 (M+H)+.