Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:22]#[N:23])=[CH:4][CH:3]=1>C(O)C>[NH2:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:22]#[N:23])=[C:9]2[NH:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1ccc(Br)cc1
Solvent: CCO
Product: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(Br)cc1
Reaction time: 4 h
Yield: 79.5 %

Procedure:
A mixture of 3.10 g (8.40 mmol) 4-[(4-bromophenyl)amino]-6-nitro-3-quinolinecarbonitrile, 155 ml ethanol, and 9.47 g (42.0 mmol) SnCl2 dihydrate was heated to reflux under N2. After 4 hours, removed heat and added ice water. Made basic with sodium bicarbonate and stirred for 2 hours. With mixture still basic, extracted with chloroform, stirred organic layer with Darco and dried with sodium sulfate. Filtered, stripped solvent and dried in vacuo, giving 2.265 g of brown-yellow solid: mass spectrum (electrospray m/e): M+H=339.0, 341.0.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[N:27]1([C:32]2[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=2)[CH:31]=[CH:30][CH:29]=[CH:28]1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:36](=[O:37])[C:35]5[CH:39]=[CH:40][C:32]([N:27]6[CH:31]=[CH:30][CH:29]=[CH:28]6)=[CH:33][CH:34]=5)[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: O=C(O)c1ccc(-n2cccc2)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)c1ccc(-n2cccc2)cc1

Procedure:
The title compound, light brown solid (90 mg, 73%), MS (ISP) m/z=498.4 [(M+H)+], mp 228° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 4-pyrrol-1-yl-benzoic acid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]3[CH2:12][CH:11]3[CH:13]=O)[CH:8]=2)[CH:3]=[CH:2]1.[CH3:15][NH:16][CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]3[CH2:12][CH:11]3[CH2:13][N:16]([CH3:17])[CH3:15])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=CC1CC1c1ccc2cc[nH]c2c1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CN(C)CC1CC1c1ccc2cc[nH]c2c1

Procedure:
The crude 2-(1H-indol-6-yl)-cyclopropanecarbaldehyde was dissolved in methanol at room temperature with stirring. Dimethylamine (1M solution in THF, 20.00 mL, 20.00 mmol) was added followed by sodium triacetoxyborohydride (4.24 g, 20.00 mmol) After 15 h of stirring at room temperature, the solution was concentrated to dryness in vacuo. The residue was then partitioned between methylene chloride and 1 N NaOH solution. The layers were separated, and the organic layer dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude amine was purified by flash chromatography (50% MeOH/EtOAc) to give [2-(1H-indol-6-yl)-cyclopropylmethyl]-dimethyl-amine as a yellow solid (0.62 g, 74% for the two reactions). 1H NMR (CDCl3): δ 8.61 (bs, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.08 (t, J=2.7 Hz, 1H), 7.06 (s, 1H), 6.86 (dd, J=11.4, 1.8 Hz, 1H), 6.47 (m, 1H), 2.51 (m, 1H), 2.35 (s, 7H), 1.85 (m, 1H), 0.99 (m, 1H), and 0.85 (m, 1H); LCMS: MH+: 215.16, 78% AP.
Reaction SMILES: [CH3:1][Mg]Br.[N:4]1[C:11](Cl)=[N:10][C:8]([Cl:9])=[N:7][C:5]=1[Cl:6]>CCOCC.C1COCC1>[Cl:6][C:5]1[N:7]=[C:8]([Cl:9])[N:10]=[C:11]([CH3:1])[N:4]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1nc(Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
Methylmagnesium bromide (9.00 mL of a 3.0 M solution in Et2O, 27.1 mmol, 1.00 equiv) was added dropwise over 1 h to a cooled (0° C.) solution of cyanuric chloride (5.00 g, 27.1 mmol, 1.00 equiv) in THF (270 mL). The reaction mixture was stirred at room temperature overnight and was then quenched with sat NH4Cl (aq). The aqueous layer was extracted 3 times using ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified using silica gel chromatography (0-40% CH2Cl2/hexanes) to afford 1.5 g (34%) of the title compound. MS (ES+): m/e 164.0 [M+H]+.
Reaction SMILES: [N:1]([C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH3:18])([N:15]=[C:16]=[O:17])[CH3:14])[CH:8]=1)([CH3:6])[CH3:5])=[C:2]=[O:3].[CH2:19]([CH:21]([NH:24][OH:25])[CH2:22][CH3:23])[CH3:20]>ClCCl>[C:9]1([C:13]([CH3:18])([NH:15][C:16]([N:24]([OH:25])[CH:21]([CH2:22][CH3:23])[CH2:19][CH3:20])=[O:17])[CH3:14])[CH:10]=[CH:11][CH:12]=[C:7]([C:4]([NH:1][C:2]([N:24]([CH:21]([CH2:22][CH3:23])[CH2:19][CH3:20])[OH:25])=[O:3])([CH3:6])[CH3:5])[CH:8]=1
Reactant: CCC(CC)NO
Reactant: CC(C)(N=C=O)c1cccc(C(C)(C)N=C=O)c1
Solvent: ClCCl
Product: CCC(CC)N(O)C(=O)NC(C)(C)c1cccc(C(C)(C)NC(=O)N(O)C(CC)CC)c1
Yield: 88.8 %

Procedure:
A solution of 1,3-Bis(1-isocyanato-1-methylethyl)benzene (2.3 ml, 10 mmol) and dichloromethane (100 ml) was charged with N-(1-ethylpropyl)hydroxylamine (2.2 g, 21.3 mmol). A precipitate formed immediately and the resulting mixture was maintained overnight. The precipitate was recovered by filtration and dried in vacuo to yield 4.0 g of the desired product as a white powder. Recrystallization from N,N-dimethylformamide.backslash.water provided an analytically pure sample: MP: 170.5-172.0° C. ; 1H NMR (300 MHz, DMSO): δ 8.91 (s, 2H), 7.37 (s, 1H), 7.18 (apparent d, J=1.0 Hz, 3H), 6.53 (s, 2H), 3.75-3.65 (m, 2H), 1.57 (s, 12H), 1.51-1.30 (m, 8H), 0.80 (t, J=7.3 Hz, 12 H); 13C NMR (75 MHz, DMSO): δ 159.3, 147.7, 127.1, 122.2, 121.0, 59.5, 54.3, 29.8, 24.4, 11.2; IR (KBr): 3436, 3160, 2963, 2928, 2873, 1632, 1520, 1380, 1361, 1270, 1232, 1160, 790, 702 cm-1 ; Anal. calc'd for C24H42N4O4 : C, 63.97; H, 9.39; N, 12.43. Found: C, 63.81; H, 9.35; N, 12.48.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[CH:10]([OH:12])[CH3:11]>C1COCC1.[O-2].[O-2].[Mn+4]>[NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10](=[O:12])[CH3:11]
Reactant: CC(O)c1cc2ccncc2[nH]1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: CC(=O)c1cc2ccncc2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(1H-pyrrolo[2,3-c]pyridin-2-yl)ethanol (Example 68) (0.65 g, 4.0 mmol) in THF (80 mL) was added manganese dioxide (4.18 g, 48 mmol). After stirring 2 h at room temperature, TLC analysis indicated that the reaction was completed. The reaction mixture was filtered through diatomaceous earth and rinsed with EtOAc. The filtrate was concentrated and triturated with Et2O to provide 1-(1H-pyrrolo[2,3-c]pyridin-2-yl)ethanone as an off-white solid: mp 236-242° C. dec.; 1H NMR (300 MHz, CD3OD) δ2.63 (3H, s), 7.34 (1H, s), 7.70-7.73 (1H, m), 8.13 (1H, d, J=5.7 Hz), 8.80 (1H, s); ESI MS m/z 161 [C9H8N2O+H]+; HPLC (Method A) 92.7% (AUC), tR=7.75 min.
Reaction SMILES: [CH3:1][C:2]([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[CH2:3].C(OOC(=O)C1C=CC=CC=1)(C)(C)C.[PH2:23]([OH:25])=[O:24]>>[CH3:3][CH:2]([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])[CH2:1][PH:23](=[O:24])[OH:25]
Reactant: O=[PH2]O
Reactant: C=C(C)CC(C)(C)C
Agent: CC(C)(C)OOC(=O)c1ccccc1
Product: CC(C[PH](=O)O)CC(C)(C)C

Procedure:
A mixture of diisobutylene (112 g, 1 mol) and hypophosphorous acid (30%, 230 mL) are reacted in the presence of t-butylperbenzoate. After aqueous work up, 45 g of oily product are obtained. It is characterized by 1H NMR and 31P NMR which shows formation of product (64% pure).
Reaction SMILES: [F:1][C:2]([F:11])([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[C:3](O)=[O:4]>C(OC(=O)C)(=O)C>[F:1][C:2]1([F:11])[CH2:6][CH2:7][C:8](=[O:10])[O:9][C:3]1=[O:4]
Reactant: O=C(O)CCC(F)(F)C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1CCC(F)(F)C(=O)O1

Procedure:
A solution of 5 g of 2,2-difluoroglutaric acid in 20 ml of acetic anhydride is refluxed for two hrs, 5 ml of the resulting solution is distilled off at ordinary pressure and the residual solution freed from acetic anhydride under reduced pressure. The resulting oil consists of 2,2-difluoroglutaric anhydride.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][C@H:14]([C:16](OCCCC)=[O:17])[O:13][C:12]3=[O:23])=[CH:10][C:5]=2[S:4][C:3]1=[O:24].[NH3:25]>CO.O1CCCC1>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][C@H:14]([C:16]([NH2:25])=[O:17])[O:13][C:12]3=[O:23])=[CH:10][C:5]=2[S:4][C:3]1=[O:24]
Reactant: N
Reactant: CCCCOC(=O)[C@H]1CN(c2ccc3c(c2)sc(=O)n3C)C(=O)O1
Solvent: CO
Solvent: C1CCOC1
Product: Cn1c(=O)sc2cc(N3C[C@H](C(N)=O)OC3=O)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The butyl (5R)-3-(2,3-dihydro-3-methyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxylate (Step 2, 685 mg, 1.95 mmol) is treated with 7N ammonia in MeOH (19 mL) with vigorous stirring, and the mixture is diluted with additional MeOH (20 mL) and tetrahydrofuran (20 mL) and stirred at ambient temperature for 1 h. The resulting slurry is concentrated under reduced pressure and then triturated and filtered from acetone to give the title compound, mp 274–276° C. (dec.); MS (ESI−) for C12H11N3O4S m/z 292 (M−H)−; [α]25D−27 (c 0.98, DMSO).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:15][O:16][C:17](=[O:23])[C:18](=O)[CH:19](Br)[CH3:20].C(OCC)(=O)C.[OH-].[Na+]>O1CCCC1>[CH3:15][O:16][C:17]([C:18]1[N:1]=[C:2]2[C:7]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])=[CH:6][CH:5]=[CH:4][N:3]2[C:19]=1[CH3:20])=[O:23]
Reactant: COC(=O)C(=O)C(C)Br
Reactant: CC(C)(C)C(=O)Nc1cccnc1N
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1nc2c(NC(=O)C(C)(C)C)cccn2c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 78 %

Procedure:
To a stirred solution of 30 g of 2-amino-3-pivaloylaminopyridine in 300 ml of dry tetrahydrofuran are added dropwise under argon 40 g of 3-bromo-2-oxobutanoic acid methylester. The brown solution is stirred at ambient temperature for 3 d. The resulting suspension is poured onto a mixture of icewater and ethyl acetate and the mixture is neutralised by adding 10 M sodium hydroxide solution. The organic phase is separated and the aqueous layer extracted two times with ethyl acetate. The combined organic phases are washed with water and dried over anhydrous sodium sulfate. The solvent is removed in vacuo and the blue coloured residue purified by column chromatography on silica gel to yield 35 g (78%) of a light brown solid (m.p. 132° C.).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C@@H:9]1[O:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([NH:23][C:24](=[O:35])[CH:25]=[CH:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=3)[CH3:22])[CH:16]=2)[CH2:10]1)(C)(C)C.Cl>CO>[NH2:7][CH2:8][CH:9]1[O:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[C:17]([C@@H:21]([NH:23][C:24](=[O:35])[CH:25]=[CH:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=3)[CH3:22])[CH:18]=[CH:19][CH:20]=2)[CH2:10]1
Reactant: CC(NC(=O)C=Cc1ccc(F)c(F)c1)c1cccc(N2CCO[C@@H](CNC(=O)OC(C)(C)C)C2)c1
Agent: Cl
Solvent: CO
Product: C[C@H](NC(=O)C=Cc1ccc(F)c(F)c1)c1cccc(N2CCOC(CN)C2)c1

Procedure:
The solution of (S)-[4-(3-{1-[3-(3,4-difluoro-phenyl)-acryloylamino]-ethyl}-phenyl)-morpholin-2-ylmethyl]-carbamic acid tert-butyl ester, Example 125 (about 24 mg), and hydrochloric acid (1.0M solution in diethyl ether) (0.3 ml) in methanol (0.3 ml) was stirred at room temperature overnight. Concentrated under vacuum and sticky oil was filtered through 2 g anion-exchange cartridge with methanol. Filtrate was concentrated under vacuum and the title compound was obtained as pale yellow solid (quantitative yield).
Reaction SMILES: ClCCl.[CH3:4][N:5]=[C:6]=[S:7].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)[N:16]2[CH2:19][C:18](=[CH:20][S:21]([CH2:24][C:25]3[CH:26]=[C:27]([N:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)[CH:28]=[CH:29][CH:30]=3)(=[O:23])=[O:22])[CH2:17]2)=[CH:11][CH:10]=1>O>[CH3:4][NH:5][C:6]([N:34]1[CH2:35][CH2:36][N:31]([C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([CH2:24][S:21]([CH:20]=[C:18]3[CH2:17][N:16]([CH:15]([C:12]4[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=4)[C:37]4[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=4)[CH2:19]3)(=[O:22])=[O:23])[CH:26]=2)[CH2:32][CH2:33]1)=[S:7]
Reactant: O=S(=O)(C=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)Cc1cccc(N2CCNCC2)c1
Reactant: CN=C=S
Solvent: ClCCl
Solvent: O
Product: CNC(=S)N1CCN(c2cccc(CS(=O)(=O)C=C3CN(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)C3)c2)CC1
Reaction time: 6 h
Yield: 99.1 %

Procedure:
2 cm3 of dichloromethane and then 11 mg of methyl isothiocyanate are successively added, at a temperature close to 20° C., to 54.25 mg of 1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine. After stirring for 6 hours at a temperature close to 20° C., 0.05 cm3 of water is added to the reaction mixture. After stirring for 15 minutes at the same temperature, the reaction medium is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 40° C. 61 mg of 4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine-1-carbothioic acid N-methylamide are thus obtained in the form of a beige lacquer [1H NMR spectrum (400 MHz, CDCl3), δ in ppm): 2.77 (s, 3H), 3.20 (d, J=5 Hz, 3H), 3.32 (t, J=5.5 Hz, 4H), 3.81 (mt, 2H), 4.00 (t, J=5.5 Hz, 4H), 4.33 (mt, 2H), 4.49 (s, 1H), 5.63 (broad q, J=5 Hz, 1H), 6.80 (d, J=8 Hz, 1H), 6.85 (dd, J=8 and 2.5 Hz, 1H), 6.94 (broad s, 1H), from 7.20 to 7.30 (mt, 5H), 7.32 (d, J=8 Hz, 4H)].
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH2:13][O:14][CH3:15])[C:9]([F:16])=[CH:8][C:7]=2[C:17]2[C:18]3[NH:25][CH:24]=[C:23]([C:26](O)=[O:27])[C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:3][CH2:2]1.[NH2:29][CH:30]1[CH2:35][CH2:34][N:33]([C:36]([OH:38])=[O:37])[CH2:32][CH2:31]1>>[C:1]([O:37][C:36]([N:33]1[CH2:34][CH2:35][CH:30]([NH:29][C:26]([C:23]2[C:19]3[N:20]=[CH:21][N:22]=[C:17]([C:7]4[CH:8]=[C:9]([F:16])[C:10]([O:12][CH2:13][O:14][CH3:15])=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:18]=3[NH:25][CH:24]=2)=[O:27])[CH2:31][CH2:32]1)=[O:38])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CCN(C(=O)O)CC1
Reactant: COCOc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c[nH]c23)cc1F
Product: COCOc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)c[nH]c23)cc1F

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-4-methoxymethoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A84) and commercially available 4-amino-piperidine-1-carboxylic acid the title compound is obtained as colorless foam.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH3:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]2[C:10]3[C:7](=[CH:2][CH:3]=[CH:4][CH:9]=3)[CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CCCCCC
Reactant: Brc1ccc(I)cc1
Product: Brc1ccc(-c2cccc3ccccc23)cc1

Procedure:
An Rf value of the desired substance by a silica gel thin layer chromatography (TLC) (developing solvent: hexane) was 0.38 and that of 4-bromoiodobenzene was 0.57.
Reaction SMILES: C([O:5][C:6](=[O:24])[CH2:7][C:8]1[C:9]([CH3:23])=[N:10][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[CH:22])=[CH:17][CH:16]=2)[C:12]=1[CH3:13])(C)(C)C.[Cl:25][C:26]1[CH:27]=[CH:28][C:29](I)=[C:30]([NH2:32])[CH:31]=1.C(N(C(C)C)CC)(C)C>O1CCCC1.CN1CCCC1=O>[Cl:25][C:26]1[CH:31]=[C:30]2[C:29]([CH:22]=[C:21]([C:18]3[CH:17]=[CH:16][C:15]([CH2:14][N:11]4[C:12]([CH3:13])=[C:8]([CH2:7][C:6]([OH:5])=[O:24])[C:9]([CH3:23])=[N:10]4)=[CH:20][CH:19]=3)[NH:32]2)=[CH:28][CH:27]=1
Reactant: C#Cc1ccc(Cn2nc(C)c(CC(=O)OC(C)(C)C)c2C)cc1
Reactant: Nc1cc(Cl)ccc1I
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1nn(Cc2ccc(-c3cc4ccc(Cl)cc4[nH]3)cc2)c(C)c1CC(=O)O
Temperature: 50 °C
Reaction time: 18 h
Yield: 37.9 %

Procedure:
To a stirred solution of 1-(4-ethynylbenzyl)-3,5-dimethyl-1H-pyrazol-4-yl-acetic acid tert.-butyl ester (4.4 g) and 5-chloro-2-iodophenylamine (3.4 g) in tetrahydrofuran (100 ml) at room temperature is added diisopropylethylamine (5.8 ml). The reaction is degassed and put under argon. Copper(I)iodide (260 mg) and bis(triphenylphosphine)palladiumdichloride (475 mg) are added. After 18 h, the reaction mixture is absorbed onto Extrelut and purified by flash chromatography (7:3 isocratic-cyclohexane:ethyl acetate) to yield a solid (4.3 g; HPLC retention time 1.66 min (Method J)). The solid (4.2 g) is dissolved in N-methyl-2-pyrrolidone (25 ml) and the solution degassed and put under argon. Potassium tert-butoxide (4.1 g) is added and the reaction is then heated to 50° C. After 15 h, further potassium tert-butoxide (1.0 g) is added. After 15 h the reaction temperature is increased to 75° C. After 3 h, the reaction mixture is allowed to cool to room temperature and a copious amount of water is added. The reaction mixture is extracted twice with ethyl acetate and the aqueous phase is acidified to pH 3 with 1M aqueous hydrochloric acid. The resultant precipitate is filtered off and triturated with hot acetonitrile to yield (1-[4-(6-Chloro-1H-indol-2-yl)-benzyl]-3,5-dimethyl-1H-pyrazol-4-yl)-acetic acid (2.0 g; [M+H]=394; HPLC retention time 1.51 min (Method E)).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[O:11]1[CH2:14][CH2:13][CH:12]1[CH2:15][OH:16].CC(C)([O-])C.[K+]>CN(C)C=O>[O:11]1[CH2:14][CH2:13][CH:12]1[CH2:15][O:16][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1
Reactant: O=C(O)c1cnc(Cl)cn1
Reactant: OCC1CCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1cnc(OCC2CCO2)cn1
Temperature: 120 °C
Yield: 221.7 %

Procedure:
In a microwave vial 5-chloropyrazine-2-carboxylic acid (100.0 mg, 0.631 mmol), dimethylformamide (5 mL), oxetan-2-ylmethanol (83.4 mg, 0.946 mmol) and potassium tert-butoxide (176.9 mg, 1.58 mmol) are added. A small exotherm is observed. After 1 minute at room temperature the vial is sealed and the mixture heated at 120° C. for 30 minutes in the microwave. The reaction mixture is then quenched with aqueous NH4Cl and the solvent evaporated under reduced pressure. The resultant residue is triturated in 2-propanol. The filtrate is concentrated under reduced pressure to give the title compound as a cream solid (0.294 g, 99%) and is used without further purification. ES/MS (m/e): 211.0 (M+1), 208.8 (M−H).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=2[O:12][CH3:13])[CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.CCOC(C)=O.O.[OH-].[Na+]>[CH:1]1([C:4]2[N:9]=[C:8]([CH2:10][NH2:11])[CH:7]=[CH:6][C:5]=2[O:12][CH3:13])[CH2:2][CH2:3]1
Reactant: COc1ccc(C#N)nc1C1CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CN)nc1C1CC1
Temperature: 25 °C

Procedure:
To a solution of 6-cyclopropyl-5-methoxypyridine-2-carbonitrile (9-5, 115 mg, 0.66 mmol, 1 equiv) in THF (2.6 mL) at 0° C. was added LAH (1 M, 1.98 mL, 1.98 mmol, 3 equiv) slowly. The reaction mixture was stirred and allowed to warm to ambient temperature over 3 hours. The reaction mixture was then diluted with EtOAc (2 mL), and water (50 uL), NaOH (aq., 20 wt. %, 50 uL) and water (100 uL) were added sequentially. The reaction mixture was then dried over MgSO4, filtered and concentrated to afford the product (9-6). ESI+MS [M+H]+ C10H15N2O: 179.1 found, 179.2 required.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]#[C:17][C:18]3[CH:19]=[CH:20][C:21]([O:27][CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][CH:33]([CH3:36])[CH2:32][CH2:31]4)=[C:22]([C:24](=[O:26])[CH3:25])[CH:23]=3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1>O.CCO>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]#[C:17][C:18]3[CH:19]=[CH:20][C:21]([O:27][CH2:28][CH2:29][N:30]4[CH2:31][CH2:32][CH:33]([CH3:36])[CH2:34][CH2:35]4)=[C:22]([CH:24]([OH:26])[CH3:25])[CH:23]=3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1
Reactant: CC(=O)c1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCC(C)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1CCN(CCOc2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc2C(C)O)CC1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A solution of 30 mg (0.74 mmol) of sodium borohydride in 3 mL of water was added to a solution of 0.32 g (0.68 mmol) of 1-{5-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-[2-(4-methylpiperidin-1-yl)ethoxy]phenyl}ethanone (Example 13.1) in 8 mL of EtOH and the mixture was stirred for 30 minutes at 50° C. The reaction mixture was evaporated down in vacuo, and the residue was stirred for 5 minutes with 4 mL of 1N aqueous HCl, diluted with EtOAc, and neutralized with saturated aqueous sodium bicarbonate solution. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried over magnesium sulfate and evaporated down in vacuo. The residue was triturated with acetonitrile and a little EtOAc, the precipitate was filtered off, and dried in the air. Yield: 100 mg (31% of theoretical); C29H31ClN2O2 (M=475.021); calc.: molpeak (M+H)+: 475/477 (Cl); found: molpeak (M+H)+: 475/477 (Cl); HPLC-MS: 5.20 minutes (method A).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:9])[CH2:6][C:7]#[N:8].F[C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([O:18][CH3:19])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21].Cl>CN(C)C=O>[CH3:3][O:4][C:5](=[O:9])[CH:6]([C:7]#[N:8])[C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([O:18][CH3:19])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21]
Reactant: COc1cc([N+](=O)[O-])c(F)cc1C
Reactant: COC(=O)CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C#N)c1cc(C)c(OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.7 %

Procedure:
To a suspension of sodium hydride (0.86 g) in N,N-dimethylformamide (5 mL) was added dropwise a solution of cyano acetic acid methyl ester (0.35 g) in N,N-dimethylformamide (3 mL) under ice cooling and this mixture was stirred for 15 minutes. To this reaction mixture was added dropwise a solution of 1-fluoro-4-methoxy-5-methyl-2-nitrobenzene (0.44 g) under ice cooling and this mixture was stirred at room temperature for 30 minutes, and then stirred at 70° C. overnight. After cooling to ambient temperature, 1 mol/L hydrochloric acid (5 mL) was added to this reaction mixture. This resulting mixture was extracted with ethyl acetate. This organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (0.45 g).
Reaction SMILES: FC(F)(F)S(O)(=O)=O.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:11]=1.[CH3:22][Si:23]([C:26]#[CH:27])([CH3:25])[CH3:24].C(N(CC)CC)C.O>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:27]#[C:26][Si:23]([CH3:25])([CH3:24])[CH3:22])=[C:12]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:11]=1
Reactant: C#C[Si](C)(C)C
Reactant: Clc1cccc(C2CCCCC2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(Cl)cc1C1CCCCC1
Temperature: 100 °C

Procedure:
21 g (61.3 mmol) of 7, 25.8 ml (183.8 mmol) of trimethylsilylacetylene, 2.15 g (3 mmol) of bis(triphenylphosphine)palladium(II) chloride and 21.2 ml (153.2 mmol) of triethylamine are dissolved in 60 ml of N,N-dimethylformamide under nitrogen, and the mixture is heated at 100° C. overnight. 100 ml of water are added to the cooled solution, and the mixture is extracted twice with methyl t-butyl ether (100 ml). The combined organic phases are washed with water, dried over sodium sulfate and evaporated in vacuo. The residue is purified by column chromatography, giving the product 8, which is employed in the next step without further purification.