Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH:12]([O:17][Si:18]([CH2:23][CH3:24])([CH2:21][CH3:22])[CH2:19][CH3:20])[CH2:13][N+:14]([O-])=O)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Cl-].[NH4+]>CCO.O.[Fe]>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH:12]([O:17][Si:18]([CH2:19][CH3:20])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:13][NH2:14])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CC[Si](CC)(CC)OC(C[N+](=O)[O-])c1c(Cl)cnc2ccccc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC[Si](CC)(CC)OC(CN)c1c(Cl)cnc2ccccc12
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a clear yellow solution of 3-chloro-4-(2-nitro-1-((triethylsilyl)oxy)ethyl)quinoline (0.511 g, 1.39 mmol) in EtOH (7.96 mL) and water (1.99 mL) at room temperature was added iron powder (0.778 g, 13.9 mmol) and ammonium chloride (0.745 g, 13.9 mmol). The dark brown mixture was stirred and heated at 60° C. After 4 h, the mixture was cooled to room temperature and filtered through a celite pad and washed the pad with MeOH (3×30 mL). The combined filtrates were concentrated in vacuo. The residue was partitioned between EtOAc (100 mL) and water (50 mL). The mixture (pH ˜4.0) washed with saturated aqueous NaHCO3 (1×50 mL), water (1×50 mL), and brine (1×50 mL), dried over anhydrous Na2SO4, concentrated in vacuo, and dried under high vacuum to give 2-(3-chloroquinolin-4-yl)-2-((triethylsilyl)oxy)ethanamine (A275-6) as a yellow syrup. 1H NMR (400 MHz, DMSO-d6) δ 8.84 (1H, s), 8.72 (1H, d, J=8.2 Hz), 8.04 (1H, dd, J=8.4, 1.0 Hz), 7.76 (1H, ddd, J=8.4, 6.9, 1.4 Hz), 7.64 (1H, ddd, J=8.5, 7.0, 1.3 Hz), 5.52 (1H, dd, J=7.6, 5.5 Hz), 3.16 (1H, dd, J=13.0, 7.9 Hz), 2.88 (1H, dd, J=13.0, 5.4 Hz), 1.74 (1H, br. s.), 0.71-0.80 (1H, m), 0.71-0.80 (9H, m), 0.37-0.57 (6H, m); LCMS (ESI) m/z 337.1 (M+H)+.
Reaction SMILES: CC[O-].[Na+].C([O:7][CH:8]=[C:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10](OCC)=O)C.O.[NH2:21][NH2:22].Cl>CCO>[OH:7][C:8]1[C:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][NH:22][N:21]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: NN
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c[nH]nc1O
Temperature: 80 °C
Yield: 54.4 %

Procedure:
To a solution of NaOEt in EtOH (60 mL, 21 w %) were added diethyl 2-(ethoxymethylene)malonate (10.4 mL, 52.0 mmol) and hydrazine monohydrate (5.04 mL, 104 mmol) with cooling in an ice-water bath. The resulting mixture was then heated at 80° C. for 4 h. After cooling to rt, HCl (1 N, 180 mL) was added to the reaction mixture and then extracted with EtOAc three time. The combined organic layers were washed with brine and dried over Na2SO4. A solid obtained after evaporation was washed with ether and dried under high vacuum to afford the titled compound as an off-white solid (4.42 g), which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[C:45]([CH3:47])[N:44]=[C:43]([CH3:48])[CH:42]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:11]([C:20]([F:21])([F:22])[F:23])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:42]=[C:43]([CH3:48])[N:44]=[C:45]([CH3:47])[CH:46]=2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1N
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(C)n1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N4CCOCC4)cc3NC(=O)OC(C)(C)C)c2)cc(C)n1

Procedure:
The title compound was prepared from (2-amino-5-morpholin-4-yl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J28) (271 mg, 0.75 mmol) and 3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K15) (244 mg, 0.75 mmol) according to the general procedure M.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[N:14]=[N:13][C:12]([C:15]2[S:19][C:18]([NH:20][C:21](=[O:23])[CH3:22])=[N:17][C:16]=2[CH3:24])=[CH:11][C:10]=1[NH:25]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CO>ClCCl>[NH2:25][C:10]1[CH:11]=[C:12]([C:15]2[S:19][C:18]([NH:20][C:21](=[O:23])[CH3:22])=[N:17][C:16]=2[CH3:24])[N:13]=[N:14][C:9]=1[Cl:8]
Reactant: CC(=O)Nc1nc(C)c(-c2cc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)c(Cl)nn2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(=O)Nc1nc(C)c(-c2cc(N)c(Cl)nn2)s1
Temperature: 0 °C

Procedure:
Trifluoroacetic acid (1.5 mL) was added to a stirred mixture of N-[5-(6-chloro-5-tritylaminopyridazin-3-yl)-4-methyl-1,3-thiazol-2-yl]acetamide (300 mg), methanol (0.5 mL) and dichloromethane (4 mL) that had been cooled to 0° C. The resultant mixture was heated to 55° C. for 5 hours. The mixture was evaporated and the residue was basified to pH8 by the addition of a saturated aqueous sodium bicarbonate solution. The resultant solid was isolated and washed with diethyl ether. The solid was dissolved in dichloromethane and a 7M methanolic ammonia solution was added. The mixture was evaporated to give N-[5-(5-amino-6-chloropyridazin-3-yl)-4-methyl-1,3-thiazol-2-yl]acetamide as a solid; Mass Spectrum: M+H+ 282.
Reaction SMILES: [Br:1][C:2]1[N:3]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]3[CH2:20][CH2:19]3)=[CH:10][CH:9]=2)[C:4]([SH:7])=[N:5][N:6]=1.Br[C:22]([CH3:29])([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Br:1][C:2]1[N:3]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]3[CH2:20][CH2:19]3)=[CH:10][CH:9]=2)[C:4]([S:7][C:22]([CH3:29])([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:5][N:6]=1
Reactant: Sc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Reactant: CCOC(=O)C(C)(C)Br
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)(C)Sc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Yield: 90.5 %

Procedure:
A solution of 5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol (50 mg, 0.144 mmol), ethyl 2-bromo-2-methylpropanoate (22 μL, 0.144 mmol) and diisopropylethylamine (76 μL, 0.433 mmol) in DMF (1 mL) was heated to 60° C. for 20 hours. The mixture was then concentrated, sonicated in ethyl ether until fully dissolved, and washed with 1N HCl. The mixture was extracted with diethyl ether (2×5 mL), and the combined organic extracts dried over sodium sulfate, filtered, and concentrated to provide ethyl 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoate as a brown oil (60 mg, 91%).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][C:6]1[CH:38]=[CH:37][C:9]([O:10][C:11]2[CH:12]=[CH:13][C:14]3[N:18]=[C:17]([CH2:19][O:20][C:21]4[CH:34]=[CH:33][C:24]([CH2:25][CH:26]5[S:30][C:29](=[O:31])[NH:28][C:27]5=[O:32])=[CH:23][CH:22]=4)[N:16]([CH3:35])[C:15]=3[CH:36]=2)=[CH:8][CH:7]=1.C(N(CC)CC)C.[CH:46]([C:49]1[CH:54]=[C:53]([CH:55]([CH3:57])[CH3:56])[CH:52]=[C:51]([CH:58]([CH3:60])[CH3:59])[C:50]=1[S:61]([Cl:64])(=[O:63])=[O:62])([CH3:48])[CH3:47]>CN(C)C=O>[ClH:64].[O:31]=[C:29]1[NH:28][C:27](=[O:32])[CH:26]([CH2:25][C:24]2[CH:33]=[CH:34][C:21]([O:20][CH2:19][C:17]3[N:16]([CH3:35])[C:15]4[CH:36]=[C:11]([O:10][C:9]5[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][NH:3][S:61]([C:50]6[C:51]([CH:58]([CH3:59])[CH3:60])=[CH:52][C:53]([CH:55]([CH3:57])[CH3:56])=[CH:54][C:49]=6[CH:46]([CH3:48])[CH3:47])(=[O:63])=[O:62])=[CH:38][CH:37]=5)[CH:12]=[CH:13][C:14]=4[N:18]=3)=[CH:22][CH:23]=2)[S:30]1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(CCN)cc3)cc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)c1cc(C(C)C)c(S(=O)(=O)NCCc2ccc(Oc3ccc4nc(COc5ccc(CC6SC(=O)NC6=O)cc5)n(C)c4c3)cc2)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 66.7 %

Procedure:
To a mixture of 5-[4-[6-[4-(2-aminoethyl)phenoxy]-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (0.3 g), triethylamine (0.17 g) and anhydrous N,N-dimethylformamide (10 ml) was added 2,4,6-triisopropylbenzenesulfonyl chloride (0.17 g) and the mixture was stirred at room temperature for 4.5 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. The residue was chromatographed on a silica gel column using ethyl acetate:n-hexane=2:1 as the eluant. To a solution of the product in ethyl acetate (15 ml) was added 4N hydrogen chloride in 1,4-dioxane (2 ml) and the mixture was stirred at room temperature for 20 minutes. The precipitate was isolated by filtration and washed with ethyl acetate to afford the title compound (0.28 g, mp 134-136° C.).
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C@@H:16]1([NH2:26])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1>>[CH:1]1([O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH2:11][NH:26][C@@H:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH2:17]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1cccc(OC2CCCCC2)c1
Reactant: N[C@H]1CCCc2ccccc21
Product: c1cc(CN[C@H]2CCCc3ccccc32)cc(OC2CCCCC2)c1

Procedure:
The product from Example 54A and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:35]=[CH:34][C:30]([CH:31]([OH:33])[CH3:32])=[CH:29][CH:28]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:27]3[CH:35]=[CH:34][C:30]([CH:31]([OH:33])[CH3:32])=[CH:29][CH:28]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(O)c1ccc(Br)cc1
Product: CC(O)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and commercially available 4-bromo-methylbenzylalcohol (181 mg, 1.0 mmol, [CAS 5391-88-8]) according to general procedure II. Obtained as an orange solid (115 mg, 24%). MS (ISP) 476.2 [(M+H)+]; mp 175-178° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[NH2:14][CH:15]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:30])[C:16]([N:18]1[CH2:22][CH2:21][S:20][CH2:19]1)=[O:17]>>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][CH:15]([NH:14][C:11]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)=[O:13])[C:16](=[O:17])[N:18]1[CH2:22][CH2:21][S:20][CH2:19]1
Reactant: NC(Cc1ccccc1Cl)C(=O)N1CCSC1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Product: O=C(NC(Cc1ccccc1Cl)C(=O)N1CCSC1)c1cc2cc(Cl)ccc2[nH]1

Procedure:
From 5-chloro-1H-indole-2-carboxylic acid and (±)-2-amino-3-(2-chloro-phenyl)-1-thiazolidin-3-yl-propan-1-one. mp 214-216° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[Br:19][C:20]1[S:24][C:23]([S:25](Cl)(=[O:27])=[O:26])=[CH:22][CH:21]=1>>[Br:19][C:20]1[S:24][C:23]([S:25]([NH:18][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[C:7]([F:8])[C:6]=2[NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])(=[O:27])=[O:26])=[CH:22][CH:21]=1
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Product: O=S(=O)(Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F)c1ccc(Br)s1

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene1,2-diamine was reacted with 5-bromothiophene-2-sulfonyl chloride to obtain the title compound. 1H NMR (300 MHz, CDCl3): δ 7.39-7.29 (m, 2H), 7.20-7.05 (m, 3H), 6.96 (d, J=3.6 Hz, 1H), 5.85(dt, J=2.1, 9.0 & 17.4 Hz, 1H), 5.54 (br s, 1H).
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:14][CH:13]([C:15]2[N:19]3[C:20]4[CH:26]=[CH:25][N:24](S(C5C=CC(C)=CC=5)(=O)=O)[C:21]=4[N:22]=[CH:23][C:18]3=[N:17][N:16]=2)[CH:12]([CH2:37][CH3:38])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-]#N.[K+]>CO>[C:1]([O:9][CH:10]1[CH2:14][CH:13]([C:15]2[N:19]3[C:20]4[CH:26]=[CH:25][NH:24][C:21]=4[N:22]=[CH:23][C:18]3=[N:17][N:16]=2)[CH:12]([CH2:37][CH3:38])[CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC1CC(OC(=O)c2ccccc2)CC1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Product: CCC1CC(OC(=O)c2ccccc2)CC1c1nnc2cnc3[nH]ccc3n12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl benzoate (5.00 g, 7.84 mmol, prepared from Example #4 Step J using II with benzoic acid, and B) in MeOH (16 mL) was added a solution of potassium cyanide (0.74 mL, 17.2 mmol) in MeOH (16 mL). The reaction was stirred at ambient temperature for about 16 h. The reaction mixture was concd under reduced pressure to afford a residue. The residue was partitioned between water (20 mL) and DCM (20 mL). The layers were separated and the aqueous layer was extracted with DCM (3×10 mL). The extract was then washed with saturated aqueous NaHCO3, dried over anhydrous MgSO4, filtered, and concd under reduced pressure to afford a crude oil. The crude material was purified by silica gel chromatography eluting with a gradient of 0-10% MeOH in DCM to 3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl benzoate (2.30 g, 78%) as a red tinted solid. LC/MS (Table 1, Method a) Rt=2.08 min; MS m/z: 376 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][CH3:17])[C:11]=2[C:18]#[C:19][C:20]2[CH:21]=[N:22][C:23]([NH2:26])=[CH:24][CH:25]=2)=[CH:6][C:5]=1[F:27].[OH-].[Na+]>C1COCC1>[NH2:26][C:23]1[N:22]=[CH:21][C:20]([C:19]#[C:18][C:11]2[C:12]([CH2:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:28])=[O:2])=[C:5]([F:27])[CH:6]=2)=[CH:25][CH:24]=1
Reactant: CCc1nccc(-c2ccc(C(=O)OC)c(F)c2)c1C#Cc1ccc(N)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1nccc(-c2ccc(C(=O)O)c(F)c2)c1C#Cc1ccc(N)nc1
Temperature: 95 °C
Reaction time: 2 h

Procedure:
The title compound is synthesized according to general procedure GP4 starting from 2.36 g (6.3 mmol) 4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-benzoic acid methyl ester (A-37) using 9.4 mL (9.4 mmoL) 1N NaOH in 40 mL THF. The reaction mixture is stirred for 2 h at 95° C. The solvent is removed under reduced pressure, the crude product is taken up with water and the pH is adjusted to 5 (with 1N HCl). The precipitate is collected by filtration. Yield after drying: 2.2 g (97%).
Reaction SMILES: C1CO[C:3]2([CH2:8][CH2:7][CH:6]([C:9]#[C:10][CH2:11][CH2:12][CH3:13])[CH2:5][CH2:4]2)[O:2]1.N.[Na]>O1CCCC1>[CH:9](/[CH:6]1[CH2:5][CH2:4][C:3](=[O:2])[CH2:8][CH2:7]1)=[CH:10]\[CH2:11][CH2:12][CH3:13]
Reactant: CCCC#CC1CCC2(CC1)OCCO2
Agent: N
Agent: [Na]
Solvent: C1CCOC1
Product: CCC/C=C/C1CCC(=O)CC1
Reaction time: 8 h
Yield: 83.5 %

Procedure:
A solution of 4.5 g of 1,1-ethylenedioxy-4-(1-pentynyl)cyclohexane in 54 ml of tetrahydrofuran was treated dropwise with about 50 ml of pre-condensed ammonia in a sulphonation flask provided with a magnetic stirrer. The mixture was subsequently treated portionwise at -78° C. within 7 hours with 1.3 g of sodium. 1.5 hours after the last addition the ammonia was removed by evaporation and the mixture was neutralized with 25% hydrochloric acid and left to stand overnight. The mixture was then partitioned three times in water/diethyl ether. The aqueous phases were back-extracted with diethyl ether. The organic phases were dried over magnesium sulphate and then freed from solvent on a rotary evaporator. The resulting, pale yellow liquid (3.8 g) was treated with 200 ml of acetone and 0.1 ml of concentrated sulphuric acid. The mixture was heated to reflux for 10 minutes, then treated with water and freed from acetone on a rotary evaporator. The residue was partitioned three times in methylene chloride/water. The aqueous phases were back-extracted with methylene chloride. The organic phases were dried over magnesium sulphate and evaporated. Chromatographic separation of the resulting, yellow liquid (3.5 g) on silica gel with ethyl acetate/petroleum ether (vol. 7:93) gave 3.0 g (83.5%) of 4-(trans-1-pentenyl)cyclohexanone as a pale yellow liquid.
Reaction SMILES: C([Li])CCC.[CH:6]1[C:14]2[C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[O:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[C:19](=[O:21])=[O:20]>CCCCCC.C1COCC1.C(OCC)C.[OH-].[Na+]>[CH:6]1[C:14]2[C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[O:11][C:10]=2[C:9]([C:19]([OH:21])=[O:20])=[CH:8][CH:7]=1
Reactant: c1ccc2c(c1)oc1ccccc12
Reactant: O=C=O
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: O=C(O)c1cccc2c1oc1ccccc12
Temperature: 20 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
A solution of 1.6M n-butyllithium in hexane (18.5 ml) was added dropwise to a stirred solution of dibenzofuran (5.0 g) in anhydrous THF (25 ml) at −78° C. under a nitrogen atmosphere. The resulting suspension was allowed to warm to 20° C. where it was stirred for 3 h. It was then cooled to −78° C. and added to a mixture of excess solid carbon dioxide in diethyl ether (250 ml) under a nitrogen atmosphere. The resulting white suspension was allowed to stand for 1 h at 20° C. and was then diluted with 2M sodium hydroxide (500 ml). The aqueous extract was washed with ether (3×200 ml), acidified to pH 1 with 6M hydrochloric acid and extracted with ethyl acetate (3×200 ml). The combined organic extracts were washed with brine (50 ml), dried over magnesium sulphate and evaporated in vacuo to give the title compound as a white solid (3.64 g, 58%). LCMS: Rt 5.06 min; m/z 213 (MH+).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C@@H:7]2[CH2:9][C@H:8]2[CH:10]([NH:12][O:13][CH3:14])[CH3:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:22][N:23]1[CH:27]=[C:26]([C:28](Cl)=[O:29])[C:25]([C:31]([F:34])([F:33])[F:32])=[N:24]1>ClCCl.O>[Cl:1][C:2]1[S:6][C:5]([CH:7]2[CH2:9][CH:8]2[CH:10]([N:12]([O:13][CH3:14])[C:28]([C:26]2[C:25]([C:31]([F:34])([F:33])[F:32])=[N:24][N:23]([CH3:22])[CH:27]=2)=[O:29])[CH3:11])=[CH:4][CH:3]=1
Reactant: CONC(C)[C@@H]1C[C@H]1c1ccc(Cl)s1
Reactant: Cn1cc(C(=O)Cl)c(C(F)(F)F)n1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C(=O)c1cn(C)nc1C(F)(F)F)C(C)C1CC1c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.8 %

Procedure:
To a stirred solution of trans N-{1-[2-(5-chloro-thiophen-2-yl)-cyclopropyl]-ethyl}-O-methyl-hydroxylamine (0.19 g; 0.83 mmol) prepared as described in example P18 and triethylamine (0.16 ml; 1.08 mmol) in dichloromethane (5.0 ml) at ambient temperature was added dropwise 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl chloride (0.18 g; 0.83 mmol). The reaction mixture was stirred for 16 hours at ambient temperature then poured in water (3 ml) and extracted with dichloromethane (3×1 ml). Combined organic layers were washed with water (1 ml) and dried over anhydrous sodium sulphate. The solvent was removed in vacuo and the residue was purified by flash chromatography over silica gel (elution gradient: cyclohexane/ethyl acetate 99:1 to 30:70) to afford 0.26 g (79% of theory) of 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid {1-[2-(5-chloro-thiophen-2-yl)-cyclopropyl]-ethyl}-methoxy-amide as a resin.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([OH:23])=O)[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[CH3:56][N:57]([CH3:73])[CH:58]1[CH2:62][CH2:61][N:60]([CH2:63][C:64]2[CH:69]=[CH:68][C:67]([CH2:70][NH:71][CH3:72])=[CH:66][CH:65]=2)[CH2:59]1>C(Cl)Cl>[CH3:73][N:57]([CH3:56])[CH:58]1[CH2:62][CH2:61][N:60]([CH2:63][C:64]2[CH:69]=[CH:68][C:67]([CH2:70][N:71]([CH3:72])[C:21]([C:18]3[CH:17]=[C:16]([CH2:15][N:13]([S:10]([C:6]4[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[CH3:24])(=[O:11])=[O:12])[CH3:14])[O:20][CH:19]=3)=[O:23])=[CH:66][CH:65]=2)[CH2:59]1
Reactant: CNCc1ccc(CN2CCC(N(C)C)C2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)Cc3ccc(CN4CCC(N(C)C)C4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 5-{[(4-methoxy-2,6-dimethyl-benzenesulfonyl)-methyl-amino]-methyl}-furan-3-carboxylic acid (35 mg, 0.10 mmol), EDCI (27 mg, 0.14 mmol), HOBt (20 mg, 0.15 mmol), DIPEA (0.03 mL, 0.20 mmol), dimethyl-[1-(4-methylaminomethyl-benzyl)-pyrrolidin-3-yl]-amine hydrochloride (30 mg, 0.09 mmol) and DCM (10 mL).
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:12][NH:13][OH:14].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:14][N:13]([CH3:12])[C:8](=[O:9])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CNO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(O)C(=O)Cc1ccccc1

Procedure:
At 0° C. phenyl-acetyl chloride (11.2 mL) is added drop wise to a solution of N-methyl-hydroxylamine hydrochloride (7.07 g) and triethylamine (59 mL) in DCM (300 mL). After stirring for 90 min a sat. aqueous NaHCO3 solution is added, the layers are separated and the aqueous layer is extracted twice with DCM (2×200 mL). The solvents are removed in vacuo and the residue is purified by flash chromatography (EA/heptane 1/1) to give the desired N-hydroxy-acetamide as a colorless liquid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([CH:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]#[N:20])[CH:12]=1)(C)(C)C.Cl>O1CCOCC1>[NH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([CH:18]([CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:19]#[N:20])[CH:12]=1
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(F)c(C(C#N)Cc2ccccc2)c1
Agent: Cl
Solvent: C1COCCO1
Product: N#CC(Cc1ccccc1)c1cc(OCCN)ccc1F
Temperature: 25 °C

Procedure:
To {2-[3-(benzyl-cyano-methyl)-4-fluoro-phenoxy]-ethyl}-carbamic acid tert-butyl ester (7 g, 18.21 mmol) was added 25 ml of a 4 N hydrochloric acid solution in dioxane and stirred at room temperature over night. Solvents were evaporated, 2 N sodium hydroxide was added, which was extracted twice with dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated to obtain the free amine as a brown oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>>[N:11]1([CH2:10][CH2:9][N:1]2[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C1CCNCC1
Reactant: ClCCN1CCCC1
Product: O=C1CCN(CCN2CCCC2)CC1

Procedure:
1-(2-(1-Pyrrolidinyl)ethyl)-4-piperidone is prepared from 4-piperidone and 1-(2-chloroethyl)pyrrolidine essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH:5]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.S(OCC)(O[CH2:21][CH3:22])(=O)=O>>[CH2:21]([O:1][CH2:2][CH2:3][O:4][CH:5]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:22]
Reactant: CCOS(=O)(=O)OCC
Reactant: OCCOC1CCCCCCCCCCC1
Product: CCOCCOC1CCCCCCCCCCC1

Procedure:
The 2-ethoxyethyl-cyclododecyl-ether was prepared in correspondence with the description of Example 1 from 114 g (0.5 mol) of 2-hydroxyethyl-cyclododecyl-ether and 54 g (0.35 mol) of diethyl sulfate.