Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:8]=[C:9]([C:13]#[C:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])[CH:10]=[N:11][CH:12]=1.CN(C)[CH:25]=[O:26]>O1CCCC1.C(OCC)(=O)C>[CH:25]([C:7]1[CH:8]=[C:9]([C:13]#[C:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])[CH:10]=[N:11][CH:12]=1)=[O:26]
Reactant: CN(C)C=O
Reactant: N#Cc1cccc(C#Cc2cncc(Br)c2)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1cccc(C#Cc2cncc(C=O)c2)c1
Reaction time: 1 h
Yield: 37 %

Procedure:
Add a 2 M solution of isopropylmagnesium chloride in tetrahydrofuran (220 mg, 2.12 mmol) to a −20° C. solution of 3-(5-bromopyridin-3-ylethynyl)-benzonitrile, (prepared essentially as described in PREPARATION 19), (300 mg, 1.06 mmol) in tetrahydrofuran (2 mL) and stir for 1 h. Add N,N-dimethylformamide (150 mg, 2.12 mmol) in one portion, warm to room temperature, dilute with ethyl acetate and an aqueous saturated solution of sodium bicarbonate and separate the layers. Dry (magnesium sulfate), filter and concentrate. Purify by silica gel chromatography, eluting with 0:100 to 60:40 tetrahydrofuran:hexanes to give the title compound (92 mg, 37%).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]/[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[S:9][CH:10]=1)C.[OH-].[Na+]>C1COCC1>[O:30]=[C:12]([NH:11][C:8]1[S:9][CH:10]=[C:6]([CH2:5][C:4]([OH:31])=[O:3])[N:7]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]/[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCC/C=C/CCCCCCCC(=O)Nc1nc(CC(=O)OCC)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCCC/C=C/CCCCCCCC(=O)Nc1nc(CC(=O)O)cs1
Reaction time: 15 h
Yield: 66 %

Procedure:
A mixture of the above ester (7.4 g, 16.5 mmol) and sodium hydroxide (1.44 g, 36.1 mmol) was combined in THF (150 mL) and cooled in ice under N2 atmosphere. Enough distilled water was added portionwise until the hydroxide was dissolved (~15 mL) and the mixture was maintained at 0° for 2 h, then allowed to warm to ambient temperatures with stirring for 15 h. The reaction mixture was evaporated in vaccuo, the residue cooled in ice and treated with 2M aqueous HCl solution with stirring. The whim precipitate was collected by vacuum filtration, washed with water and air dried. This material was crystallized from boiling heptane, filtered hot, and dried overnight on an abderhalden apparatus (refluxing acetone) to give 4.6 g of the title compound as a white powder, mp 116°-118° C.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.Cl[CH2:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:27][C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: ClCc1ccncc1
Agent: Cl
Product: Clc1ccc(-c2nn(Cc3ccncc3)c3c2CCNCC3)cc1
Yield: 19.7 %

Procedure:
The title compound (0.02 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.3 mmol) using 4-chloromethyl-pyridine hydrogen chloride (0.5 mmol) in place of 2-chloromethyl-thiophene. MS (ESI): exact mass calculated for C19H19ClN4, 338.13; found, m/z 339.3 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.49-8.48 (m, 2H), 7.43-7.41 (m, 2H), 7.33-7.31 (m, 2H), 6.90-6.89 (m, 2H), 5.28 (s, 2H), 2.92-2.87 (m, 2H), 2.75-2.73 (m, 1H), 2.66-2.64 (m, 1H).
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1)[CH3:2].[Li]CCCC.[N+:20]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=[O:27])([O-:22])=[O:21].[NH4+].[Cl-]>C1COCC1.C1(C)C=CC=CC=1.C1COCC1>[OH:27][CH:26]([C:25]1[CH:28]=[CH:29][CH:30]=[C:23]([N+:20]([O-:22])=[O:21])[CH:24]=1)[C:8]1[CH:9]=[CH:10][C:5]([C:4]([N:3]([CH2:13][CH3:14])[CH2:1][CH3:2])=[O:12])=[CH:6][CH:7]=1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CCN(CC)C(=O)c1ccc(I)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc(C(O)c2cccc([N+](=O)[O-])c2)cc1
Temperature: -78 °C
Yield: 49.5 %

Procedure:
N,N-Diethyl-4-iodobenzamide (5.0 g, 16 mmol) was dissolved in THF (150 mL) and cooled to −78° C. under nitrogen atmosphere. n-BuLi (15 mL, 1.07 M solution in hexane, 16 mmol) was added dropwise during 10 min at −65 to −78° C. The solution was then canulated into 3-nitrobenzaldehyde (2.4 g, 16 mmol) in toluene/THF (approx. 1:1, 100 mL) at −78° C. NH4Cl (aq.) was added after 30 min. After concentration in vacuo, extraction with EtOAc/water, drying (MgSO4) and evaporation of the organic phase, the residue was purified by chromatography on silica (0-75% EtOAc/heptane) to give INTERMEDIATE 2 (2.6 g, 50%). 1H NMR (CDCl3) δ 1.0-1.3 (m, 6H), 3.2, 3.5 (2m, 4H), 5.90 (s, 1H), 7.30-7.40 (m, 4H), 7.50 (m, 1H), 7.70 (d, J=8 Hz, 1H), 8.12 (m, 1H), 8.28 (m, 1H).
Reaction SMILES: [CH3:1][N:2]([C:22]1[CH:27]=[N:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=1)[C@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[N:20]=[CH:19][CH:18]=[N:17]1.CN(C1C=NC(C(F)(F)[F:47])=CN=1)[C@H]1CCC[C@@H]1N.FC1C=CC(N2N=CC=N2)=C(C=1)C(O)=O>>[F:47][C:14]1[CH:13]=[CH:12][C:11]([N:16]2[N:20]=[CH:19][CH:18]=[N:17]2)=[C:10]([CH:15]=1)[C:9]([NH:8][C@H:4]1[CH2:5][CH2:6][CH2:7][C@@H:3]1[N:2]([CH3:1])[C:22]1[CH:27]=[N:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][N:23]=1)=[O:21]
Reactant: CN(c1cnc(C(F)(F)F)cn1)[C@H]1CCC[C@@H]1N
Reactant: CN(c1cnc(C(F)(F)F)cn1)[C@H]1CCC[C@@H]1NC(=O)c1ccccc1-n1nccn1
Agent: O=C(O)c1cc(F)ccc1-n1nccn1
Product: CN(c1cnc(C(F)(F)F)cn1)[C@H]1CCC[C@@H]1NC(=O)c1cc(F)ccc1-n1nccn1

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-{methyl[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 73) from (1S,2S)-1-N-methyl-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine (Intermediate 22; 59 mg, 0.23 mmol) and 5-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 8; 56 mg, 0.27 mmol) to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]3[NH:13][CH:14]=[CH:15][C:5]=3[C:4]=2[CH:3]=1.[CH2:16]([C:18]([O-:20])=[O:19])[CH3:17].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>>[CH3:21][S:22]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]3[NH:13][CH:14]=[CH:15][C:5]=3[C:4]=2[CH:3]=1)(=[O:24])=[O:23].[CH2:16]([C:18]([O-:20])=[O:19])[CH3:17]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Agent: CCC(=O)[O-]
Product: CS(=O)(=O)Nc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Yield: 46 %

Procedure:
This compound is prepared according to synthesis 37, from 50 mg (0.18 mmol) of 8-amino-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate (synthesis 64) and 17 μL (0.20 mmol) of methanesulfonyl chloride. After recrystallization from methanol, 29 mg (45%) of 8-methanesulfonylamino-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a white solid.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:15][S:16](Cl)(=[O:18])=[O:17].O>N1C=CC=CC=1>[CH3:15][S:16]([O:10][CH2:9][CH:8]([CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:11][CH2:12][CH2:13][CH3:14])(=[O:18])=[O:17]
Reactant: CCCCC(CO)CC1CCCCC1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCC(COS(C)(=O)=O)CC1CCCCC1

Procedure:
A solution of 2-(cyclohexylmethyl)hexan-1-ol (1.3 g) in 10 ml of dry pyridine under nitrogen was cooled to 0° C. and treated dropwise with stirring with 1.0 g of methanesulfonyl chloride. After 1 hour the mixture was poured into water and extracted with ethyl acetate. The extracts were washed twice with dilute hydrochloric acid, once with brine and dried (MgSO4). Evaporation of the solvent gave an oil, 2-(cyclohexylmethyl)hex-1-yl methanesulfonate, which was used directly in the next step.
Reaction SMILES: C([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:29])[C:14]=2[NH:18][C:19](=[O:28])[CH2:20][CH:21]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:9]1=[O:30])[CH3:7])(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>O>[CH:21]1([CH2:20][C:19]([NH:18][C:14]2[C:13]([CH3:29])=[CH:12][CH:11]=[C:10]3[C:15]=2[CH:16]=[CH:17][N:8]([C@H:6]([CH3:7])[CH2:5][OH:4])[C:9]3=[O:30])=[O:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC(=O)OC[C@@H](C)n1ccc2c(NC(=O)CC3CCCCCC3)c(C)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1ccc2c(=O)n([C@H](C)CO)ccc2c1NC(=O)CC1CCCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A round bottom flask was charged with (R)-2-(5-(2-cycloheptylacetamido)-6-methyl-1-oxoisoquinolin-2(1H)-yl)propyl acetate (180.0 mg, 0.0004363 mol), potassium carbonate (180 mg, 0.0013 mol), methanol (15 mL, 0.37 mol) and few drops of water. The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and water was added to the residue and extracted with (chloroform:IPA, 3:1) and the solvent removed under reduced pressure and the residue purified by reverse phase prep BPLC to afford the product as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH2:10][OH:11])[CH:9]=1)[C:5]#[N:6].Cl[C:13]1[CH:23]=[C:17]2[N:18]([CH3:22])[CH2:19][CH2:20][CH2:21][N:16]2[C:15](=[O:24])[N:14]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH2:10][O:11][C:13]2[CH:23]=[C:17]3[N:18]([CH3:22])[CH2:19][CH2:20][CH2:21][N:16]3[C:15](=[O:24])[N:14]=2)[CH:9]=1)[C:5]#[N:6]
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: N#Cc1cc(F)cc(CO)c1
Product: CN1CCCn2c1cc(OCc1cc(F)cc(C#N)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from 3-fluoro-5-(hydroxymethyl)benzonitrile and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:8](=[N:10][OH:11])[NH2:9])[NH:5][C:6]=1[Cl:7].C(N(CC)CC)C.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>O1CCOCC1>[C:19]([O:11][N:10]=[C:8]([C:4]1[NH:5][C:6]([Cl:7])=[C:2]([Cl:1])[N:3]=1)[NH2:9])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC(=NO)c1nc(Cl)c(Cl)[nH]1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: NC(=NOC(=O)c1ccccc1)c1nc(Cl)c(Cl)[nH]1
Temperature: 50 °C
Reaction time: 2 h
Yield: 60.2 %

Procedure:
19.5 g (0.1 mol) of 4,5-dichloro-imidazole-2-carbamide-oxime and 10.1 g (0.1 mol) of triethylamine were dissolved in 150 ml of dioxane. 14.05 g (0.1 mol) of benzoyl chloride were added dropwise to this solution at 15°-20° C. The mixture was stirred for a further 1 hour at room temperature and for 2 hours at 50° C. and was then introduced into 500 ml of water. The crystals which had separated out were filtered off, washed with water and dried. 18 g (60.2% of theory) of 4,5-dichloro-imidazole-2-carbamide-O-benzoyl-oxime were obtained. Melting point: 177°-178° C. (from toluene).
Reaction SMILES: [CH2:1]([SH:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([C:10]1[O:11][CH2:12][CH2:13][N:14]=1)[CH3:9]>>[CH2:1]([S:7][CH2:12][CH2:13][NH:14][C:10](=[O:11])[CH2:8][CH3:9])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC1=NCCO1
Reactant: SCc1ccco1
Product: CCC(=O)NCCSCc1ccco1

Procedure:
In this example furfurylmercaptan and 2-ethyl-2-oxazoline are reacted to form N-furfurylthioethylpropionamide. Furfurylmercaptan (13.04 grams, 0.11 mols) is heated under nitrogen to 155° C. in a flask. 2-Ethyl-2-oxazoline (11.4 grams, 0.115 mols) is slowly added from a dropping funnel over a period of two hours. The mixture is post-reacted at 155° C. for an additional 11/2 hours. The product is isolated by distillation at reduced pressure: BP 136°-137° C. at 0.2 millimeters Hg. The spectral and elemental analyses correspond to those of the N-furfurylthioethylpropionamide mentioned above. Analysis for the crude reaction mixture by internal standard gas/liquid chromatography shows 1.7 weight percent 2-ethyl-2-oxazoline, 0.8 weight percent furfurylmercaptan and 95.8 weight percent N-(2-furfurylthioethyl)propionamide. This is a reaction yield based on starting materials of 96 percent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:14][O:15][CH2:16][CH:17]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]3)=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.F[C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH:26]=[O:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:14][O:15][CH2:16][CH:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:24]4[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=4[CH:26]=[O:27])[CH2:18]3)=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1COCC1CCCNC1
Reactant: O=Cc1ccccc1F
Product: Cc1nc(-c2ccc(Cl)cc2)sc1COCC1CCCN(c2ccccc2C=O)C1
Yield: 32.5 %

Procedure:
Using 3-[[2-(4-chlorophenyl)-4-methylthiazol-5-yl]methoxymethyl]piperidine (106 mg, 0.315 mmol) and 2-fluorobenzaldehyde (0.0329 mL, 0.315 mmol), the same procedure was followed as in Step 1c of Example 1 to give 45.2 mg (32%) of the desired compound as a colorless oil.
Reaction SMILES: [C:1]([S:5]([NH:7][C:8]1([CH:12]([CH2:16][CH3:17])[C:13]([OH:15])=[O:14])[CH2:11][O:10][CH2:9]1)=[O:6])([CH3:4])([CH3:3])[CH3:2].Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=1)=[O:21]>>[C:1]([S:5]([NH:7][C:8]1([CH:12]([CH2:16][CH3:17])[C:13]([O:15][CH2:19][C:20](=[O:21])[C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:30])([F:31])[F:32])=[CH:24][CH:23]=2)=[O:14])[CH2:9][O:10][CH2:11]1)=[O:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(C(=O)O)C1(NS(=O)C(C)(C)C)COC1
Reactant: O=C(CBr)c1ccc(OC(F)(F)F)cc1
Product: CCC(C(=O)OCC(=O)c1ccc(OC(F)(F)F)cc1)C1(NS(=O)C(C)(C)C)COC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.1 %

Procedure:
Prepared by Method E using 2-{3-[(tert-butylsulfinyl)amino]oxetan-3-yl}butanoic acid (Preparation 27, 2.658 g, 10.1 mmol) and 2-bromo-1-[4-(trifluoromethoxy)phenyl]-ethanone (3.14 g, 11.1 mmol). The reaction was stirred at room temperature for 3 hours. The residue was purified by silica gel column chromatography to afford the title compound (3.435 g, 73% yield).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[C:19]([C@H:22]1[O:30][C@H:29]2[C@H:25]([N:26]=[C:27]([N:31]([CH3:39])[C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[S:28]2)[C@@H:24]([O:40][CH2:41][CH:42]=[CH2:43])[C@@H:23]1[O:44][CH2:45][CH:46]=[CH2:47])(=[O:21])[CH3:20].[Si]([C:52]([F:55])([F:54])[F:53])(C)(C)C>C1COCC1>[CH2:45]([O:44][C@@H:23]1[C@@H:22]([C@@:19]([OH:21])([CH3:20])[C:52]([F:55])([F:54])[F:53])[O:30][C@H:29]2[C@H:25]([N:26]=[C:27]([N:31]([CH3:39])[C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:36])[CH3:37])[S:28]2)[C@H:24]1[O:40][CH2:41][CH:42]=[CH2:43])[CH:46]=[CH2:47]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: C=CCO[C@@H]1[C@H]2N=C(N(C)C(=O)OC(C)(C)C)S[C@H]2O[C@H](C(C)=O)[C@H]1OCC=C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCO[C@@H]1[C@H]2N=C(N(C)C(=O)OC(C)(C)C)S[C@H]2O[C@H]([C@](C)(O)C(F)(F)F)[C@H]1OCC=C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
A mixture of TBAF (3.7 g, 14 mmol) and 4 Å molecule sieves in THF (200 mL) was stirred for 30 min at 0° C. followed by the addition of a solution of 118 (15 g, 35 mmol) and TMS-CF3 (20 g, 141 mmol) in THF (80 mL). After stirring for additional 12 hours at 25° C., additional TBAF (14 g, 54 mmol) was added, and the mixture was stirred for 1 hour. The reaction was quenched by brine (200 mL), extracted with ethyl acetate (3×150 mL), the organic layers combined, washed with brine (3×100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue, which was purified by a silica gel column, eluted with 5%-25% ethyl acetate in petroleum ether to afford 119 (12 g, 69%) as a yellow oil; (ES, m/z) [M+H]+ 497.1. 1H NMR (300 MHz, CDCl3) δ 6.12-6.18 (m, 1H), 5.86-6.00 (m, 2H), 5.19-5.37 (m, 4H), 4.02-4.45 (m, 6H), 3.92-3.96 (m, 1H), 3.62-3.64 (m, 1H), 3.25 (d, J=3.6 Hz, 3H), 1.54-1.56 (m, 9H), 1.27-1.38 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]\[C:10]2[CH:15]=[CH:14][C:13]([S:16]([N:19]3[CH2:24][CH2:23][C:22]4[O:25][CH:26]=[CH:27][C:21]=4[CH2:20]3)(=[O:18])=[O:17])=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:28][NH:29][CH3:30].[CH2:31]=O>C(O)(=O)C>[CH3:28][N:29]([CH2:31][C:26]1[O:25][C:22]2[CH2:23][CH2:24][N:19]([S:16]([C:13]3[CH:14]=[CH:15][C:10](/[CH:9]=[CH:8]\[C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)=[CH:11][CH:12]=3)(=[O:17])=[O:18])[CH2:20][C:21]=2[CH:27]=1)[CH3:30]
Reactant: CNC
Reactant: C=O
Reactant: O=S(=O)(c1ccc(/C=C\c2cccc(Cl)c2)cc1)N1CCc2occc2C1
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CCN(S(=O)(=O)c1ccc(/C=C\c3cccc(Cl)c3)cc1)C2
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.693 g (1.733 mmol) of (Z)-5-(3-chlorostilbene-4'-sulfonyl)-4,5,6,7-tetrahydrofuro[3,2-c]pyridine in 10 ml of acetic acid, 0.23 g (2.60 mmol) of 50% aqueous dimethylamine and 0.21 g (2.60 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 0.5 hours. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with ethyl acetate 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=4/1); the resulting solid was washed with diethyl ether to yield the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][C:10]=1[CH2:11][N:12]([C:20]1[N:25]=[N:24][C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:21]=1)C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][C:10]=1[CH2:11][NH:12][C:20]1[N:25]=[N:24][C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(N(Cc2cc(Br)ccc2OCc2ccccc2)C(=O)OC(C)(C)C)nn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NCc2cc(Br)ccc2OCc2ccccc2)nn1
Reaction time: 18 h
Yield: 92 %

Procedure:
A mixture of ethyl 6-[N-(2-benzyloxy-5-bromobenzyl)-N-(tert-butoxycarbonyl)amino]-3-pyridazinecarboxylate (2.0 g) and trifluoroacetic acid (25 ml) in CH2Cl2 (25 ml) was allowed to stand for 18 hours. The solvents were evaporated, the residue dissolved in CH2Cl2 and washed with dilute aqueous Na2CO3 solution, dried (MgSO4) and evaporated to give ethyl 6-[2-benzyloxy-5-bromobenzylamino]-3-pyridazinecarboxylate as a solid (1.5 g).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[H-].[Na+].Br[CH2:20][C:21]1[N:22]=[CH:23][S:24][CH:25]=1>CN(C)C=O.C1(C)C=CC=CC=1>[CH2:7]([O:6][P:4]([CH:9]([CH2:20][C:21]1[N:22]=[CH:23][S:24][CH:25]=1)[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: BrCc1cscn1
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)C(Cc1cscn1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 35 %

Procedure:
To a solution of tert-butyl diethylphosphonoacetate (15.6 g, 62 mmol) in dimethylformamide (50 mL) was added sodiumhydride (60% dispersion in mineral oil, 2.48 g, 62 mmol) at 0° C. under nitrogen atmosphere. After 45 min, to the mixture was added a solution of 4-(bromomethyl)-1,3-thiazole in toluene (27 g). The mixture was stirred at room temperature overnight. The mixture was quenched with water and extracted with toluene/ethyl acetate (1/3). The combined organic layer washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (1/2 to 100% ethyl acetate) to afford 7.17 g (35%) of the title compound as a colorless oil:
Reaction SMILES: C([NH:4][C:5]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[CH3:17])(=O)C>Cl>[NH2:4][C:5]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[CH3:17]
Reactant: CC(=O)Nc1c(C)cc(C(=O)O)cc1[N+](=O)[O-]
Agent: Cl
Product: Cc1cc(C(=O)O)cc([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
A suspension of 4-acetamido-3-methyl-5-nitrobenzoic acid (38 g, 0.16 mol) in 3N hydrochloric acid (800 mL) was heated at reflux for 8 h and then stirred at room temperature for 8 h. The yellow solid was collected by filtration and transferred to a 2 L flask with a mixture of methylene chloride and methanol. The solvent was evaporated under high vacuum to give the title compound (23 g, 74% yield). 1H-NMR (DMSO-d6, 300 MHz) δ 12.79 (bs, 1H), 8.46 (s, 1H), 7.79 (s, 1H), 7.61 (s, 2H), 2.34 (s, 3H). 13C-NMR (d6-DMSO, 75 MHz) δ 166.0, 147.0, 135.1, 130.0, 126.4, 125.9, 116.7, 17.9. LC/MS: tR=1.23 min, 195 (MH)−
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH:7]=[C:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[NH:11][C:10]([CH3:17])([CH3:16])[CH2:9]2)=[C:5]([N+:20]([O-:22])=[O:21])[CH:4]=1.C=O.[C:25]([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>CO.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH:7]=[C:8]2[CH2:9][C:10]([CH3:17])([CH3:16])[N:11]([CH3:25])[C:12]([CH3:14])([CH3:15])[CH2:13]2)=[C:5]([N+:20]([O-:22])=[O:21])[CH:4]=1
Reactant: COc1ccc(C=C2CC(C)(C)NC(C)(C)C2)c([N+](=O)[O-])c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(C=C2CC(C)(C)N(C)C(C)(C)C2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.1 %

Procedure:
4-(4-methoxy-2-nitrobenzylidene)-2,2,6,6-tetramethylpiperidine (1.1 g; 3.23 mmol; 1 eq) is dissolved in MeOH (10 mL) then formaldehyde (0.19 g; 6.45 mmol; 2 eq) and sodium cyanoborohydride (0.41 g; 6.45 mmol; 2 eq) are added. The reaction mixture is stirred at room temperature overnight. The solvents are evaporated under reduced pressure and the residue obtained is taken up in EtOAc then a saturated aqueous solution of NaHCO3 is added. The organic phase is washed with brine, dried over MgSO4 and the solvent is evaporated under reduced pressure to afford 320 mg (31%) of the title compound as a yellow oil. 1H NMR (DMSO-d6) δ 7.53 (d, J=2.6 Hz, 1H), 7.20 (d, J=8.2 Hz, 1H), 7.10 (dd, J=8.6, 2.6 Hz, 1H), 6.49 (s, 1H), 3.87 (s, 3H), 2.22-2.15 (m, 6H), 1.20-1.10 (m, 6H), 1.00-0.90 (m, 6H). HPLC (max plot) 99.5%; Rt 2.84 min. LC/MS: (ES+): 319.1
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH2:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.C([O:38][C@@H:39]([CH3:43])[C:40](Cl)=[O:41])(=O)C>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[CH:24][C:25]([CH2:27][CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:34])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:40](=[O:41])[C@@H:39]([OH:38])[CH3:43])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)[C@H](C)O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-ethylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f50) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.