Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([C:8]1([CH3:34])[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([C:20]#[N:21])[CH:10]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:9]1)=[O:7])(C)(C)C.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>ClCCl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[Cl:19][C:15]1[CH:14]=[C:13]([CH:12]2[C:11]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:10]([CH2:29][C:30]([CH3:31])([CH3:32])[CH3:33])[NH:9][C:8]2([CH3:34])[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)CC1NC(C)(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C)(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 98 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-2-methyl-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 33b (1 g, 2 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-2-methyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.1 g, 98%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([CH2:12][CH:13]=[CH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N+]([O-])=O)[CH:16]=3)[CH2:8][CH2:9][C:10]=2[N:11]=1.C[N:25](C)C=O>[Ni]>[NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([CH2:12][CH:13]=[CH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[NH2:25])[CH2:8][CH2:9][C:10]=2[N:11]=1
Reactant: CN(C)C=O
Reactant: Nc1nc2c(s1)CCN(CC=Cc1cccc([N+](=O)[O-])c1)CC2
Agent: [Ni]
Product: Nc1nc2c(s1)CCN(CC=Cc1ccccc1N)CC2

Procedure:
Prepared by catalytic hydrogenation of 2-amino-6-(3-(3-nitro-phenyl)allyl)-4,5,7,8-tetrahydro-6H- thiazolo[5,4-d]azepine using Raney nickel in anhydrous dimethylformamide (4.5 hours at ambient temperature). After purification by column chromatography the base is dissolved in isopropanol. By the addition of ethereal hydrochloric acid, cooling, filtering and drying at 100° C./0.1 torr over phosphorus pentoxide the title compound is obtained. Yield: 37% of theory, Melting point: 160° C. (decomp.).
Reaction SMILES: [Na].Cl[CH:3]=[C:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[CH2:7][CH2:6][C:5]1=O.[Li+].[OH-].C([O:17][C:18](=[O:21])[CH2:19][SH:20])C>CCO.C1COCC1>[CH3:10][C:8]1([CH3:11])[CH2:7][CH2:6][C:5]2=[C:19]([C:18]([OH:21])=[O:17])[S:20][CH:3]=[C:4]2[CH2:9]1
Reactant: CC1(C)CCC(=O)C(=CCl)C1
Reactant: CCOC(=O)CS
Agent: [Li+]
Agent: [Na]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CCc2c(csc2C(=O)O)C1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a part (300 mL) of a freshly prepared solution of sodium (21 g, 875 mmol) in EtOH (500 mL), mercaptoacetic acid ethyl ester (50 mL) is added. The resulting solution is added over a period of 10 min to a solution of 2-chloromethylene-4,4-dimethyl-cyclohexanone (50 g, 290 mmol) in THF (170 mL). The mixture becomes warm (50° C.). Upon complete addition, the remaining part of the freshly prepared solution of sodium in EtOH (200 mL) is added to the reaction mixture. The mixture is stirred at rt for 15 min before 1 N aq. LiOH solution (300 mL) is added. The solution is refluxed for 3 h, then stirred at rt for 16 h. The THF and EtOH are removed under reduced pressure and the remaining dark solution is extracted with heptane/EA 3:1 (2×200 mL). The aqueous phase is acidified by adding citric acid (30 g) and 2 N aq. HCl (200 mL) and then extracted three times with EA. The combined organic extracts are washed three times with sat. aq. NaHCO3 solution, dried over Na2SO4 and evaporated. The resulting dark brown oil is dissolved in acetonitrile at 60° C. and crystallised at 5° C. The crystals are collected, washed with acetonitrile and dried to give 5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (31 g) as a slightly grey powder; LC-MS: tR=0.95 min, [M+1+CH3CN]+=252.18; 1H NMR (CDCl3): δ 7.15 (s, 1H), 3.05 (t, J=7.0 Hz, 2H), 2.47 (s, 2H), 1.58 (t, J=7.0 Hz, 2H), 0.97 (s, 6H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:8]1[CH2:14][S:11](=[O:13])(=[O:12])[O:10][CH2:9]1>C(O)(C)C.CCOCC>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:9][CH2:8][CH2:14][S:11]([OH:13])(=[O:12])=[O:10])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: O=S1(=O)CCCO1
Solvent: CC(C)O
Solvent: CCOCC
Product: CN1CCN(CCCS(=O)(=O)O)CC1
Reaction time: 8 h

Procedure:
N-methyl piperizine (4.68 g) was dissolved in isopropanol (25 ml) and treated with 1,3-propanesultone (5.7 g) with cooling to maintain the temperature of the reaction below 50° C. The reaction mixture was allowed to stand at room temperature overnight, then diluted with ether and the white solid filtered. On standing, the white solid became a sticky semi-solid (7.1 g). Mass spec MH+ (found)=223 MH+ (calc)=223.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Br:16][C:17]1[C:22]2[NH:23][CH2:24][CH2:25][O:26][C:21]=2[CH:20]=[C:19]([O:27][CH3:28])[CH:18]=1>>[Br:16][C:17]1[C:22]2[N:23]([C:2]3[C:3](=[O:15])[N:4]([C@H:9]([CH:12]4[CH2:14][CH2:13]4)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=3)[CH2:24][CH2:25][O:26][C:21]=2[CH:20]=[C:19]([O:27][CH3:28])[CH:18]=1
Reactant: CC[C@@H](C1CC1)n1cc(Cl)nc(Cl)c1=O
Reactant: COc1cc(Br)c2c(c1)OCCN2
Product: CC[C@@H](C1CC1)n1cc(Cl)nc(N2CCOc3cc(OC)cc(Br)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 556 using 3,5-dichloro-1-[(1S)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 5-bromo-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine as the starting materials to give an oil. 1H NMR (300 MHz, CDCl3): δ 7.03 (s, 1H), 6.73 (d, J=2.9 Hz, 1H), 6.45 (d, J=2.9 Hz, 1H), 4.44–3.89 (m, 5H), 3.75 (s, 3H), 1.96–1.70 (m, 2H), 1.12–1.00 (m, 1H), 0.92 (t, J=7.3 Hz, 3H), 0.92 (t, J=7.3 Hz, 3H), 0.84–0.72 (m, 1H), 0.56–0.44 (m, 2H), 0.35–0.25 (m, 1H); HRMS (ESI) m/z 454.0518 [(M+H)+, calcd for C19H22N3O3BrCl 454.0533].
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH:8]([C:15]1[CH:16]=[N:17][C:18](Br)=[CH:19][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[P:23]([O-:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26].CCN(CC)CC>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:5][C:6]([NH:7][CH:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:20]=[CH:19][C:18]([P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])=[N:17][CH:16]=1)=[O:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOP([O-])OCC
Reactant: CC(C)(C)OC(=O)NC(c1ccccc1)c1ccc(Br)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)c1ccc(C(NC(=O)OC(C)(C)C)c2ccccc2)cn1
Yield: 86 %

Procedure:
To tert-butyl (6-bromopyridin-3-yl)(phenyl)methylcarbamate (4-e) (3.4 g, 9.4 mmol), diethyl phosphite (1.55 g, 11.27 mmol) and Et3N (1.14 g, 11.27 mmol) in THF was added PdCl2(dppf) (200 mg). The mixture was heated at reflux under nitrogen overnight. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified over silica gel (DCM/MeOH=20/1) to provide the product, 4-f (3.4 g, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([C:20]([OH:22])=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH:23]1([C:26]2[CH:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=2)[CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])=[CH:12][N:11]=[C:10]([C:20]([NH:32][CH2:31][C:29]3[O:28][N:27]=[C:26]([CH:23]4[CH2:25][CH2:24]4)[CH:30]=3)=[O:22])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: NCc1cc(C2CC2)no1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)cn1
Product: O=C(NCc1cc(C2CC2)no1)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)cn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (example D) and 3-cyclopropyl-5-isoxazolemethanamine (CAS Registry No. 851434-73-6) as starting materials; LC-MS (UV peak area/ESI) 97.6%, 452.0973 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]([NH:5][C:6]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[O:8][N:7]=1)=[O:4].[H-].[Na+].[CH3:18]I>CN(C)C=O>[CH3:1][N:2]([CH3:15])[C:3]([N:5]([CH3:18])[C:6]1[CH:10]=[C:9]([C:11]([CH3:12])([CH3:14])[CH3:13])[O:8][N:7]=1)=[O:4]
Reactant: CN(C)C(=O)Nc1cc(C(C)(C)C)on1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)N(C)c1cc(C(C)(C)C)on1
Temperature: 80 °C
Yield: 93.3 %

Procedure:
To a solution of 1,1-dimethyl-3-(5-t-butyl-3-isoxazolyl)urea (10.99 g) in dry dimethylformamide (10 ml), 50% sodium hydride (2.75 g) is added at room temperature with stirring, and the resultant mixture is heated at 60° C. for 15 minutes. A solution of methyl iodide (8.86 g) in dry dimethylformamide (30 ml) is added at 10° C. in 1 hour thereto, and the mixture is heated at 80° C. for 5 minutes and evaporated to remove the solvent. The residue is combined with water and shaken with chloroform. The chloroform layer is dried over anhydrous sodium sulfate and the solvent is evaporated. The residue is chromatographed on a column of silica gel to give 1,1,3-trimethyl-3-(5-t-butyl-3-isoxazolyl)urea (10.94 g) as crystals melting at 90° to 91.0° C. The yield is 93.38%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:13]=[N:12][N:11]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)[N:10]=1.I[C:30]1[CH:35]=[CH:34][N:33]([CH2:36][CH2:37][C@@:38]([CH3:53])([S:49]([CH3:52])(=[O:51])=[O:50])[C:39]([NH:41][O:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][O:44]2)=[O:40])[C:32](=[O:54])[CH:31]=1.O>O1CCOCC1.[Pd]>[CH3:7][O:8][C:9]1[CH:13]=[N:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([C:30]3[CH:35]=[CH:34][N:33]([CH2:36][CH2:37][C@@:38]([CH3:53])([S:49]([CH3:52])(=[O:51])=[O:50])[C:39]([NH:41][O:42][CH:43]4[CH2:48][CH2:47][CH2:46][CH2:45][O:44]4)=[O:40])[C:32](=[O:54])[CH:31]=3)=[CH:18][CH:19]=2)[N:10]=1
Reactant: COc1cnn(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)n1
Reactant: C[C@@](CCn1ccc(I)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cnn(-c2ccc(-c3ccn(CC[C@](C)(C(=O)NOC4CCCCO4)S(C)(=O)=O)c(=O)c3)cc2)n1

Procedure:
Pd EnCat (98 mg, 0.03 mmol) was added to a mixture of potassium carbonate (171 mg, 1.24 mmol), 4-methoxy-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2H-1,2,3-triazole (138 mg, 0.457 mmol) and (2R)-4-(4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide which may be produced as in Preparation 2B(T6) (190 mg, 0.381 mmol) in dioxane:water (6 ml, 5:1mix) in a 20 ml vial. The reaction was cooled and filtered through celite (approx 1 inch). The celite was washed with additional methanol (100 ml). The filtrate was concentrated in vacuo and the crude material was purified by chromatography on silica gel (4:1heptane:EtOAc to 100% EtOAc to 85% EtOAc:15% methanol) to furnish a light tan gum (120 mg, 58% TY). MS (LC/MS) m/z 546.2 (M+1). 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.28 (s, 1 H) 1.57-1.70 (m, 2 H) 1.68-1.81 (m, 3 H) 1.78-1.92 (m, 3 H) 2.36-2.50 (m, 1 H) 2.55-2.72 (m, 1 H) 3.09-3.21 (m, 3 H) 3.56-3.70 (m, 1 H) 4.07 (s, 3 H) 4.12 (d, J=7.22 Hz, 2 H) 4.15-4.25 (m, 1 H) 4.25-4.42 (m, 1 H) 5.01-5.14 (m, 1 H) 6.76-6.85 (m, 1 H) 6.87 (s, 1 H) 7.49 (s, 1 H) 7.68-7.80 (m, 1 H) 7.85 (d, J=9.17 Hz, 2 H) 8.08 (d, J=8.98 Hz, 2 H)
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH4+].CN(C)C=O.[CH3:12][C:13]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](=[N:26][O:27][CH3:28])[C:24]#[N:25]>C(OCC)(=O)C>[CH3:28][O:27][N:26]=[C:23]([C:24]1[NH:25][N:3]=[N:2][N:1]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][O:15][C:14]1[CH:29]=[C:30]([CH3:33])[CH:31]=[CH:32][C:13]=1[CH3:12]
Reactant: CON=C(C#N)c1ccccc1COc1cc(C)ccc1C
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CON=C(c1nnn[nH]1)c1ccccc1COc1cc(C)ccc1C
Temperature: 115 °C
Reaction time: 9 h
Yield: 87.4 %

Procedure:
Sodium azide (1.30 g, 20 mmol), ammonium chloride (1.07 g, 20 mmol) and dimethylformamide (10 ml) were added to 2-(2,5-dimethylphenoxymethyl)-α-methoxyiminophenylacetonitrile (0.59 g, 2 mmol), and the mixture was stirred at 115° C. for 9 hours. After completion of the reaction, ethyl acetate (150 ml) was added, and the mixture was washed with saturated brine (100 ml) twice. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give 2-(2,5-dimethylphenoxymethyl)phenyl 1H-tetrazol-5-yl ketone O-methyloxime (0.59 g, 87.4%) as colorless crystals.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[CH2:20]([NH2:24])[CH:21]([CH3:23])[CH3:22].CCN(C(C)C)C(C)C>>[CH2:20]([NH:24][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1)[CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)CN
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CNC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, isobutylamine and DIEA to give 2-isobutylamino-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 415 (MH+).
Reaction SMILES: [O:1]=[C:2]1[CH:6]([C:7](=[N:9][C:10]2[C:14]([C:15]#[N:16])=[CH:13][NH:12][N:11]=2)[CH3:8])[CH2:5][CH2:4][O:3]1.O>C(N(CC)CC)C>[C:15]([C:14]1[CH:13]=[N:12][N:11]2[C:2](=[O:1])[C:6]([CH2:5][CH2:4][OH:3])=[C:7]([CH3:8])[NH:9][C:10]=12)#[N:16]
Reactant: CC(=Nc1n[nH]cc1C#N)C1CCOC1=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1[nH]c2c(C#N)cnn2c(=O)c1CCO
Temperature: 50 °C
Yield: 90 %

Procedure:
(i-1) 15 g of Compound (IV) [R2 =H, R3 =CN], 35 ml of water, and 9.7 ml of triethylamine were mixed and stirred at 50° C. in a warm bath to obtain a brown solution. After heating for about 5 hours, the reacted solution was allowed to stand at room temperature over night. Precipitations of brown crystals was confirmed. The solution was acidified by adding acetic acid. Deposited crystals were collected and recrystallized in dimethylformamide to obtain 13.5 g of 3-cyano-6-(2-hydroxyethyl)-5-methylpyrazolo[1,5-a]pyrimidine-7(4H)-one [R2 =H, R3 =CN in formula (V)] as slight brown crystals having a decomposition temperature of 283° C. at a yield of 90.0%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([CH:15]=[C:16](Br)Br)[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:20][N:21]([CH3:25])[C:22](Cl)=[O:23]>>[C:1]([O:5][C:6](=[O:19])[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]#[C:16][C:22](=[O:23])[N:21]([CH3:25])[CH3:20])[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C(=O)Cl
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C=C(Br)Br)CC1
Product: CN(C)C(=O)C#C[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1

Procedure:
In a similar way as described in example 26.5, trans-[4-(2,2-Dibromo-vinyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester and dimethylcarbamoyl chloride gave trans-(4-Dimethylcarbamoylethynyl-cyclohexyl)-methyl-carbamic acid tert-butyl ester, mp: 115-117° C.; MS: 309 (MH+).
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C:7]([CH2:16]O)=[C:6]1[CH3:18])(=[O:4])=[O:3].P(Br)(Br)[Br:20]>C(OCC)C.O1CCCC1>[Br:20][CH2:16][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[C:6]=1[CH3:18]
Reactant: BrP(Br)Br
Reactant: COc1ccc2c(c1)c(CO)c(C)n2S(C)(=O)=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(CBr)c(C)n2S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1-Methanesulfonyl-5-methoxy-2-methyl-1H-indol-3-yl)-methanol (1.53 g, 5.68 mmol) in anhydrous ethyl ether (50 ml) and tetrahydrofuran (20 ml) at 0° C. under N2 was added a solution of phosphorus tribromide (7.5 ml, 1 M in dichloromethane). The mixture was stirred at room temperature for 8 hours and concentrated under reduced pressure to give 3-bromomethyl-1-methane sulfonyl-5-methoxy-2-methyl-1H-indole as white solid. 1H NMR (CDCl3) δ:2.57 (s, 3H), 3.04(s, 3H), 3.89 (s, 3H), 4.63 (s, 2H), 6.93 (dd, 1H, J=9.1 Hz, 2.5 Hz), 7.04 (d, 1H, J=2.5 Hz), 7.89 (d, 1H, J=9.1 Hz).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11](#[N:15])[CH:12]([CH3:14])[CH3:13].[F:16][C:17]1[C:24]([F:25])=[CH:23][CH:22]=[C:21]([F:26])[C:18]=1[CH2:19]Br.O>C1COCC1>[CH3:13][C:12]([CH3:14])([CH2:19][C:18]1[C:21]([F:26])=[CH:22][CH:23]=[C:24]([F:25])[C:17]=1[F:16])[C:11]#[N:15]
Reactant: Fc1ccc(F)c(CBr)c1F
Reactant: CC(C)C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C#N)Cc1c(F)ccc(F)c1F
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
A solution of lithium bis(trimethylsilyl)amide (LiHMDS) (1M in THF, 26.6 mL, 26.6 mmol) was added to a solution of isobutyronitrile (2.4 mL, 26.6 mmol) in THF at −78° C. and stirred for 25 minutes. 2,3,6-trifluorobenzyl bromide (2.3 mL, 17.8 mmol) was added and the reaction was warmed to room temperature and stirred for 1.5 h. Water was added to quench the reaction and it was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield 2,2-dimethyl-3-(2,3,6-trifluorophenyl)propanenitrile (34) as a white solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][C:10]=1[N+:18]([O-])=O.CN(C)C=O.[CH3:26][O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1>>[NH2:18][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:9]=1[O:8][CH3:7])[C:13]([NH:32][C:31]1[CH:33]=[CH:34][C:28]([O:27][CH3:26])=[CH:29][CH:30]=1)=[O:15]
Reactant: COc1ccc(N)cc1
Reactant: COc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)c2ccc(OC)c(N)c2)cc1
Yield: 64.4 %

Procedure:
Prepared according to the procedure described for Example 1 using oxalyl chloride (3.0 mL, 34.39 mmol), 4-methoxy-3-nitrobenzoic acid (5.00 g, 25.36 mmol), dimethylformamide (0.5 mL, 6.5 mmol), and 4-methoxyaniline (6.25 g, 50.7 mmol) to afford the product (4.45 g); m.p. 164-167° C.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:8]=1[O:9][CH2:10][CH2:11][CH:12]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][C:13]1=[O:22]>>[Cl:6][C:7]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:8]=1[O:9][CH2:10][CH2:11][CH:12]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:19]=2)[NH:14][C:13]1=[O:22]
Reactant: O=C1Nc2ccccc2CC1CCOc1ccc(Cl)cc1Cl
Reactant: O=S(=O)(O)Cl
Product: O=C1Nc2ccc(S(=O)(=O)Cl)cc2CC1CCOc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
After cooling chlorosulfonic acid to 0° C. under N2, the 3-(2-(2,4-dichlorophenoxy)ethyl)-3,4-dihydroquinolin-2(1H)-one was added slowly and stirred at 0° C. for 1 h. The solution was heated to 50° C. for 10 minutes and cooled down to rt. After pouring the reaction mixture into ice, a white precipitate formed which was extracted with CH2Cl2. The organic layer was washed with H2O and brine, then dried over MgSO4 and concentrated in vacuo to complete dryness, giving the product as a white solid (2.4 g, 47% yield).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]2[N:10]=[C:11]([SH:13])[S:12][C:8]=2[C:7]([F:14])=[CH:6][C:5]=1[F:15].Br[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].Cl>CN(C=O)C.O>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][S:13][C:11]1[S:12][C:8]2[C:7]([F:14])=[CH:6][C:5]([F:15])=[C:4]([F:3])[C:9]=2[N:10]=1)[CH3:25]
Reactant: Fc1cc(F)c2sc(S)nc2c1F
Reactant: CCOC(=O)CCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCSc1nc2c(F)c(F)cc(F)c2s1
Yield: 63 %

Procedure:
Sodium hydride (60% in oil, 220 mg, 5.5 mmol) was suspended in DMF (2 ml) and the suspension was stirred on a water bath. To the suspension was added dropwise a solution of 4,5,7-trifluoro-2-mercaptobenzothiazole (1.1 g, 5 mmol) in DMF (5 ml) under ice cooling and the mixture was stirred for 30 min. at room temperature and then cooled on a water bath. To the cooled mixture was added dropwise a solution of ethyl 5-bromopentanoate (1.05 g, 5 mmol) in DMF (3 ml) and the mixture was stirred for 2 hours at room temperature. The resultant mixture was diluted with water, then acidified with 7% hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with an aqueous saturated saline solution, dried and then evaporated. The resulting residue was purified on a silica gel column to give 5-(4,5,7-trifluorobenzothiazol-2-ylthio)pentanoic acid ethyl ester (1.1 g, 64%) as an oil.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[S:7][CH:8]=2)[CH2:3][CH2:2]1.C(#N)C.CC(O)=O.[Br:24]N1C(=O)CCC1=O>C([O-])(O)=O.[Na+]>[Br:24][C:8]1[S:7][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[N:5][C:4]=1[CH:1]1[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)Nc1nc(C2CC2)cs1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1nc(C2CC2)c(Br)s1
Temperature: 0 °C
Yield: 86.1 %

Procedure:
To a 250 mL round-bottomed flask was added tert-butyl 4-cyclopropylthiazol-2-ylcarbamate (9.5 g, 40 mmol), ACN 100% (100 mL, 1914 mmol), and glacial AcOH (6.8 mL, 119 mmol). The solution was stirred at 0° C. and treated in portions with N-bromosuccinimide (3.4 mL, 40 mmol). The suspension was stirred for 1 hour, diluted with NaHCO3, and extracted with EtOAc. The organics were washed with saturated sodium chloride (1×50 mL) and water (1×50 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give tert-butyl 5-bromo-4-cyclopropylthiazol-2-ylcarbamate (11 g, 86% yield), m/z (%): 320.3 (100%, M++H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([CH2:15][N:16]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:33][CH3:34]>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]([CH2:33][CH3:34])[C:12]1([CH2:15][N:16]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13][CH2:14]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CN(CC1(NC(=O)OCc2ccccc2)CC1)C(=O)OC(C)(C)C
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(CC1(N(CC)C(=O)OCc2ccccc2)CC1)C(=O)OC(C)(C)C
Reaction time: 0.67 h

Procedure:
To a solution of ethyl N-[(1-{[(benzyloxy)carbonyl]amino}cyclopropyl)methyl]-N-(tert-butoxycarbonyl)glycinate (1.6 g, 3.94 mmol) in DMF (23 mL) at 0° C. under an atmosphere of nitrogen was added NaH (60% dispersion in oil, 19 mg, 7.87 mmol). The mixture was stirred for 40 min until gas evolution ceased. To the reaction was added iodoethane (346 μL, 4.33 mmol), followed stirring at room temperature for 3 h. The reaction was quenched with water, and DMF was removed in vacuo. The resulting aqueous mixture was extracted twice each with EtOAc and CH2Cl2. The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo to afford a pale yellow, sticky solid. The crude product was subjected to column chromatography eluting with a gradient of 0-50% EtOAc/hexanes. Collection and concentration of the appropriate fractions afforded the product as a colorless oil.