Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:26][CH2:27][CH2:28][N:29]=[C:30]=[O:31]>C(O)C.ClCCl>[Cl:26][CH2:27][CH2:28][NH:29][C:30]([NH:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:15])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1)=[O:31]
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: O=C=NCCCl
Solvent: CCO
Solvent: ClCCl
Product: O=C(NCCCl)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 30 %

Procedure:
To a stirred solution of [4-(6-aminopyridazin-3-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone (0.070 g, 0.200 mmol) in a mixture of ethanol and dichloromethane (1:1, 15 mL) was added 2-chloroethylisocyanate (80.0 μL, 0.79 mmol) in one portion. The mixture was then stirred for 10 minutes at room temperature and then concentrated in vacuo. The residue was washed with 5% HCl solution, water and dried. The residue was purified by column chromatography to afford the title compound in 30% yield (0.028 g). 1H NMR (300 MHz, CDCl3) δ 7.98 (b., s, 1H), 7.75 (d, J=7.0 Hz, 1H), 7.64 (t, J=7.0 Hz, 1H), 7.56 (t, J=7.0 Hz, 1H), 7.37 (d, J=7.0 Hz, 1H), 7.12 (d, J=10.0 Hz, 1H), 4.99 (m, 1H), 4.06-3.89 (m, 2H), 3.69-3.59 (m, 6H), 3.56-3.53 (m, 2H), 3.47-3.44 (m, 2H), 3.35-3.33 (m, 2H).
Reaction SMILES: [CH:1]1([NH:4][CH3:5])[CH2:3][CH2:2]1.[CH3:6][N:7]1[C:11]([C:12](=[O:29])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[N:18]([N:20]=[C:21]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[N:22]=3)[CH:19]=2)=[C:10]([C:30](O)=[O:31])[CH:9]=[N:8]1>>[CH:1]1([N:4]([CH3:5])[C:30]([C:10]2[CH:9]=[N:8][N:7]([CH3:6])[C:11]=2[C:12]([NH:13][C:14]2[CH:15]=[CH:16][C:17]3[N:18]([N:20]=[C:21]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[N:22]=3)[CH:19]=2)=[O:29])=[O:31])[CH2:3][CH2:2]1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccc2nc(-c3cccnc3)nn2c1
Reactant: CNC1CC1
Product: CN(C(=O)c1cnn(C)c1C(=O)Nc1ccc2nc(-c3cccnc3)nn2c1)C1CC1

Procedure:
Using cyclopropyl-methyl-amine and 1-methyl-5-(2-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid, the title compound was prepared in the same manner as described for example 2. White solid (71 mg, 44%). Mp.: 237° C. MS: m/z=417.3 (M+H+). Ames test negative.
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]CC)=[N+:2]=[N-:3].N(CCN)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[N+:2]=[N-:3]
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Agent: [N-]=[N+]=NCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Yield: 68880.4 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, (0.262 g, 1.19 mmol) was reacted with 2-azidoethanamine (0.103 g, 1.19 mmol) and triethylamine (0.242 g, 2.39 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)dodecanamide (0,220 g, 69%). 1H NMR (300 MHz, CDCl3) δ 6.11 (s, 1H), δ 3.40 (d, 2H), δ 3.37 (d, 2H), δ 2.17 (t, 2H), δ 1.59 (q, 2H), δ 1.22 (s, 14H), δ 0.84 (t, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 173.8, 51.1, 39.1, 36.8, 32.1, 29.8, 29.7, 29.6, 29.5, 29.5, 29.2, 25.9, 22.9, 14.3 ppm; HRMS (ESI) calcd for C14H28N4O (M+) 268.2263. Found 268.2259.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]3[CH:15]=[CH:14][CH:13]=[C:12](Cl)[C:9]=3[CH2:10][CH2:11][C:5]=2[CH:4]=1.[Cu](C#N)[C:22]#[N:23].CN1CCCC1=O.O.N>S([O-])([O-])(=O)=O.[Cu+2].O>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]3[CH:15]=[CH:14][CH:13]=[C:12]([C:22]#[N:23])[C:9]=3[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: N#C[Cu]C#N
Reactant: FC(F)(F)c1ccc2c(c1)CCc1c(Cl)cccc1S2
Agent: [Cu+2]
Agent: N
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1cccc2c1CCc1cc(C(F)(F)F)ccc1S2
Reaction time: 18.5 h
Yield: 14.7 %

Procedure:
The mixture of 450mg of 2-trifluoromethyl-9-chloro-10,11-dihydrodibenzo[b,f]thiepin, 0.4g of copper cyanide, 0.05g of anhydrous copper sulfate and 10ml of N-methylpyrrolidone was stirred at 180° to 210° C for 18.5 hrs. while preventing the moisture. A ter cooling, to the mixture was added 2.5ml of conc. ammonia water and 35ml of water and the resulting mixture was filtered with the use of celite. The thus obtained solution was extracted with benzene and the extract was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 0.3g of a brown oily substance, which was chromatographed on a silica gel, eluted with n-hexane, and there was obtained 64mg of the desired product. This was recrystallized from n-hexane to afford 2-trifluoromethyl-9-cyano-10,11-dihydrodibenzo-[b,f]thiepin having a melting point of 113° to 114.5° C as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:11])=[CH:6][C:7]=1[C:8](O)=[O:9].O=S(Cl)[Cl:14]>C1(C)C=CC=CC=1.CN(C=O)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:11])=[CH:6][C:7]=1[C:8]([Cl:14])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Cl)nnc1Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cc(Cl)nnc1Cl

Procedure:
To a suspension of 3,6-dichloropyridazine-4-carboxylic acid (1.16 g, 6 mmol) in toluene (20 mL) were added DMF (2 drops) and SOCl2 (4 mL) and the mixture was heated at reflux temperature for 3 h. The volatiles were removed and the residue was stripped with toluene. The resulting brown oil (3,6-dichloropyridazine-4-carbonyl chloride) was used without purification.
Reaction SMILES: [C:1]1([N:7]([CH2:30][CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])(C)C)=[O:34])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:40].C(O)C.C(=O)([O-])[O-].[NH4+:48].[NH4+]>ClCCl.C(O)C>[ClH:40].[ClH:40].[C:1]1([N:7]([CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:39])=[O:34])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:20]=[CH:21][C:22]([C:25](=[NH:26])[NH2:48])=[CH:23][CH:24]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(=O)N(CCCC(=O)OC(C)(C)C)c3ccccc3)ccc21
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CCCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Yield: 68 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-tert-butyloxycarbonylpropyl)amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 68% of theory, C29H32N6O3 (512.6); Rf value: 0.12 (silica gel; dichloromethane/ethanol=4:1); EKA mass spectrum: (M+H)+=513; (M+H+Na)++=268.
Reaction SMILES: Cl[C:2]1[C:3]([CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[C:12]2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[N:17]=2)=[N:4][CH:5]=[C:6]([O:8][CH3:9])[N:7]=1.C([Sn](CCCC)(CCCC)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)CCC>C1(C)C=CC=CC=1.C(Cl)Cl.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>[F:22][C:18]1[N:17]=[C:16]([C:12]2[N:11]([CH2:10][C:3]3[C:2]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[N:7][C:6]([O:8][CH3:9])=[CH:5][N:4]=3)[CH:15]=[CH:14][N:13]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: COc1cnc(Cn2ccnc2-c2cccc(F)n2)c(Cl)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cnc(Cn2ccnc2-c2cccc(F)n2)c(-c2ccccn2)n1
Temperature: 110 °C
Yield: 86.1 %

Procedure:
A mixture of 3-chloro-2-[2-(6-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-5-methoxy-pyrazine (80 mg, 0.25 mmol), 2-tributylstannylpyridine (138 mg, 0.37 mmol), and PdCl2(PPh3)2 (18 mg, 0.026 mmol) in toluene (10 mL) is heated at 110° C. in a sealed tube for 16 hours. On cooling, the mixture is diluted with DCM (20 mL) and filtered. After the solvent is removed, the residue is purified by PTLC (silica gel; 5% MeOH in DCM) to give 78 mg of 2-[2-(6-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-5-methoxy-3-pyridin-2-yl-pyrazine. 1H NMR (CDCl3) 8.59 (d, 1H), 8.15 (d, 1H), 8.08 (s, 1H), 8.02 (d, 1H), 7.85(t, 1H), 7.72 (dd, 1H), 7.32 (dd, 1H), 7.10 (s, 1H), 7.15 (s, 1H), 6.65 (dd, 1H), 6.31 (s, 2H), 4.01 (s, 3H). G. 2-[1-(3-Chloro-5-methoxy-pyrazin-2-ylmethyl)-1H-imidazol-2-yl]-pyrimidine (Compound 8) 1. Synthesis of 2-(1H-imidazol-2-yl)-pyrimidine hydrochloride
Reaction SMILES: [CH3:1][O:2][C:3]1[C:35]([O:36][CH3:37])=[CH:34][C:6]2[CH2:7][C:8](=[O:33])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:32])[CH2:16][CH2:17][CH2:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=3)(=[O:21])=[O:20])[CH2:10][CH2:11][C:5]=2[CH:4]=1.[Se](=O)=[O:39]>>[CH3:1][O:2][C:3]1[C:35]([O:36][CH3:37])=[CH:34][C:6]2[C:7](=[O:39])[C:8](=[O:33])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:32])[CH2:16][CH2:17][CH2:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=3)(=[O:21])=[O:20])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: O=[Se]=O
Reactant: COc1ccc(S(=O)(=O)CCCN(C)CCCN2CCc3cc(OC)c(OC)cc3CC2=O)cc1OC
Product: COc1ccc(S(=O)(=O)CCCN(C)CCCN2CCc3cc(OC)c(OC)cc3C(=O)C2=O)cc1OC

Procedure:
The title compound is prepared from N-[3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-propyl]-N-[3-(3,4-dimethoxy-phenylsulfonyl)-propyl]-methylamine and selenium dioxide analogously to Example 55.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16]([OH:18])=O)[NH:13][C:12]1=[O:19])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:20]([SH:24])[CH2:21][CH2:22][CH3:23].C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O>[Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16]([S:24][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18])[NH:13][C:12]1=[O:19])[CH3:10])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1CC(=O)O
Reactant: CCCCS
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCSC(=O)C[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
542 mg (1.89 mmole) of (3S, 4R)-3-[(R)-1-t-butyldimethylsilyloxyethyl]-4-carboxymethyl-2-azetidinone, 212 mg (2.36 mmole) of butyl mercaptan, 381 mg (3.77 mmole) of triethylamine and 1.04 g (3.78 mmole) of diphenylphosphoryl azide were dissolved in 10 ml of N,N-dimethylformamide and the solution was allowed to stand overnight at room temperature. After dilution with ethyl acetate, the mixture was washed with water several times and then dried. The solvent was distilled off and the residue (1.25 g) was purified by column chromatography through 23 g of silical gel, eluted with mixtures of hexane and ethyl acetate in volume ratios ranging from 4:1 to 2:1, to give 649 mg (yield 96%) of the title product. Recrystallization from hexane gave colourless needles, melting at 56.5°-57° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH2:11][NH2:12]>CO.O>[NH:11]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)[NH2:12]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: NN
Solvent: CO
Solvent: O
Product: NNc1ccc([N+](=O)[O-])cn1
Temperature: 10 °C

Procedure:
To a slurry of 47.6 g (0.3 mol) of 2-chloro-5-nitropyridine in a mixture of 400 ml methanol and 60 ml water and cooled to 10° C. was added with cooling below 30° 86 g hydrazine (95 percent) over about 10 minutes. The solids first went into solution, then a greenish-yellow precipitate separated. The mixture was stirred at reflux for 30 minutes. The greenish solid was filtered off and washed with cold methanol. The solid was slurried in 200 ml of cold water, washed and vacuum dried. The yield was 40.1 g (87 percent).
Reaction SMILES: [Na].[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:12].BrCCCCCCCCBr.[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>>[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][O:33][C:24]1[CH:25]=[CH:26][C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=1
Reactant: Oc1ccc2ccccc2c1
Reactant: CCCCCCCCOc1ccc2ccccc2c1
Agent: BrCCCCCCCCBr
Agent: [Na]
Product: c1ccc2cc(OCCCCCCCCOc3ccc4ccccc4c3)ccc2c1

Procedure:
Using the method described in Example 1, the crude solids were prepared using 5.5 g (0.24 gram atoms) sodium metal, 34.6 g (0.24 mole) 2-naphthol, and 27.2 g (0.100 mole) 1,8-dibromooctane. Recrystallization from ethyl acetate gave 30.0 g, mp 128° C., and 0.8 g, mp 125°-126° C., of pure 1,8-bix (2-naphthoxy) octane. The NMR spectrum was consistent with the structure and showed the absence of impurities.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N+:19]([O-:21])=[O:20])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.CN.[C:24]([BH3-])#[N:25].[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C(O)(=O)C.CO>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[CH3:1][O:2][C:3]1[C:10]([O:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N+:19]([O-:21])=[O:20])=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][CH2:24][NH2:25]
Reactant: [BH3-]C#N
Reactant: COc1c(C=O)cccc1Oc1cc(C)ccc1[N+](=O)[O-]
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1c(CCN)cccc1Oc1cc(C)ccc1[N+](=O)[O-]
Yield: 38.8 %

Procedure:
2-Methoxy-3-(5-methyl-2-nitrophenoxy)benzaldehyde (0.36 g, 1.3 mmol), methylamine (2M in methanol, 3.0 mL, 6.0 mmol) and sodium cyanoborohydride (100 mg, 1.6 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (50 mL) for 18 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.14 g, 1.2 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with hot methanol and allowed to cool overnight. The filtrate was collected, the solvent removed in vacuo. The residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give [2-methoxy-3-(5-methyl-2-nitrophenoxy)benzyl]methylamine fumarate (195 mg, 38%) as a beige solid.
Reaction SMILES: [N:1]1([C:5]2([C:15]#N)[CH2:14][CH2:13][C:8]3([O:12][CH2:11][CH2:10][O:9]3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[C:17]1([Mg]Cl)[CH:22]=[CH:21]C=[CH:19][CH:18]=1.[Cl-].[NH4+].O>O1CCCC1>[C:15]1([C:5]2([N:1]3[CH2:4][CH2:3][CH2:2]3)[CH2:14][CH2:13][C:8]3([O:12][CH2:11][CH2:10][O:9]3)[CH2:7][CH2:6]2)[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: N#CC1(N2CCC2)CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(C2(N3CCC3)CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 8-azetidin-1-yl-1,4-dioxaspiro[4,5]decane-8-carbonitrile (2.20 g, 9.9 mmol) in anhydrous tetrahydrofuran (25 ml) was added dropwise under argon and with ice cooling to a 2 M solution of phenyl magnesium chloride in tetrahydrofuran (12 ml, 24 mmol) and then the mixture was stirred overnight at room temperature. After adding saturated ammonium chloride solution (5 ml) and water (5 ml) the phases were separated and the aqueous phase was extracted with diethyl ether (3×50 ml). The combined organic phases were dried with sodium sulfate and concentrated to small volume under vacuum. The crude product was purified by flash chromatography (100 g, 20×4.0 cm) with ethyl acetate/cyclohexane (1:1). Yield: 670 mg (25%), colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[C:15](=[O:33])[N:16]([CH3:32])[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[C:19]=3[CH3:20])=[C:12]([S:34]([OH:37])(=O)=[O:35])[CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].P(Cl)(Cl)([Cl:40])=O>C(#N)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[C:15](=[O:33])[N:16]([CH3:32])[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[C:19]=3[CH3:20])=[C:12]([S:34]([Cl:40])(=[O:37])=[O:35])[CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cc1c(-c2c(S(=O)(=O)O)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Cc1c(-c2c(S(=O)(=O)Cl)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a suspension of the compound prepared in Example 191 (10.0 g) in acetonitrile (70 ml) was added phosphorus oxychloride (7.04 ml) and the resulting mixture was stirred at 90° C. for two hours. The mixture was concentrated on evaporator instrument under reduced pressure and to the residue were then added ethyl acetate (50 ml) and hexane (50 ml) and the mixture was stirred for thirty minutes. The precipitated solids were collected by filtration and washed with ethyl acetate/hexane=1/1 to afford 1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonylchloride (10.3 g). UPLC/MS 550 (M+H)/1.08 min. (measurement condition 9).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[CH2:10][CH2:9][CH2:8]2)(=[O:3])[CH3:2].[CH:16]1([CH:21]=O)[CH2:20][CH2:19][CH2:18][CH2:17]1.N1CCCC1.Cl>CO>[CH:16]1(/[CH:21]=[C:10]2/[C:11](=[O:15])[C:12]3[CH:13]=[CH:14][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][C:7]=3[CH2:8][CH2:9]/2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC(=O)Nc1ccc2c(c1)CCCC2=O
Reactant: O=CC1CCCC1
Agent: Cl
Solvent: CO
Solvent: C1CCNC1
Product: CC(=O)Nc1ccc2c(c1)CC/C(=C\C1CCCC1)C2=O
Temperature: 55 °C
Yield: 72.4 %

Procedure:
A mixture of 6-acetamido-1-tetralone (200 mg, 0.98 mmol) and cyclopentanecarboxaldehyde (0.21 mL, 1.9 mmol) in methanol (2 mL) was treated with pyrrolidine (0.25 mL, 2.9 mmol) at room temperature for 1 hour then heated at 55° C. overnight. The mixture was cooled to room temperature, treated with 1N Hydrogen chloride (4 mL) was filtered thru a Chem Elute tube (CE101 1) eluting with 90% dichloromethane/10% ethyl acetate and condensed filtrate to give (E)-N-(6-(cyclopentylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)acetamide (200 mg, 0.71 mmol, 72% n yield) as a tan foam. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25-1.44 (m, 2H), 1.52-1.76 (m, 4H), 1.77-1.90 (m, 2H), 2.08 (s, 3H), 2.70-2.92 (m, 5H), 6.63 (d, J=9.67 Hz, 1H), 7.49 (dd, J=8.59, 2.15 Hz, 1H), 7.59-7.66 (m, 1H), 7.86 (d, J=8.59 Hz, 1H), 10.23 (s, 1H). ES-MS m/z 284 (M+H).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C@H:25]3[CH2:29][CH2:28][CH2:27][N:26]3[CH3:30])=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C.O>[CH3:30][N:26]1[CH2:27][CH2:28][CH2:29][C@@H:25]1[C:22]1[N:20]2[CH:21]=[C:16]([O:12][C@H:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C@@H:2]([NH2:1])[CH2:3][CH2:4]3)[CH:17]=[CH:18][C:19]2=[N:24][N:23]=1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: CN1CCC[C@@H]1c1nnc2ccc(F)cn12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC[C@@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of Intermediate A (245 mg, 1.50 mmol) in DMF (4 mL) was added NaH (60% dispersion in oil, 180 mg, 4.50 mmol) and the mixture stirred at RT for 0.5 h. A solution of Intermediate 60a (330 mg, 1.50 mmol) in DMF (5 mL) was added and the mixture stirred at 60° C. for 2 h. The cooled solution was diluted with water and extracted with DCM (5×20 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-15% [2M NH3 in MeOH] in DCM, to give the title compound as a brown solid after freeze-drying (408 mg, 74%). LCMS (Method 3): Rt 0.44 min, m/z 364 [MH+].
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([OH:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=1)=[O:5])C.[H-].[Na+].Br[CH2:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>CN(C=O)C>[CH3:24][C:23]([CH3:26])([CH3:25])[C:22](=[O:27])[CH2:21][O:11][C:9]1[N:8]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:7]=[C:6]([C:4]([OH:3])=[O:5])[CH:10]=1
Reactant: CCOC(=O)c1cc(O)n(-c2ccccc2)n1
Reactant: CC(C)(C)C(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)COc1cc(C(=O)O)nn1-c1ccccc1
Reaction time: 2 h

Procedure:
To a solution of 5 g 5-Hydroxy-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester in 12 ml of DMF was added at 0° C. 1.29 g of sodium hydride (60% in mineral oil). After 15 min at this temperature 3.85 g of 1-Bromo-3,3-dimethyl-butan-2-one were added. After 2 h at RT the mixture was poured on ice/water and extracted with ethyl acetate. The organic phase was washed with brine and dried over sodium sulfate followed by evaporation. The residue was taken up in 20 ml of THF and treated with 21.5 ml of 2M NaOH. After 2 h, additional 15 ml 2M NaOH were added. Finally, after 3 h the THF was evaporated and the residue acidified with 2M HCl resulting in the precipitation of a gum. The gum was dissolved in ethyl acetate and coevaporated with toluene. Stirring in ethyl acetate/hepatne 1:1 gave a gummy substance which solidified on evaporation.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.[Br:5][C:6]1[N:11]=[C:10]([CH:12](O)[CH3:13])[CH:9]=[CH:8][CH:7]=1>>[N:1]1([CH:12]([C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([Br:5])[N:11]=2)[CH3:13])[CH2:4][CH2:3][CH2:2]1
Reactant: CC(O)c1cccc(Br)n1
Reactant: C1CNC1
Product: CC(c1cccc(Br)n1)N1CCC1

Procedure:
The title compound was prepared according to the procedure in Example 139 Step 1 using azetidine (0.141 g, 2.48 mmol) and 1-(6-bromopyridin-2-yl)ethanol (0.500 g, 2.48 mmol) as the starting materials.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:26])[N:14]([CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:26])[N:14]([CH2:18][C:19]([OH:21])=[O:20])[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Cn1cccc(NC(=O)OCc2ccccc2)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)Cn1cccc(NC(=O)OCc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4.00 g of tert-butyl 2-(3-(benzyloxycarbonylamino)-2-oxopyridin-1(2H)-yl)acetate (11.2 mmol) are dissolved in 50 mL of dichloromethane and treated with 50 mL of trifloroacetic acid. It is stirred at RT for 3 h, before the volatile components are removed in vacuo. After drying under high vacuum a brown solid is obtained and it is suitable for the further use without purification.