Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]#[C:2]Br.C(=O)(O)[O-].[Na+].[Cl:9][C:10]1[CH:18]=[C:17]2[C:13]([C:14]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:15][NH:16]2)=[CH:12][CH:11]=1.O>CS(C)=O>[Cl:9][C:10]1[CH:18]=[C:17]2[C:13]([C:14]([CH:19]3[CH2:24][CH2:23][N:22]([C:2]#[N:1])[CH2:21][CH2:20]3)=[N:15][NH:16]2)=[CH:12][CH:11]=1
Reactant: N#CBr
Reactant: Clc1ccc2c(C3CCNCC3)n[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CN1CCC(c2n[nH]c3cc(Cl)ccc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
To a stirred mixture of cyanogen bromide (1.8 g, 0.017 mol), sodium bicarbonate (2.80 g) and dimethyl sulfoxide (DMSO) (40 ml) was added dropwise 6-chloro-3-(4-piperidinyl)-1H-indazole (4.0 g, 0.017 mol) of Example 52 dissolved in DMSO (50 ml). The reaction was stirred at ambient temperature for 1 hour and poured into water. The resulting solid was collected, dried and weighed 4.0 g. Recrystallization from toluene-hexane afforded 3.1 g (70%) of 4-(6-chloro-1H-indazol-3-yl)piperidine-1-carbonitrile, m.p. 180°-188° C. To a stirred mixture of 4-(6-chloro-1H-indazol-3-yl)piperidine-1-carbonitrile (3.0 g., 0.015 mol) in methanol (30 ml) was added a solution of 25% sodium methoxide in methanol (2.5 ml). The reaction was warmed on a steam bath to effect solution and then stirred at ambient temperature for 16 hours. Most of the methanol was removed in vacuo and the residue was diluted with water. An initial oil solidified and 3.5 g of a solid was collected. This was recrystallized from methanol-water to yield 2.9 g (66%) of 4-(6-chloro-1H-indazol-3-yl)piperidine-1-carboximidic acid methyl ester, mp 173°-175° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[CH3:13][O:14][C:15](=[O:31])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[NH2:30])[CH:17]=1>CCO>[CH3:13][O:14][C:15](=[O:31])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[NH:30][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:17]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: COC(=O)c1cccc(Oc2ccc(Cl)cc2N)c1
Solvent: CCO
Product: COC(=O)c1cccc(Oc2ccc(Cl)cc2Nc2ccnc3nc(C)ccc23)c1
Temperature: 80 °C

Procedure:
The product from Example 1d (175 mg, 0.979 mmol) and the product from Example 208b (272 mg, 0.979 mmol) were dissolved in 2 mL of abs EtOH and heated to 80° C. for 16 hrs. At this time the reaction mixture was cooled and solvent removed yielding the title compound as a brown foam that was taken forward without purification (410 mg, 93%).
Reaction SMILES: [CH3:1][CH2:2][O-:3].[Na+].[CH3:5][C:6]1([CH3:41])[CH2:11][CH:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]2[N:22]=[C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]3[CH2:33][C:32]([CH3:35])([CH3:34])[NH:31][C:30]([CH3:37])([CH3:36])[CH2:29]3)[N:20]=[C:19](Cl)[N:18]=2)[CH2:9][C:8]([CH3:40])([CH3:39])[NH:7]1>C1(C)C=CC=CC=1>[CH2:2]([O:3][C:19]1[N:20]=[C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]2[CH2:33][C:32]([CH3:34])([CH3:35])[NH:31][C:30]([CH3:37])([CH3:36])[CH2:29]2)[N:22]=[C:17]([NH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:10]2[CH2:9][C:8]([CH3:40])([CH3:39])[NH:7][C:6]([CH3:41])([CH3:5])[CH2:11]2)[N:18]=1)[CH3:1]
Reactant: CC[O-]
Reactant: CC1(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)NC(C)(C)C3)n2)CC(C)(C)N1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOc1nc(NCCCCC2CC(C)(C)NC(C)(C)C2)nc(NCCCCC2CC(C)(C)NC(C)(C)C2)n1
Temperature: 25 °C
Yield: 74 %

Procedure:
g)1. 63.5 g (0. 195 mol) of a 21% solution of sodium ethylate in toluene are added dropwise at room temperature under nitrogen to a solution of 69.7 g (0.13 mol) of 2,4-bis[N-(2,2,6,6-tetramethyl-4-piperidinyl)butylamino]-6-chloro-1,3,5-triazine [EP-A-314 472, Sankyo] in 400 ml of toluene. The reaction mixture is then refluxed for 20 hours. After cooling to room temperature, the reaction mixture is washed successively with water, 1N sodium hydrogen carbonate solution and saturated sodium chloride solution. The organic phases are combined, dried over potassium carbonate and concentrated on a vacuum rotary evaporator. Crystallisation of the residue from acetonitrile gives 52.2 g (74%) of 2-ethoxy-4,6-bis[N-(2,2,6,6-tetramethyl-4-piperidinyl)butylamino]-1,3,5-triazine, m.p. 95°-104° C., in the form of a white powder. 1H-NMR (300 MHz, CDCl3): δ=4.345 ppm (q, J=7 Hz) --OCH2CH3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:14])=[C:9]([C:11]([OH:13])=O)[N:10]=2)[N:7]=1.Cl.[CH2:16]([O:18][C:19](=[O:22])[CH2:20][NH2:21])[CH3:17].C(N(CC)CC)C>CN(C)C=O>[CH2:16]([O:18][C:19](=[O:22])[CH2:20][NH:21][C:11]([C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[N:7][N:6]2[C:8]=1[CH3:14])=[O:13])[CH3:17]
Reactant: CCOC(=O)CN
Reactant: Cc1c(C(=O)O)nc2ccc(Cl)nn12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)c1nc2ccc(Cl)nn2c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
3.9 g of ethyl 6-chloro-3-methylimidazo[1,2-b]pyridazine-2-carboxylate was suspended in 40 ml of tetrahydrofuran; 30 ml of a 1 N aqueous solution of sodium hydroxide was added, followed by stirring at room temperature for 3 hours. The mixture was concentrated under reduced pressure. The residue was adjusted to pH 4 by the addition of 50 ml of water and 1 N hydrochloric acid; the crystal precipitated was collected by filtration and dried to yield 2.55 g of 6-chloro-3-methylimidazo[1,2-b]pyridazine-2-carboxylic acid. 1.27 g of this carboxylic acid was dissolved in 20 ml of N,N-dimethylformamide; 1.07 g of N,N′-carbonyldiimidazole was added, followed by stirring at room temperature for 30 minutes. To this mixture, 0.922 g of glycine ethyl ester hydrochloride and 0.915 ml of triethylamine were added, followed by further stirring for 3 hours. 60 ml of ice water was added to the reaction mixture; the crystal precipitated was collected by filtration, washed with water and dried to yield 1.18 g of the title compound.
Reaction SMILES: [O:1]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]2[CH:8]=[CH:9][CH:10]=[C:11]([NH2:12])[C:2]1=2.Cl[C:14]1[N:19]=[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:23][C:22]=2[O:33][CH3:34])[C:17]([Cl:35])=[CH:16][N:15]=1>>[Cl:35][C:17]1[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)=[CH:23][C:22]=2[O:33][CH3:34])=[N:19][C:14]([NH:12][C:11]2[C:2]3[O:1][CH2:7][CH2:6][CH2:5][CH2:4][C:3]=3[CH:8]=[CH:9][CH:10]=2)=[N:15][CH:16]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1cccc2c1OCCCC2
Product: COc1cc(N2CCOCC2)ccc1Nc1nc(Nc2cccc3c2OCCCC3)ncc1Cl

Procedure:
The title compound was prepared from 2,3,4,5-tetrahydro-benzo[b]oxepin-9-ylamine and (2,5-dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine in an analogous manner to Example 179. Product was isolated as a light brown solid (51 mg, 40%). LCMS (m/e) 482 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 8.88 (broad s, 1H), 8.43 (broad s, 1H), 8.28 (s, 1H), 7.66 (d, 1H, J=8 Hz), 7.37 (d, 1H, J=9 Hz), 6.80 (d, 1H, J=7.58 Hz), 6.71 (s, 1H), 6.67 (dd, 1H, J=7.58, 8 Hz), 6.54 (d, 1H, J=8 Hz), 3.94 (m, 2H), 3.78 (m, 6H), 3.18 (m, 5H), 2.70 (m, 2H), 1.89 (m, 2H), 1.62 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[OH:19].Cl[CH2:21][C:22]#[N:23].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH:14]1([C:7]2([CH3:13])[CH2:6][C:5]3[C:9](=[C:10]([Cl:11])[C:2]([Cl:1])=[C:3]([O:19][CH2:21][C:22]#[N:23])[CH:4]=3)[C:8]2=[O:12])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: N#CCCl
Reactant: CC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C2CCCC2)Cc2cc(OCC#N)c(Cl)c(Cl)c2C1=O
Yield: 83.8 %

Procedure:
A mixture of 6,7-dichloro-2-cyclopentyl-5-hydroxy-2-methyl-2,3-dihydro-1H-inden-1-one (9.0 g, 30 mmole), chloroacetonitrile (2.5 g, 33 mmole), potassium carbonate (4.15 g), and potassium iodide (0.5 g) in acetone (150 ml) was stirred at reflux for 19 hours. Concentration to dryness in vacuo yielded an oil that crystallized upon trituration with water. Recrystallization from benzene-cyclohexane (ca. 1:3 by volume) gave the title compound (8.5 g), m.p. 129°-131°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16]Cl)[N:9]=[CH:8][NH:7][C:6]2=[O:18].[NH:19]1[CH2:24][CH2:23][S:22][CH2:21][CH2:20]1.C(O)(CC)C>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:19]1[CH2:24][CH2:23][S:22][CH2:21][CH2:20]1)[N:9]=[CH:8][NH:7][C:6]2=[O:18]
Reactant: C1CSCCN1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCCCl
Solvent: CO
Solvent: CCC(C)O
Product: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCSCC1
Temperature: 105 °C
Reaction time: 7.5 h
Yield: 87.6 %

Procedure:
In a 100 mL volume glass vessel equipped with a stirrer and a thermometer were placed 4.0 g (14.9 mmol) of 6-methoxy-7-(3-chloropropoxy)quinazolin-4-one prepared by procedures similar to those of Reference Example V-1, 5.0 g (48.5 mmol) of thiomorpholine, and 16 mL of sec-butyl alcohol. The resulting mixture was stirred at 105° C. for 7.5 hours. After the reaction was complete, 16 mL of methanol was added to the reaction mixture. The reaction mixture was refluxed for one hour and cooled to room temperature. Thus precipitated crystalline product was collected by filtration and dried at 60° C. under reduced pressure, to give 4.38 g (isolated yield: 81%) of 6-methoxy-7-(3-thiomorpholinopropoxy)quinazolin-4-one.
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)=O.P(Cl)(Cl)(Cl)=O.[N+:14]([C:17]1[N:21]([CH3:22])[C:20]([C:23]2[N:27]3[N:28]=[C:29]([NH2:32])[CH:30]=[CH:31][C:26]3=[N:25][N:24]=2)=[N:19][CH:18]=1)([O-:16])=[O:15]>O1CCOCC1>[N+:14]([C:17]1[N:21]([CH3:22])[C:20]([C:23]2[N:27]3[N:28]=[C:29]([N:32]=[CH:1][N:3]4[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]4)[CH:30]=[CH:31][C:26]3=[N:25][N:24]=2)=[N:19][CH:18]=1)([O-:16])=[O:15]
Reactant: O=CN1CCCCC1
Reactant: Cn1c([N+](=O)[O-])cnc1-c1nnc2ccc(N)nn12
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1c([N+](=O)[O-])cnc1-c1nnc2ccc(N=CN3CCCCC3)nn12
Reaction time: 1.5 h

Procedure:
2.85 ml. N-formyl-piperidine in 10 ml. dioxan were stirred with 2.4 ml. phosphorus oxychloride, which was introduced portionwise at 35° - 40° C., for 30 minutes at this temperature, then 1.5 g. crude 3-(5-nitro-1-methyl-2-imidazolyl)-6-amino-s-triazolo[4,3-b]pyridazine was added and the reaction mixture was stirred for 1.5 hours at 35° - 40° C. The solution obtained was now poured into 75 ml. ice water, filtered with suction and the clear filtrate was rendered alkaline (about pH 10) with concentrated aqueous ammonia, cooled, left to stand for some time and the resultant crystals (1.28 g.) filtered off with suction and recrystallized from 25 ml. isopropanol, with the addition of charcoal, 0.82 g. of the desired 3-(5-nitro-1-methyl-2 -imidazolyl)-6-(1-piperidinyl-methyleneamino)-s-triazolo[4,3-b]pyridazine thereby being obtained in the form of yellowish-white crystals which melt at 187° - 189° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH2:19]O)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:26])=O>>[Cl:1][C:2]1[C:3]([F:23])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH2:19][Cl:26])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CO
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CCl
Reaction time: 0.5 h
Yield: 100 %

Procedure:
{4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methanol (0.20 g, 0.604 mmol) was added to neat thionyl chloride (1 ml) over a period of 5 minutes. The resulting solution was stirred for 30 minutes, concentrated to dryness and the residue was subjected to an azeotropic distillation with toluene (2×10 ml). The resulting solid was triturated with acetonitrile (5 ml) filtered and dried to a constant weight in a vacuum oven at 40° C. to give the hydrochloride salt of N-(3-chloro-2-fluorophenyl)-6-(chloromethyl)-7-methoxyquinazolin-4-amine (0.21 g, 100%) as a white solid; Mass Spectrum: (M+H)+ 352.
Reaction SMILES: [OH:1]O.[CH2:3]([S:5][C:6]([CH2:11][CH3:12])=[CH:7][N+:8]([O-:10])=[O:9])[CH3:4]>C(O)=O>[CH2:3]([S:5]([C:6]([CH2:11][CH3:12])=[CH:7][N+:8]([O-:10])=[O:9])=[O:1])[CH3:4]
Reactant: OO
Reactant: CCSC(=C[N+](=O)[O-])CC
Solvent: O=CO
Product: CCC(=C[N+](=O)[O-])S(=O)CC
Temperature: 25 °C
Reaction time: 18 h
Yield: 25 %

Procedure:
2-Ethylsulfinyl-1-nitrobutene was prepared by the dropwise addition of aqueous hydrogen peroxide (1.05 g., 0.0093 mol) to a stirred solution of 2-ethylthio-1-nitrobutene (1.50 g., 0.0093 mol) in formic acid (20 ml.). The resulting solution was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure and the residue was dissolved in methylene chloride, washed successively with saturated aqueous sodium bicarbonate (1×50 ml.) and deionized water (1×50 ml.), dried over anhydrous magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (2:1 hexanes/ethyl acetate) afforded the isomeric mixture of the product as a yellow oil, 0.42g., 25% yield. 1H-NMR (CDCl3): δ 1.26, m, 3H, CH3 ; 1.5, t, 3H, CH3 ; 2.5-2.85, m, 2H, --CH2 --; 2.85-3.2, m, 2H, SCH2 --; 7.2+7.3, 2s, 1H, olefinic H.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][OH:12])[CH:7]=[CH:8][CH:9]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>C(#N)C>[OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][O:12][C:13](=[O:15])[CH3:14])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: OCCc1cccc(CCO)c1
Solvent: CC#N
Product: CC(=O)OCCc1cccc(CCO)c1
Yield: 41.6 %

Procedure:
2-[3-(2-Hydroxy-ethyl)-phenyl]-ethanol (2.49 g, 15.0 mmol) was dissolved in ACN (5 ml) and acetic anhydride (3.06 g, 30 mmol) added. The mixture was stirred under reflux for 1 h and then evaporated to dryness. Silica gel chromatography (HEP/EA gradient) of the residue yielded 1.30 g of the title compound (mono-acetylated product).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:12]=[CH:11][N:10]3[N:13]=[C:14]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)[C:15]([C:16](=[O:18])[CH3:17])=[C:9]3[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.CO[CH:30](OC)[N:31]([CH3:33])[CH3:32]>>[CH:1]1([NH:6][C:7]2[CH:12]=[CH:11][N:10]3[N:13]=[C:14]([C:19]4[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=4)[C:15]([C:16](=[O:18])[CH:17]=[CH:30][N:31]([CH3:33])[CH3:32])=[C:9]3[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(OC)N(C)C
Reactant: COc1ccc(-c2nn3ccc(NC4CCCC4)cc3c2C(C)=O)cc1
Solvent: O
Product: COc1ccc(-c2nn3ccc(NC4CCCC4)cc3c2C(=O)C=CN(C)C)cc1
Temperature: 25 °C
Yield: 80 %

Procedure:
A solution of 1-[5-(cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3yl]ethanone (1.14 g, 3.26 mmol) in N,N-dimethylformamide dimethyl acetal (25 mL) was heated at reflux for 5 days. The mixture was allowed to cool to room temperature. Water was added and the resulting mixture was extracted with ethyl acetate. The organic phase was dried (magnesium sulfate), filtered and concentrated. The resulting residue was crystallized from ethyl acetate to give 1-[5-(cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one (1.05 g, 80%) as a yellow solid. 1H NMR (CDCl3): δ 8.11 (d, 1H), 7.56 (m, 3H), 7.41 (d, 1H), 6.95 (d, 2H), 6.22 (dd, 1H), 5.07 (d, 1H), 4.11 (d, 1H), 3.95 (m, 1H), 3.84 (s, 3H), 3.0–2.3 (broad, 6H), 2.12 (m, 2H), 1.74–1.48 (m, 6H); MS m/z 405 (M+1).
Reaction SMILES: [Cl:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5](O)=[O:6].[CH2:10]([SH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(OCC)(=O)C>CN(C)C=O>[Cl:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5]([S:17][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6]
Reactant: SCc1ccccc1
Reactant: O=C(O)CCC(F)(F)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(CCC(F)(F)Cl)SCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
4.0 g of 4-chloro-4,4-difluorobutyric acid are added dropwise over the course of 45 minutes to a solution of 4.5 g of N,N'-carbonyldiimidazole in 30 ml of dimethylformamide at 0° C. After the solution has been stirred at 0° C. for 2 hours, 2.82 g of benzyl mercaptan are added and the mixture is allowed to warm to room temperature over the course of 17 hours. Then 100 ml of ethyl acetate are added and the organic solution is washed with saturated sodium chloride solution. The organic phase is dried over MgSO4 and evaporated. The resulting crude product is purified by chromatography on silica gel (mobile phase: hexane/ethyl acetate 9:1). This results in 4.0 g of S-benzyl 4-chloro-4,4-difluorothiobutyrate as an oil, nD20 : 1.5220.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:21])[CH2:4][NH:5][C:6](=[O:20])[C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]([C:16]([O:18]C)=[O:17])[CH:8]=1.O1CCOCC1.[OH-].[Na+]>O>[CH3:1][NH:2][C:3](=[O:21])[CH2:4][NH:5][C:6](=[O:20])[C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]([C:16]([OH:18])=[O:17])[CH:8]=1
Reactant: CNC(=O)CNC(=O)c1cc(C(=O)OC)cc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)CNC(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1

Procedure:
443.0 g. (1.5 moles) of N-(3-methoxycarbonyl-5-nitrobenzoyl)-glycine methylamide in 5.5 l. of dioxane is agitated for 2 hours at room temperature with the addition of 3.3 l. of 0.5 N sodium hydroxide solution. Thereafter, 400 ml. of water is added to the reaction mixture, the dioxane is distilled off under vacuum, and the acid is precipitated with concentrated hydrochloric acid, vacuum-filtered, washed free of salt with water, and dried under vacuum at 70° C.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[Cl:14][C:15]1[C:35]([O:36][C@H:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39])=[CH:34][CH:33]=[CH:32][C:16]=1[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([C:27](O)=[O:28])=[CH:24][CH:25]=2)[C:20]([CH3:30])=[C:19]1[CH3:31]>>[Cl:14][C:15]1[C:16]([CH2:17][N:18]2[C:26]3[C:21](=[CH:22][C:23]([C:27](=[O:28])[NH:13][C@H:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([CH:2]([CH3:4])[CH3:3])[CH:6]=4)[CH3:12])=[CH:24][CH:25]=3)[C:20]([CH3:30])=[C:19]2[CH3:31])=[CH:32][CH:33]=[CH:34][C:35]=1[O:36][C@H:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39]
Reactant: CC(C)c1cccc([C@H](C)N)c1
Reactant: COC(=O)[C@@H](C)Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1Cl
Agent: Cl
Product: COC(=O)[C@@H](C)Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)c1Cl

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (R)-1-(2-chloro-3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:15]3[C:11](=[N:12][N:13]=[C:14]3[C@H:16]3[CH2:21][CH2:20][C@H:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:18][CH2:17]3)[CH2:10][NH:9][CH2:8][C:7]=2[CH:29]=1.C(N(CC)CC)C.[CH3:37][N:38]([CH3:43])[CH2:39][C:40](O)=[O:41].Cl.CN(C)CCCN=C=NCC>O1CCCC1>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:15]3[C:11](=[N:12][N:13]=[C:14]3[C@H:16]3[CH2:17][CH2:18][C@H:19]([O:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:20][CH2:21]3)[CH2:10][N:9]([C:40](=[O:41])[CH2:39][N:38]([CH3:43])[CH3:37])[CH2:8][C:7]=2[CH:29]=1
Reactant: Clc1ccc2c(c1)CNCc1nnc([C@H]3CC[C@H](Oc4ccccc4)CC3)n1-2
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)CC(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](Oc3ccccc3)CC2)C1
Reaction time: 0.17 h

Procedure:
To a mixture of trans-8-chloro-1-(4-phenoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride (0.179 g, 0.41 mmol) in tetrahydrofuran (2 ml) was added triethylamine (0.058 ml, 0.41 mmol). The suspension was stirred for 10 minutes. The ammonium salts were removed by filtration. The filtrate was concentrated in vacuo. The residue was redissolved in tetrahydrofuran (3 ml) followed by consecutive addition of N,N-dimethylglycine (0.056 g, 0.54 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.104 g, 0.54 mmol. Stirring for 18 h at 50° C. was followed by partitioning between water (50 ml) and dichloromethane (50 ml). The organic layer was separated. The aqueous layer was extracted with one 50-ml portion of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash-chromatography with n-heptane/ethyl acetate as eluent gave the title compound (0.057 g, 28%) as white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:30]O)([CH3:4])([CH3:3])[CH3:2].C1COCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:58]>CCOC(C)=O>[C:1]([O:5][C:6](=[O:32])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:30][Br:58])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CBr)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
A 100 mL round bottomed flask was charged with 3-{2-hydroxymethyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl}propionic acid tert-butyl ester (1.0 g, 2.29 mmol), anhydrous THF (25 mL), and then triphenylphosphine (1.20 g, 4.57 mmol) and CBr4 (1.52 g, 4.57 mmol). The yellow mixture was stirred at ambient temperature under a nitrogen atmosphere for 1 h and was poured into EtOAc (100 mL). The organic layer was washed with brine, dried (Na2SO4), and concentrated. The crude product was purified using radial chromatography (EtOAc:hexanes 15:85 to 25:75) to give a colorless oil (0.95 g, 83%). MS (ES) m/e 501 (M+1).
Reaction SMILES: Br[CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[NH2:12][C:13]([NH2:15])=[S:14]>CCO>[CH3:11][C:2]1[S:14][C:13]([NH2:15])=[N:12][C:3]=1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NC(N)=S
Reactant: CC(Br)C(=O)c1ccccc1
Solvent: CCO
Product: Cc1sc(N)nc1-c1ccccc1
Yield: 109.7 %

Procedure:
A mixture of 2-bromo-1-phenylpropan-1-one (3.00 g, 19.5 mmol) and thiourea (1.56 g, 20.5 mmol) in 95% EtOH (30 mL) was heated at reflux for 60 min. The solution was concentrated and mixed with water (100 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 5-methyl-4-phenylthiazol-2-amine (4.07 g) as yellow solids in 77% yield: 1H NMR (500 MHz, DMSO-d6) δ 8.85 (s, 2H), 7.54-7.49 (m, 5H), 2.28 (s, 3H).
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])=[O:5].[OH2:17].[OH-].[Na+]>CO>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH:7]1[CH2:8][CH:6]1[C:4]([OH:17])=[O:5]
Reactant: CON(C)C(=O)C1CC1c1ccccc1Cl
Reactant: O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CC1c1ccccc1Cl
Temperature: 25 °C

Procedure:
A mixture of 2-(2-chloro-phenyl)-cyclopropanecarboxylic acid methoxy-methyl-amide (9.6 g), water (20 mL), and NaOH (3.2 g) in MeOH (40 mL) was refluxed for 3 h. The reaction mixture was cooled down to room temperature and concentrated in vacuo. The residue was acidified by 6 N HCl followed by extraction with CH2Cl2. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo to give the title compound (7.8 g).