Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([C:21]3[CH2:22][CH2:23][NH:24][CH2:25][CH:26]=3)[CH:16]=2)[CH2:13][C:12]([C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])=[N:11]1.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([C:21]3[CH2:22][CH2:23][N:24]([S:42]([CH3:41])(=[O:44])=[O:43])[CH2:25][CH:26]=3)[CH:16]=2)[CH2:13][C:12]([C:27]([F:32])([F:33])[C:28]([F:30])([F:31])[F:29])=[N:11]1
Reactant: CS(=O)(=O)Cl
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2ccnc(C3=CCNCC3)c2)c(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CC=C(c2cc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)ccn2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.5 %

Procedure:
1-(2,4-Difluoro-phenyl)-5-[2-(1,2,3,6-tetrahydropyridin-4-yl)-pyridin-4-yl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.06 mmol) prepared in Example 190, triethylamine (42.0 uL, 0.30 mmol) and methanesulfonyl chloride (7.0 uL, 0.09 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 18 hours, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 5.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([F:22])([F:21])[C@H:6]([OH:20])[C@H:7]([CH2:16][CH:17]([CH3:19])[CH3:18])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])C.[OH-].[Na+].C(O)(=O)C(C(C(O)=O)O)O>CO.O>[C:9]([NH:8][C@H:7]([C@H:6]([C:5]([F:21])([F:22])[C:4](=[O:3])[OH:23])[OH:20])[CH2:16][CH:17]([CH3:19])[CH3:18])([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10]
Reactant: CCOC(=O)C(F)(F)[C@H](O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C(F)(F)C(=O)O

Procedure:
1 g N--BOC--(4S,3R)-2,2-difluorostatine ethyl ester is dissolved in methanol/water and reacted with 0.25 g of concentrated aqueous sodium hydroxide. After 2 hours the mixture is made acidic with 2N tartaric acid solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated to dryness. N--BOC--(4S,3R)-2,2-difluorostatine is obtained (crude).
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[C:8](=[O:18])[N:9]([CH2:14][CH2:15][CH2:16][OH:17])[N:10]=[CH:11][C:12]=1[OH:13].[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:6][C:7]1[C:8](=[O:18])[N:9]([CH2:14][CH2:15][CH2:16][OH:17])[N:10]=[CH:11][C:12]=1[O:13][CH2:24][C:23]1[CH:26]=[CH:27][C:20]([Cl:19])=[CH:21][CH:22]=1
Reactant: O=c1c(Cl)c(O)cnn1CCCO
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c(Cl)c(OCc2ccc(Cl)cc2)cnn1CCCO
Yield: 74.7 %

Procedure:
To 150 ml of N,N-dimethylformamide were added 10.2 g of 4-chloro-5-hydroxy-2-(3'-hydroxypropyl)-3(2H)-pyridazinone (0.05 mol), 8.4 g of 4-chlorobenzyl chloride (0.052 mol) and 10.4 g of anhydrous potassium carbonate (0.075 mol) and heated for about 3 hours at 100° C. to 120° C. After reaction, the mixture solution was poured into water and extracted with ethyl acetate. The resulting solution was washed with water and then with aqueous solution of 5% sodium hydroxide and further with saturated saline. The solution was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The solid product thus obtained was washed with n-hexane and dried to obtain 12.3 g of 4-chloro-5-(4'-chlorobenzyloxy)-2-(3'-hydroxypropyl)-3(2H)-pyridazinone.
Reaction SMILES: C([N:8]1[C:20]([CH3:21])=[C:19]2[C:10]([C:11]([NH2:22])=[N:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=32)=[N:9]1)C1C=CC=CC=1>Br.C(O)(=O)C>[CH3:21][C:20]1[NH:8][N:9]=[C:10]2[C:19]=1[C:18]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:12]=[C:11]2[NH2:22]
Reactant: Cc1c2c(nn1Cc1ccccc1)c(N)nc1ccccc12
Agent: Br
Agent: *C(F)(F)C(*)(F)F
Solvent: CC(=O)O
Product: Cc1[nH]nc2c(N)nc3ccccc3c12
Temperature: 140 °C

Procedure:
A poly(tetrafluoroethylene)-lined steel pressure vessel containing a solution of 2-benzyl-1-methyl-2H-pyrazolo[3,4-c]quinolin-4-amine (prepared as described in Example 36, 0.8821 g, 3.06 mmol) in anhydrous hydrogen bromide in acetic acid (10 mL) was heated in a 140° C. oven for 17 hours. The vessel was allowed to cool to room temperature. A solid formed that was isolated by filtration and washed with water to yield 1-methyl-2H-pyrazolo[3,4-c]quinolin-4-amine that was used in the next step.
Reaction SMILES: [CH3:1][C:2]1([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[N:6]([C:7](Cl)=[O:8])[CH2:5][C:4]([CH3:11])([CH3:10])[O:3]1.[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][C:2]1([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[N:6]([C:7]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[O:8])[CH2:5][C:4]([CH3:11])([CH3:10])[O:3]1
Reactant: CCCCCCC1(C)OC(C)(C)CN1C(=O)Cl
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCC1(C)OC(C)(C)CN1C(=O)n1ccnc1
Yield: 92 %

Procedure:
A mixture comprising 2.6 g (0.01 mole) of 2-methyl-2-n-hexyl-3-chlorocarbonyl-5,5-dimethyl-1,3-oxazolidine, 1.0 g (0.015 mole) of imidazole and 2.1 g (0.015 mole) of potassium carbonate was stirred with 30 ml of dimethylformamide (DMF) as the solvent at 50° C. to 60° C. for one hour. After completion of the reaction, water was added and then the mixture was extracted with toluene. The toluene layer was washed with water, dried and condensed, and then purified by a column chromatography, thereby obtaining 2.7 g of the title compound having pale yellow color.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH:10]=[C:9]([CH3:23])[N:8]=2)=[CH:4][CH:3]=1.[NH2:24][C:25]1[N:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1>>[CH3:23][C:9]1[N:8]=[C:7]([C:5]2[S:6][C:2]([C:28]3[CH:27]=[N:26][C:25]([NH2:24])=[N:30][CH:29]=3)=[CH:3][CH:4]=2)[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:10]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccc(Br)s2)n1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccc(-c3cnc(N)nc3)s2)n1

Procedure:
The title compound was prepared from 2-(5-bromo-thiophen-2-yl)-6-methyl-4-(4-trifluoromethyl-phenyl)-pyridine (example E.86) (0.20 g, 0.502 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.124 g, 0.552 mmol) according to the general procedure VI. Obtained as a yellow solid (0.045 g, 21%). MS (ISP) 413.2 [(M+H)+]; mp>250° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Br:9])[C:7]=1[OH:8].O.[C:14]([OH:18])(=[O:17])[CH:15]=O>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:10](=[O:12])/[CH:11]=[CH:15]/[C:14]([OH:18])=[O:17])[CH:5]=[C:6]([Br:9])[C:7]=1[OH:8]
Reactant: O=CC(=O)O
Reactant: CC(=O)c1cc(Br)c(O)c(Br)c1
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)/C=C/C(=O)c1cc(Br)c(O)c(Br)c1
Yield: 78.5 %

Procedure:
A mixture of 1-(3,5-dibromo-4-hydroxyphenyl)ethanone (5.0 g, 17.01 mmol) and glyoxylic acid monohydrate (1.566 g, 17.01 mmol) in acetic acid (10 mL) was stirred and heated at reflux for 5 days. After this time, the precipitate formed was collected and recrystallised from toluene. This gave the title compound as a brown solid (4.674 g, 78%). 1H NMR δ (ppm) (DMSO-d6): 6.70 (1 H, d, J=15.45 Hz), 7.93 (1 H, d, J=15.46 Hz), 8.24 (2 H, s).
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].C([Mg]Br)(C)C.[CH:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C.C(OCC)C>[C:11]1([CH:10]([OH:17])[CH2:3][C:2]#[CH:1])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C#CCBr
Reactant: O=Cc1ccccc1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: CC(C)[Mg]Br
Agent: Cl
Solvent: CCOCC
Product: C#CCC(O)c1ccccc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
To 0.425 ml (1.43 mmol) of tetraisopropoxytitanium and 10 ml of ethyl ether solution of propargyl bromide (0.127 ml, 1.43 mmol) was added dropwise at −50° C. 1.90 ml of 1.43M ethyl ether solution containing isopropylmagnesium bromide (2.72 mmol). After stirring at −50° C. to −40° C. for 1 hour, the reaction liquid was given 0.102 ml (1.0 mmol) of benzaldehyde at −40° C. and heated to −20° C. over 30 minutes. With 1N hydrochloric acid added, the solution was heated to room temperature and separated into layers. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate. After drying with anhydrous magnesium sulfate, the solution was freed of solvent by vacuum distillation. The residues were purified by silica gel chromatography. Thus there was obtained 124 mg of 4-phenyl-1-butyn-4-ol (85% yields based on benzaldehyde).
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH:9]=[C:10]([CH3:28])[CH2:11][CH2:12][CH:13]=[C:14]([CH:26]=[O:27])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:25])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23].C(=O)([O-])O.[Na+].[BH4-].[Na+].C([O-])(=O)C>CO.C(O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[OH:27][CH2:26]/[C:14](/[CH2:15][CH2:16]/[CH:17]=[C:18](\[CH3:25])/[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])=[CH:13]/[CH2:12][CH2:11]/[C:10](/[CH3:28])=[CH:9]/[CH2:8][OH:7]
Reactant: CC(C)=CCCC(C)=CCCC(C=O)=CCCC(C)=CCOC1CCCCO1
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Solvent: CCO
Solvent: O
Solvent: CO
Product: CC(C)=CCC/C(C)=C/CC/C(=C\CC/C(C)=C/CO)CO
Reaction time: 8 h
Yield: 83.7 %

Procedure:
In 100 ml of methanol was dissolved 10.0 g of 7-formyl-3,11,15-trimethyl-2,6,10,14-hexadecatetraen-1-ol tetrahydropyranyl ether prepared in Example 2-(1), and to this solution was added 100 mg of p-toluenesulfonic acid. The mixture was allowed to stand overnight at room temperature and neutralized with an aqueous sodium hydrogencarbonate solution. The methanol was distilled off, and the residue was extracted with ether, (E,E,E)-7-Formyl-3,11,15-trimethyl-2,6,10,14-hexadecatetraen-1-ol obtained from the ethereal layer was dissolved in 60 ml of ethanol. After addition of 5.5 g of sodium borohydride under ice-cooling, the solution was vigorously stirred for 2 hours. The mixture was then treated with dilute acetate acid and, after addition of water, extracted with ether. The oil obtained from the ethereal layer was purified by the silica gel column chromatography, yielding 6.6 g of the desired (E,E,E)-7-hydroxymethyl-3,11,15-trimethyl-2,6,10,14-hexadecatetraen-1-ol.
Reaction SMILES: [CH2:1]1[CH:8]2[C:4]3([C:10]([NH:12][C:13]4[S:21][C:16]5[CH2:17][O:18][CH2:19][CH2:20][C:15]=5[C:14]=4[C:22](O)=[O:23])=[O:11])[CH2:5][CH:6]([CH2:9][CH:2]1[CH2:3]3)[CH2:7]2.[F:25][C:26]([F:31])([F:30])[CH2:27][CH2:28][NH2:29]>>[CH2:7]1[CH:8]2[C:4]3([C:10]([NH:12][C:13]4[S:21][C:16]5[CH2:17][O:18][CH2:19][CH2:20][C:15]=5[C:14]=4[C:22]([NH:29][CH2:28][CH2:27][C:26]([F:31])([F:30])[F:25])=[O:23])=[O:11])[CH2:3][CH:2]([CH2:9][CH:6]1[CH2:5]3)[CH2:1]2
Reactant: NCCC(F)(F)F
Reactant: O=C(O)c1c(NC(=O)C23CC4CC(CC2C4)C3)sc2c1CCOC2
Product: O=C(NCCC(F)(F)F)c1c(NC(=O)C23CC4CC(CC2C4)C3)sc2c1CCOC2

Procedure:
The title compound was prepared from 2-[(hexahydro-2,5-methano-pentalene-3a-carbonyl)-amino]-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid. (Example 10A) and 3,3,3-trifluoropropylamine according to the procedure described for Example 166C. 1H NMR (DMSO-d6, 300 MHz) δ 1.62-1.67 (m, 4H), 1.76-1.88 (m, 4H), 1.98-2.02 (m, 2H), 2.33 (br s, 2H), 2.51-2.63 (m, 3H), 2.81 (t, J=5.3 Hz, 2H), 3.52 (q, J=6.8 Hz, 2H), 3.85 (t, J=5.4 Hz, 2H), 4.65 (br s, 2H), 7.50 (t, J=5.6 Hz, 1H), 11.83 (br s, 1H). MS (ESI+) m/z 443.1 (M+H)+. Anal. calcd. for C21H25F3N2O3S: C, 57.00; H, 5.69; N, 6.33. Found: C, 57.24; H, 5.56; N, 6.27.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:14][C:13](=[O:15])[O:12][C:10](=O)[CH2:9]2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:25]=[C:21]([C:22]([NH2:24])=[O:23])[C:20]([NH2:26])=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:9][C:10]2[N:24]=[C:22]([OH:23])[C:21]3[C:20](=[CH:19][CH:18]=[C:17]([Cl:16])[CH:25]=3)[N:26]=2)[CH2:14][C:13]([OH:12])=[O:15])=[CH:6][CH:7]=1
Reactant: O=C1CC(c2ccc(Cl)cc2)CC(=O)O1
Reactant: NC(=O)c1cc(Cl)ccc1N
Product: O=C(O)CC(Cc1nc(O)c2cc(Cl)ccc2n1)c1ccc(Cl)cc1

Procedure:
By a procedure similar to that of 1.133, starting from 3-(4-chlorophenyl)glutaric anhydride and 5-chloroanthranilamide, 3-(4-chlorophenyl)-4-(6-chloro-4-hydroxy-2-quinazolinyl)butanoic acid was obtained as colourless solid.
Reaction SMILES: [OH-].[Na+].[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[S:8](Cl)(=[O:10])=[O:9].[Br:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[CH:16][NH:17]2>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.S1C=CC=C1S(Cl)(=O)=O>[Br:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[CH:16][N:17]2[S:8]([C:4]1[S:3][CH:7]=[CH:6][CH:5]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: Brc1cccc2[nH]ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Product: O=S(=O)(c1cccs1)n1ccc2c(Br)cccc21
Reaction time: 22 h
Yield: 95.7 %

Procedure:
Aq. 2.5M NaOH (3 mL) was added to a stirring mixture of 2-thiophenesulfonyl chloride (1.03 g, 5.61 mmol), 4-bromoindole (1.00 g, 5.10 mmol) and tetrabutylammonium hydrogen sulfate (87 mg, 0.05 mmol). The reaction was stirred over night (22 h). Additional 2-thiophenesulfonyl chloride (50 mg, 0.27 mmol) was added with continuous stirring for 3 h. The layers were allowed to separate. The organic layer was washed twice with water, dried and concentrated to get the title compound (1.67 g, 96%) as a gray solid.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH:6]1([CH3:16])[CH2:11][CH2:10][CH:9]([CH:12]([CH3:14])[CH3:13])[CH:8]([OH:15])[CH2:7]1.N1C=CC=CC=1>C(OCC)C>[Cl:1][CH2:2][C:3]([O:15][CH:8]1[CH:9]([CH:12]([CH3:13])[CH3:14])[CH2:10][CH2:11][CH:6]([CH3:16])[CH2:7]1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CC1CCC(C(C)C)C(O)C1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC1CCC(C(C)C)C(OC(=O)CCl)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
A solution of chloroacetyl chloride (6.4 mL, 80 mmol) in 40 mL anhydrous diethyl ether was added dropwise within 2 h to a solution of (−)-menthol (3a) (12.5 g, 80 mmol) and pyridine (6.5 mL, 80 mmol) in anhydrous diethyl ether (160 mL) at 0° C. After warming to RT, the white suspension was stirred for 2 h and the resulting mixture was then filtered. The filtrate was washed with HCl (60 mL, 2 N), saturated. NaHCO3 (60 mL), brine and dried with Na2SO4. Removal of the solvent and drying under vacuum afford (−)-menthyl chloroacetate (4a) (17.64 g, 94%), which was used without further purification. U.S. Pat. No. 4,456,611; Helv. Chim. Acta 1988, 71, 1553.
Reaction SMILES: CS[CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][N:13]3[CH2:17][CH2:16][O:15][C:14]3=[O:18])[CH:10]=2)[NH:5][C:4]1=[O:19]>C(O)(=O)C.[Zn]>[O:18]=[C:14]1[N:13]([CH2:12][C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[NH:5][C:4](=[O:19])[CH2:3]3)[CH2:17][CH2:16][O:15]1
Reactant: CSC1C(=O)Nc2ccc(CN3CCOC3=O)cc21
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C1Cc2cc(CN3CCOC3=O)ccc2N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the compound obtained in Step C in glacial acetic acid (320 ml) there is added powdered zinc (1 mol). The reaction mixture is stirred overnight at ambient temperature and is then filtered. The filtrate is concentrated, and then 100 ml of water are added. The solid formed is filtered off and then recrystallised from ethanol to yield the title product.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[C:47](Cl)(=[O:51])[CH2:48][CH2:49][CH3:50].C(N(CC)CC)C>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH:46][C:47](=[O:51])[CH2:48][CH2:49][CH3:50])[CH:43]=[CH:44][CH:45]=2)=[N:8]1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: CCCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(=O)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.200 g, 0.33 mmol) in 4 mL of tetrahydrofuran was added butanoyl chloride (0.052 mL, 0.49 mmol) followed by triethyl amine (0.230 mL, 0.167 mmol). The reaction was stirred at room temperature for 15 hours. The reaction mixture was partitioned between water and ethyl acetate. The residue was not purified (yield not calculated). ES-MS (m/z) 673 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:65])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([NH:61]C(=O)C)=[N:58][CH:57]=1)(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.Cl>>[CH3:1][O:2][C:3](=[O:65])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:38]=[CH:39][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:41][CH:42]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([NH2:61])=[N:58][CH:57]=1)(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1cnc(NC(C)=O)s1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1cnc(N)s1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-2-({(S)-7-(2-Acetylamino-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester was treated with HCl according to General Procedure N to give (S)-2-({(S)-7-(2-Amino-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([C:17]([F:20])([F:19])[F:18])[N:10]([CH3:21])[N:9]=2)=[CH:4][CH:3]=1.[N+:22]([O-])([OH:24])=[O:23]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([F:15])([F:16])[F:14])=[C:11]([C:17]([F:20])([F:18])[F:19])[N:10]([CH3:21])[N:9]=2)=[CH:4][C:3]=1[N+:22]([O-:24])=[O:23]
Reactant: Cn1nc(-c2ccc(Cl)cc2)c(C(F)(F)F)c1C(F)(F)F
Reactant: O=[N+]([O-])O
Product: Cn1nc(-c2ccc(Cl)c([N+](=O)[O-])c2)c(C(F)(F)F)c1C(F)(F)F
Temperature: 0 °C

Procedure:
9 g (27 mmol) of 3-(4-chlorophenyl)-1-methyl-4,5-di(trifluoromethyl)-1H-pyrazole were added at (-40)° C. to 100 ml of concentrated nitric acid, whereupon the mixture was stirred for 2 hours at this temperature. The solution, which was subsequently warmed to 0° C., was treated with ice-water. The product was subsequently extracted with methyl tert-butyl ether. The organic phase was washed with water, dried over magnesium sulfate and concentrated.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][SH:7].[OH-].[K+].Cl.Cl[CH2:12][CH2:13][NH2:14].C1(C)C=CC=CC=1>O>[NH2:14][CH2:13][CH2:12][S:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: NCCCl
Reactant: SCc1cccs1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: NCCSCc1cccs1
Reaction time: 3 h

Procedure:
The crude product from (a) was taken up under nitrogen in a solution of 128 g of potassium hydroxide (2.3 moles) in 150 ml of water. A solution of 88.2 g (0.76 mole) of 2-chloroethyl amine hydrochloride in 100 ml of water was then added dropwise with stirring at 323° K. After 3 hours on a steam bath, the reaction mixture was taken up with 200 ml of toluene, the toluene phase was washed with 200 ml of water, dried with sodium chloride, concentrated and fractionated in vacuo.
Reaction SMILES: C([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C@H:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:11][C@H:10]1[NH:20][C:21]([C:23]1[S:24][C:25]2[CH2:26][N:27]([CH3:32])[CH2:28][CH2:29][C:30]=2[N:31]=1)=[O:22])=O)(C)(C)C.Cl.[Cl:34][C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][CH:43]=1)[NH:40][C:39](C(O)=O)=[CH:38]2>C(O)C>[Cl:34][C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][CH:43]=1)[NH:40][C:39]([C:6]([NH:8][C@H:9]1[CH2:14][C@H:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:11][C@H:10]1[NH:20][C:21]([C:23]1[S:24][C:25]3[CH2:26][N:27]([CH3:32])[CH2:28][CH2:29][C:30]=3[N:31]=1)=[O:22])=[O:5])=[CH:38]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CCOC(=O)[C@@H]1CC[C@@H](NC(=O)c2nc3c(s2)CN(C)CC3)[C@@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)[C@@H]1CC[C@@H](NC(=O)c2nc3c(s2)CN(C)CC3)[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)C1

Procedure:
(1R*,2S*,4R*)-N2-tert-Butoxycarbonyl-4-ethoxycarbonyl-N1-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine was treated with a saturated ethanol solution of hydrochloric acid and then condensed with 5-chloroindole-2-carboxylic acid in a similar manner to Example 118 to obtain the title compound.
Reaction SMILES: [Cl:1][CH:2]=[CH:3][CH2:4][N:5]([CH2:8][CH:9]=[CH:10][Cl:11])C#N.OS(O)(=O)=O>O>[Cl:1][CH:2]=[CH:3][CH2:4][NH:5][CH2:8][CH:9]=[CH:10][Cl:11]
Reactant: N#CN(CC=CCl)CC=CCl
Agent: O=S(=O)(O)O
Solvent: O
Product: ClC=CCNCC=CCl
Temperature: 25 °C
Yield: 85 %

Procedure:
N,N-Bis-(3-chloroallyl)cyanamide (38.2 g; 0.2 mole) was placed in a flask, and 16 milliliters (ml) of concentrated H2SO4 in 92 ml of water was added. The resulting mixture was refluxed for four hours under stirring, and then after the mixture was cooled to room temperature, 50 ml of water was added. The mixture was extracted with 50 ml of ether, and the ether extract was discarded. To the water phase, 200 ml of water was added. In an ice bath under stirring, a solution of 47.4 g of NaOH in 92 ml of water was slowly added dropwise. After the addition was completed, the mixture was extracted three times with ether; the ether phases were combined, washed with water twice, dried over magnesium sulfate, filtered and stripped. The yield was 85%. The product (28.2 g) was recovered as an orange-brown liquid.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[CH:2]1.[H-].[Na+].CS(O[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][CH2:22]1)(=O)=O.C(OC(=O)NC1CCN(CCN2C3C(=CC=C(F)C=3)N=CC2=O)CC1)(C)(C)C>>[C:31]([O:30][C:28](=[O:29])[NH:27][CH:24]1[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[CH:3]=[CH:2]2)[CH2:22][CH2:23]1)([CH3:34])([CH3:33])[CH3:32]
Reactant: O=c1cc[nH]c2ccccc12
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Agent: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)NC1CCN(CCn2ccc(=O)c3ccccc32)CC1
Yield: 76 %

Procedure:
Quinolin-4(1H)-one (250 mg, 1.7 mmol) was deprotonated with sodium hydride (60% in oil, 70 mg, 1.7 mmol) and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6) (1.7 mmol) as described for Intermediate 141. The precipitate formed in the reaction mixture was collected by filtration to give 480 mg (76%) of product as a colorless solid.