Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([O:9][CH3:10])[C:2](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:3][CH3:4].[I:11]I>C(O)C>[I:11][C:7]1[CH:8]=[C:1]([O:9][CH3:10])[C:2]([O:3][CH3:4])=[CH:5][CH:6]=1
Reactant: II
Reactant: COc1ccccc1OC
Solvent: CCO
Product: COc1ccc(I)cc1OC
Yield: 70 %

Procedure:
A solution of veratrole (28.0 ml, 0.22M) in 95% ethanol (75 ml) was heated to 60° C. and, while stirring, was treated with iodine (50 g, 0.197M) and yellow mercuric oxide (30.0 g, 0.1385M). The iodine and mercuric oxide were added alternately in small portions over a period of 1.5 hours. After the addition was complete, the cooled mixture was filtered through Celite and concentrated. The residue was taken up in Et2O and again filtered. The Et2O solution was washed with solutions of sodium thiosulfate, 2N NaOH, saturated NaCl, dried over anhydrous K2CO3 and evaporated. The residue was distilled under reduced pressure to give 40.88 g, bp 110°-112° C. (2mm) pure 4-iodoveratrole [70% yield, literature: Gutzke et al., J. Org. Chem. 22, 1271 (1957), bp 80°-85° C. (1 mm)]. NMR (CDCl3) δ 3.80 ppm (s, 6H, (2x) OCH3), 6.57 (d, 1H, ArH6), 7.20 (m, 2H, ArH3 and ArH5).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:14]O)[CH:5]=[C:6]([C:8]2[N:12]([CH3:13])[N:11]=[N:10][N:9]=2)[CH:7]=1>CO.Cl.[Pd]>[CH3:14][C:4]1[CH:3]=[C:2]([NH2:1])[CH:7]=[C:6]([C:8]2[N:12]([CH3:13])[N:11]=[N:10][N:9]=2)[CH:5]=1
Reactant: Cn1nnnc1-c1cc(N)cc(CO)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1cc(N)cc(-c2nnnn2C)c1
Yield: 77.1 %

Procedure:
A solution of [3-Amino-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-methanol (450 mg) in MeOH (20 ml) with a few drops of conc. HCl (aq) was hydrogenated on a H-cube apparatus at 30° C., and 10 bar with a flow rate of 1 mL/min using a Pd/C cartridge. After reaction completion, the mixture was concentrated in vacuum and the residue basified with a dilute K2CO3(aq). This was extracted with EtOAc and the organic layer was separated, dried and concentrated in vacuum. The residue was purified by flash chromatography (98:2 DCM:MeOH) to give the title compound (320 mg).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[N:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[NH2:21][C@@H:22]([CH2:27][CH:28]1[CH2:30][CH2:29]1)[C:23]([CH3:26])([OH:25])[CH3:24]>>[CH:28]1([CH2:27][C@H:22]([NH:21][C:12]([C:10]2[CH:9]=[N:8][C:7]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[C:23]([OH:25])([CH3:26])[CH3:24])[CH2:30][CH2:29]1
Reactant: CC(C)(O)[C@@H](N)CC1CC1
Reactant: O=C(O)c1cnc(N2CC(F)(F)C2)c(OCC2CC2)n1
Product: CC(C)(O)[C@H](CC1CC1)NC(=O)c1cnc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 15, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid (Example 8d, 100 mg, 0.35 mmol) and (S)-3-amino-4-cyclopropyl-2-methyl-butan-2-ol (60.21 mg, 0.42 mmol) as starting materials, and isolated (50 mg, 34.72%) as white solid, LC-MS (UV peak area, ESI) 96.42%, 410.8 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[NH:13][CH:12]=[CH:11]3)[CH2:2]1.[C:19](OC(N1CCC[C@@H](OS(C)(=O)=O)C1)=O)(C)(C)C.OC1C=C2C(=CC=1C)C(=O)NC=C2>>[CH3:19][C:17]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][NH:13][C:14]2=[O:18])=[CH:9][C:8]=1[O:7][CH:3]1[CH2:4][CH2:5][CH2:6][NH:1][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](OS(C)(=O)=O)C1
Reactant: O=c1[nH]ccc2cc(O[C@H]3CCCNC3)ccc12
Agent: Cc1cc2c(=O)[nH]ccc2cc1O
Product: Cc1cc2c(=O)[nH]ccc2cc1OC1CCCNC1

Procedure:
Prepared according to Example 24C and 24D using (R)-3-methanesulphonyloxy-piperidine-1-carboxylic acid tert-butyl ester and 6-hydroxy-7-methyl-2H-isoquinolin-1-one to afford 7-Methyl-6-(piperidin-3-yloxy)-2H-isoquinolin-1-one El-MS: m/z=259.1 [M+H]+.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.[OH-].[K+]>C(O)C>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([C:12]2[C:13]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:10][CH:11]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: COc1ccc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2c[nH]c3ncccc23)cc1OC
Temperature: 120 °C

Procedure:
1-Benzenesulfonyl-3-(3,4-dimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine (5, 290 mg, 0.74 mmol) was dissolved in ethanol (4 mL) and potassium hydroxide pellets (330 mg, 5.9 mmol) were added. The reaction was heated in a CEM Discover microwave instrument at 120° C. for 10 minutes. The reaction mixture was concentrated to dryness and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic portions were dried with anhydrous magnesium sulfate, filtered and the filtrate concentrated to provide the desired product, 1, which was used without further purification (191 mg). MS(ESI) [M+H+]+=255.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]#[N:16])([CH3:4])([CH3:3])[CH3:2].[N-:18]=[N+:19]=[N-:20].[Na+].[Cl-].[NH4+].C(OCC)(=O)C>CN(C)C=O>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[NH:20][N:19]=[N:18][N:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccccc1C#N
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccccc1-c1nnn[nH]1
Temperature: 25 °C

Procedure:
A solution of (2-cyano-benzyl)-carbamic acid tert-butyl ester (35 mg, 0.15 mmol), sodium azide (49 mg, 0.75 mmol), ammonium chloride (40 mg, 0.75 mmol) in dimethylformamide (0.5 ml) was heated to 110° C. for 8 h. After cooling to room temperature, ethyl acetate was added and the resultant solid filtered. Concentration of the filtrate gave [2-(1H-tetrazol-5-yl)-benzyl]-carbamic acid tert-butyl ester; 1H NMR (CD3OD, 400 MHz) δ7.71(d, 1H, J=7.5 Hz), 7.58 (m, 2H), 7.48 (m, 1H), 4.44 (s, 2H), 1.42 (s, 9H).
Reaction SMILES: [C:1]1([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[C:2]([OH:11])=[CH:3][CH:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2.[P:22](Cl)(Cl)Cl.[C:26]1([P:32]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]=2[C:43]2[C:52]3[C:47](=[CH:48][C:49]([CH:53]=[CH2:54])=[CH:50][CH:51]=3)[CH:46]=[CH:45][C:44]=2[OH:55])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:56]1([P:32]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]=2[C:43]2[C:52]3[C:47](=[CH:48][C:49]([CH:53]=[CH2:54])=[CH:50][CH:51]=3)[CH:46]=[CH:45][C:44]=2[O:55][C:13]2[CH:14]=[CH:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:12]=2[C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][C:2]=2[O:11][PH2:22])[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1
Reactant: ClP(Cl)Cl
Reactant: C=Cc1ccc2c(-c3c(P(c4ccccc4)c4ccccc4)ccc4ccccc34)c(O)ccc2c1
Reactant: Oc1ccc2ccccc2c1-c1cccc2ccccc12
Product: C=Cc1ccc2c(-c3c(P(c4ccccc4)c4ccccc4)ccc4ccccc34)c(Oc3ccc4ccccc4c3-c3c(OP)ccc4ccccc34)ccc2c1

Procedure:
Finally, 1,1'-binaphthalene-2,2'-dioxychlorophosphine (XIV), obtained, e.g., by heating an optically active binaphthol (VII) together with phosphorus trichloride, is reacted with the 2'-diphenylphosphino-2-hydroxy-6-vinyl-1,1'-binaphthyl (XIII) obtained above, whereby 2'-diphenylphosphino-6-vinyl-1,1'-binaphthalen-2-yloxy(1,1'-binaphthalene-2,2'-diyloxy)phosphine (XV) is obtained as the target compound.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.[CH3:26][S:27]([OH:30])(=[O:29])=[O:28]>CCO>[S:27]([OH:30])(=[O:29])(=[O:28])[CH3:26].[NH:12]([C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Clc1ncnc2cccnc12
Reactant: Nc1ccccc1
Agent: CS(=O)(=O)O
Solvent: CCN(CC)CC
Solvent: CCO
Product: c1ccc(Nc2ncnc3cccnc23)cc1
Reaction time: 2 h
Yield: 57.2 %

Procedure:
A solution of 4-chloropyrido[3,2-d]pyrimidine (84 mg, 0.5 mmol), aniline (56 mg, 0.6 mmol) and triethylamine (62 mg, 0.6 mmol) in EtOH (2 mL) are refluxed under N with stirring for 2 h. The crude reaction mixture is purified on a preparative tic plate (silica), eluting once with 3% MeOH in CHCl3. The major band is extracted, and evaporated to dryness under reduced pressure, and the residual solid is dissolved in acetone, (5 mL), filtered, and methanesulfonic acid (32 μL, 0.5 mmol) is added slowly with swirling. The precipitate is collected by suction filtration, rinsed with acetone and dried in a vacuum oven to give 4-anilinopyrido[3,2-d]pyrimidine mesylate (91 mg, 57%) as dull yellow needles. 1H NMR (DMSO) δ 11.75 (1H, slbrs), 9.11 (1H, dd, J=1.5, 4.3 Hz), 8.97 (1H, s), 8.32 (1H, dd, J=1.5, 8.4 Hz), 8.12 (1H, dd, J=4.3, 8.5 Hz), 7.88 (2H, d, J=8.2 Hz), 7.49 (2H, t, J=8.0 Hz), 7.32 (1H, t, J=7.0 Hz), 2.34 (3H, s)
Reaction SMILES: [S:1]1(=[O:15])(=[O:14])[C:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[NH:5][C:4]=2[C:3](=[O:13])[NH:2]1.Cl[CH2:17][C:18](=[O:20])[CH3:19]>CS(C)=O>[CH2:17]([N:2]1[C:3](=[O:13])[C:4]2[NH:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:12]=2[S:1]1(=[O:15])=[O:14])[C:18]([CH3:19])=[O:20]
Reactant: O=C1NS(=O)(=O)c2c1[nH]c1ccccc21
Reactant: CC(=O)CCl
Solvent: CS(C)=O
Product: CC(=O)CN1C(=O)c2[nH]c3ccccc3c2S1(=O)=O

Procedure:
The starting compounds of the formula VI can, for example, be obtained from an alkali metal salt of a 2H-isothiazolo[4,5-b]-indole-3(4H)-one-1,1-dioxide of the formula Xa by reaction with a halo-acetone, such as chloroacetone, in dimethylsulfoxide and at a temperature of 100° to 150° C., to form a corresponding 2-acetonyl-2H-isothiazolo[4,5-b]indol-3(4H)-one-1,1-dioxide. This compound is then subjected to a base-catalyzed rearrangement reaction in the presence of 2 to 3 equivalents of an alkali metal alcoholate, which yields a 3-acetyl-2,5-dihydro-4-hydroxy-1,2-thiazino[5,6-b]-indole-1,1-dioxide of the formula ##STR12## wherein R2 and Y have the meanings defined above.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([CH:12]=1)[C:7]([N:9]([CH3:11])[CH3:10])=[O:8].[Br:16]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([CH:12]=1)[C:7]([N:9]([CH3:10])[CH3:11])=[O:8]
Reactant: Cc1ccc([N+](=O)[O-])c(C(=O)N(C)C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CN(C)C(=O)c1cc(CBr)ccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 2 h
Yield: 10.5 %

Procedure:
The 5, N,N-Trimethyl-2-nitrobenzamide (4.16 g) obtained in Example 9-5b), N-bromosuccinimide (3.56 g) and 2,2′-azobisisobutyronitrile (328 mg) were suspended in carbon tetrachloride (80 mL). The suspension was stirred at 90° C. for 2 hours, filtered through a Celite pad and purified by column chromatography on silica gel with hexane:ethyl acetate=5:4 to give the title compound (602 mg).
Reaction SMILES: C1(OC)C=CC=CC=1.[CH:9]([C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]([CH2:22][CH2:23][CH3:24])[N:16]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[S:38]([NH:41]C(C)(C)C)(=[O:40])=[O:39])=[CH:28][CH:27]=1)[C:15]2=[O:46])([CH3:11])[CH3:10]>FC(F)(F)C(O)=O>[CH:9]([C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]([CH2:22][CH2:23][CH3:24])[N:16]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[S:38]([NH2:41])(=[O:40])=[O:39])=[CH:28][CH:27]=1)[C:15]2=[O:46])([CH3:10])[CH3:11]
Reactant: CCCC1Nc2ccc(C(C)C)cc2C(=O)N1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCCC1Nc2ccc(C(C)C)cc2C(=O)N1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Anisole is added to a stirred solution of the compound from Step 1 (0.554 mmol) in trifluoroacetic acid (6 ml) under nitrogen at room temperature. The solution is stirred at room temperature for 8 h then the solvent removed in vacuo. Flash chromatography affords the titled product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][NH:6][C:5]1=[O:9].[Br:10][C:11]1[C:16]2[S:17][C:18]([C:20]3[C:25]([F:26])=[CH:24][N:23]=[C:22](Cl)[N:21]=3)=[CH:19][C:15]=2[CH:14]=[CH:13][CH:12]=1>O1CCOCC1>[Br:10][C:11]1[C:16]2[S:17][C:18]([C:20]3[C:25]([F:26])=[CH:24][N:23]=[C:22]([NH:1][CH2:2][CH2:3][N:4]4[CH2:8][CH2:7][NH:6][C:5]4=[O:9])[N:21]=3)=[CH:19][C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: NCCn1cc[nH]c1=O
Reactant: Fc1cnc(Cl)nc1-c1cc2cccc(Br)c2s1
Solvent: C1COCCO1
Product: O=C1NCCN1CCNc1ncc(F)c(-c2cc3cccc(Br)c3s2)n1
Reaction time: 3 h
Yield: 51.8 %

Procedure:
Combine 1-(2-aminoethyl)-2-imidazolone (100 g, 774 mmol) with 4-(7-bromo-benzo[b]thiophen-2-yl)-2-chloro-5-fluoro-pyrimidine (90 g, 262 mmol) in 1,4-dioxane (650 mL) and heat to 90° C. with stirring under nitrogen for 3 hours. Cool the reaction to room temperature. Filter and wash the solid with water (3×500 mL) and diethyl ether (500 mL). Vacuum-dry at 50° C. to give the title compound (59.2 g, 52%) as a yellow solid. MS (ES) m/z 436 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=2[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.CCN(CC)CC.FC(F)(F)S(O[Si:31]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33])(=O)=O>CN(C=O)C>[CH:32]([Si:31]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[O:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]2[S:5][C:4]3[CH:14]=[CH:15][CH:16]=[CH:17][C:3]=3[C:2]=2[Br:1])=[CH:12][CH:11]=1)([CH3:34])[CH3:33]
Reactant: Oc1ccc(-c2sc3ccccc3c2Br)cc1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)[Si](Oc1ccc(-c2sc3ccccc3c2Br)cc1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
A solution of 3-bromo-2-(4-hydroxyphenyl)benzo[b]-thiophene (9.4 g, 30.8 mmol) in 50 mL of dry DMF was treated with Et3N (6.3 g, 61.6 mmol) and cooled to 0° C. To this was added in a dropwise manner 14.2 g (46.2 mmol) triisopropylsilyl trifluoromethanesulfonate. The cooling bath was removed and the reaction allowed to stir at ambient temperature for 2 h before pouring into 100 mL brine. This was extracted with EtOAc (2×50 mL). The combined extracts were washed with brine (2×100 mL), dried over MgSO4 and concentrated under reduced pressure to 4.8 g of an oil. The crude product was purified by chromatography (SiO2 ; hexanes) to recover 11.7 g (25.4 mmol, 82%) of the desired product as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18]Br)=[CH:14][CH:13]=1.BrCC1C=CC=C(F)C=1>>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][O:10][C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=2)=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: BrCc1ccc(Br)cc1
Agent: Fc1cccc(CBr)c1
Product: Nc1cccc(OCc2ccc(Br)cc2)c1

Procedure:
3-Nitro-phenol was reacted with 1-bromo-4-bromomethyl-benzene according to the procedure from Example 199A substituting 1-bromo-4-bromomethyl-benzene for 1-bromomethyl-3-fluoro-benzene then reduced according to the procedure from Example 199B to provide the title compound.
Reaction SMILES: [Cl-].[NH3+:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[Cl:13])[NH:9][C:8](=[O:14])[C:7](=[O:15])[NH:6]2.[CH3:16][C:17]1(OC)[CH2:21][CH2:20][C:19]([CH3:24])(OC)O1>>[CH3:16][C:17]1[N:2]([C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][C:12]=2[Cl:13])[NH:9][C:8](=[O:14])[C:7](=[O:15])[NH:6]3)[C:19]([CH3:24])=[CH:20][CH:21]=1
Reactant: [NH3+]c1cc2[nH]c(=O)c(=O)[nH]c2cc1Cl
Reactant: COC1(C)CCC(C)(OC)O1
Agent: [Cl-]
Product: Cc1ccc(C)n1-c1cc2[nH]c(=O)c(=O)[nH]c2cc1Cl

Procedure:
14.2 mmol of 6-ammonio-7-chloro-2,3(1H,4H)-quinoxalinedione chloride were reacted with 14.2 mmol of 2,5-dimethyl-2,5-dimethoxytetrahydrofuran by the method of Example 5d.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:12]=[C:13]([NH:18][C:19](=[O:24])[O:20][CH2:21][CH:22]=[CH2:23])[CH:14]=[CH:15][C:16]=2[F:17])=O)[CH:5]=[CH:4][N:3]=1.[CH2:25]1C(=O)N(Br)C(=O)C1.[CH3:33][CH:34]([CH3:38])[C:35](=[S:37])[NH2:36]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:37][C:35]([C:34]([CH3:25])([CH3:38])[CH3:33])=[N:36][C:9]=2[C:11]2[CH:12]=[C:13]([NH:18][C:19](=[O:24])[O:20][CH2:21][CH:22]=[CH2:23])[CH:14]=[CH:15][C:16]=2[F:17])[CH:5]=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C=CCOC(=O)Nc1ccc(F)c(C(=O)Cc2ccnc(Cl)n2)c1
Reactant: CC(C)C(N)=S
Product: C=CCOC(=O)Nc1ccc(F)c(-c2nc(C(C)(C)C)sc2-c2ccnc(Cl)n2)c1
Yield: 44.9 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 6 using 2-propen-1-yl {3-[(2-chloro-4-pyrimidinyl)acetyl]-4-fluorophenyl}carbamate (20 g, 57.3 mmol), NBS (10.2 g, 57.3 mmol) and 2-methylpropanethioamide (7.4 g, 63 mmol) the title compound of Step C was obtained (11 g, 44.9% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.90-9.98 (br, 1H), 8.61 (d, J=5.3 Hz, 1H), 7.65-7.72 (m, 1H), 7.49-7.54 (m, 1H), 7.21-7.30 (m, 1H), 7.10 (d, J=5.3 Hz, 1H), 5.90-6.05 (m, 1H), 5.20-5.40 (m, 2H), 4.58-4.63 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[N:9][C:8]([O:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([NH:18][CH:19]=O)[CH2:14][CH2:13]2)=[CH:7][C:6]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:23][CH:22]=1)[CH2:2][CH2:3][CH3:4]>C1COCC1>[CH2:1]([C:5]1[N:10]=[N:9][C:8]([O:11][C@H:12]2[CH2:13][CH2:14][C@H:15]([NH:18][CH3:19])[CH2:16][CH2:17]2)=[CH:7][C:6]=1[C:21]1[CH:22]=[CH:23][C:24]([O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:25][CH:26]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nnc(O[C@H]2CC[C@H](NC=O)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Solvent: C1CCOC1
Product: CCCCc1nnc(O[C@H]2CC[C@H](NC)CC2)cc1-c1ccc(OC2CCCCC2)cc1

Procedure:
A solution of trans-N-{4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-cyclohexyl}-formamide in anhydrous THF at 0° C. may be treated with borane-THF complex in THF (1 M, excess). The reaction may be allowed to come to room temperature and may be monitored by LCMS until the reaction is complete. The reaction may be quenched with MeOH and the solvents may be removed under reduced pressure. The crude product may be purified by flash chromatography using with 1-5% (2N NH3 in MeOH) in DCM to give trans-{-4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-cyclohexyl}-methyl-amine. The neutral amine may be treated with 2N HCl in diethyl ether and DCM. The volatiles may be removed under reduced pressure and the salt may be triturated with diethyl ether and filtered to provide the title compound. LCMS: m/z 439 [M+1].
Reaction SMILES: [CH2:1]([O:5][CH2:6][Cl:7])[CH2:2][CH2:3][CH3:4].[CH2:8]([N:11]([CH3:13])[CH3:12])[CH:9]=[CH2:10]>C(OCC)(=O)C>[Cl-:7].[CH2:8]([N+:11]([CH2:6][O:5][CH2:1][CH2:2][CH2:3][CH3:4])([CH3:13])[CH3:12])[CH:9]=[CH2:10]
Reactant: CCCCOCCl
Reactant: C=CCN(C)C
Solvent: CCOC(C)=O
Product: C=CC[N+](C)(C)COCCCC
Product: [Cl-]
Reaction time: 24 h

Procedure:
24.7 grams of chloromethyl butyl ether was added to 17 grams of allyl dimethylamine in 32 grams of ethyl acetate. The reaction was highly exothermic and two layers formed very rapidly. Stirring was continued at 25° C. for 24 hours, after which the solvent was removed by vacuum. Chloride analysis of the rather viscous liquid product indicated 91% of theoretical.
Reaction SMILES: [C:1]([NH:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=2)[C:10]([N:21]2C(=O)C3C(=CC=CC=3)C2=O)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].NN>C1COCC1>[C:1]([NH:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([F:20])([F:18])[F:19])=[CH:14][CH:15]=2)[C:10]([NH2:21])=[N:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)n1nc(N2C(=O)c3ccccc3C2=O)c2cc(C(F)(F)F)ccc21
Agent: NN
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)n1nc(N)c2cc(C(F)(F)F)ccc21

Procedure:
3-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-5-trifluoromethyl-indazole-1-carboxylic acid tert-butyl amide (1.41 g, 3.28 mmol) in THF (5 mL) was treated with hydrazine (315 mg, 9.84 mmol) at room temperature for 30 min. The solvent was removed and the residue was purified by silica gel column chromatography using 1:1 hexanes and ethyl acetate to afford the title compound as white solid.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(OC([NH:52][C:53]1([C:58](O)=[O:59])[CH2:57][CH2:56][CH2:55][CH2:54]1)=O)(C)(C)C>CN(C=O)C>[NH2:52][C:53]1([C:58]([N:21]2[CH2:22][CH2:23][CH:18]([N:4]([CH:1]3[CH2:3][CH2:2]3)[S:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=3)(=[O:6])=[O:7])[CH2:19][CH2:20]2)=[O:59])[CH2:57][CH2:56][CH2:55][CH2:54]1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CCNCC1)C1CC1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: NC1(C(=O)N2CCC(N(C3CC3)S(=O)(=O)c3cccc(C(F)(F)F)c3)CC2)CCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-Cyclopropyl-N-piperidin-4-yl-3-trifluoromethyl-benzenesulfonamide (14) (0.400 g, 1.15 mmol) was taken up in 10 mL of dry DMF. To this mixture, HOBt (0.154 g, 1.15 mmol), EDCI (0.218 g, 1.15 mmol), and 1-tert-butoxycarbonylaminocyclopentane-1-carboxylic acid (0.263 g, 1.15 mmol) were added. The mixture was allowed to stir at room temperature for 16 hours. The reaction mixture was concentrated to dryness under reduced pressure and the crude material was chromatographed on silica eluting with 25% ethyl acetate/hexane. The combined product fractions were concentrated to dryness and the pure BOC-protected material was deprotected in 40 mL of ethyl acetate/concentrated HCl (19:1). The solvent was removed leaving a white solid material. This material was triturated with diethyl ether and vacuum filtered affording the desired sulfonamide (48) as the HCl-salt. LC: 97%. MS (e/z): 460 (M+H+). 1H NMR of salt (CD3OD): δ 8.02 (m, 2H), 7.83 (d, 1H, J=7.86 Hz), 7.66 (t, 1H, J=7.86 Hz), 4.01 (m, 2.5H), 2.80 (bs, 1.5H), 2.11 (m, 2H), 1.7-2.0 (m, 10H), 1.51 (m, 2H), 0.60 (m, 2H), 0.50 (m, 2H).
Reaction SMILES: [NH2:1][OH:2].[C:3]([OH:11])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[C:3]([O-:11])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH:2][NH3+:1]
Reactant: O=C(O)c1ccccc1
Reactant: NO
Solvent: CO
Product: O=C([O-])c1ccccc1
Product: [NH3+]O
Temperature: 0 °C
Yield: 96.8 %

Procedure:
A solution of hydroxylamine in methanol prepared as in example 31 was used (4.1 g NH2OH in 100 mL solution). The hydroxylamine solution (41 mL) was placed in a 250 mL Erlenmeyer flask furnished with magnetic stirring bar and was kept cooled in ice-water bath (about 10° C.). The pH was 7.6. A solution of benzoic acid (6.1 g; 0.05 mol) in absolute methanol (50 mL) was slowly added with stirring (pH 6.3). The clear mixture was then stirred for one hour at room temperature and then carefully evaporated to dryness. Hydroxylamine benzoate was collected as a white crystalline solid (7.5 g). Yield 96.8%.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:6]=1.[Li]CCCC.CON(C)[C:19](=[O:21])[CH3:20]>C1COCC1>[C:7]([N:5]1[CH:6]=[C:2]([C:19](=[O:21])[CH3:20])[CH:3]=[N:4]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)n1cc(Br)cn1
Reactant: CON(C)C(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)c1cnn(C(C)(C)C)c1
Temperature: -78 °C
Reaction time: 1.33 h

Procedure:
A solution of 4-bromo-1-tert-butyl-1H-pyrazole (973 mg, 4.79 mmol) in anhydrous THF (9.5 ml) was cooled to −78° C. under argon. A solution of n-BuLi in Hexanes (1.6 M, 3.2 mL, 5.12 mmol) was then added dropwise over 5 min and reaction mixture was stirred at −78° C. for 80 min. A solution of N-methoxy-N-methylacetamide (0.55 ml, 5.17 mmol) in THF (3 mL) was added dropwise and mixture was warmed to 0° C. After 4 hours, reaction mixture was quenched via addition of NH4Cl (aq) (10 mL) and mixture was extracted with ethyl acetate. Combined organic layers were washed with 50% brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. Resulting residue was purified by silica gel column chromatography (0-50% ethyl acetate in hexanes) to yield 1-(1-tert-butyl-1H-pyrazol-4-yl)ethanone 5.14.