Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[CH3:36][S:37][CH2:38][CH2:39][CH2:40][NH2:41]>>[CH3:14][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:41][CH2:40][CH2:39][CH2:38][S:37][CH3:36])[N:7]=2)=[C:9]([C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:10]=1)([CH3:16])[CH3:15]
Reactant: CSCCCN
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Product: CSCCCNc1nccc(-c2sc(C(C)(C)C)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1
Yield: 90 %

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (110 mg, 0.204 mmol) and [3-(methylthio)propyl]amine (200 mg, 1.90 mmol) the title compound of Step A was obtained (124 mg, 90% yield). MS (ESI): 608.1 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([CH3:18])=[CH:5][C:6]([NH:10]C(=O)OC(C)(C)C)=[N:7][C:8]=1[CH3:9].C1C=NC2N(O)N=NC=2C=1.N1C(C)=CC(C)=CC=1C.[CH3:38][O:39][C:40]1[CH:54]=[CH:53][C:43]([CH2:44][N:45]2[CH:49]=[C:48]([C:50](O)=[O:51])[CH:47]=[N:46]2)=[CH:42][CH:41]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[NH2:10][C:6]1[N:7]=[C:8]([CH3:9])[C:3]([CH2:2][NH:1][C:50]([C:48]2[CH:47]=[N:46][N:45]([CH2:44][C:43]3[CH:53]=[CH:54][C:40]([O:39][CH3:38])=[CH:41][CH:42]=3)[CH:49]=2)=[O:51])=[C:4]([CH3:18])[CH:5]=1
Reactant: COc1ccc(Cn2cc(C(=O)O)cn2)cc1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: COc1ccc(Cn2cc(C(=O)NCc3c(C)cc(N)nc3C)cn2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of tert-butyl 5-(aminomethyl)-4,6-dimethylpyridin-2-ylcarbamate (80.0 mg, 0.318 mmol) in DCM (3 ml) were added HOAt (87.0 mg, 0.637 mmol), collidine (0.127 ml, 0.955 mmol), 1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylic acid (73.9 mg, 0.318 mmol) and HATU (81.0 mg, 0.212 mmol). After stirring for 2 h at rt, all volatiles were removed in vacuo. The crude intermediate was purified by column chromatography (CombiFlash Companion, 12 g SiO2, TBME to TBME+10% MeOH), dissolved in DCM (3 ml) and TFA (1 ml), kept for 14 h at rt, and concentrated. Purification by column chromatography (CombiFlash Rf, 13 g RediSep Rf C18, MeCN:water 5:95+0.1% TFA to MeCN) afforded the title compound as. 1H-NMR (DMSO-d6, 400 MHz): 2.37 (s, 3H), 3.73 (s, 3H), 4.27 (d, 2H), 5.24 (s, 1H), 6.64 (s, 1H), 6.91 (d, 2H), 7.23 (d, 2H), 7.70 (br, s, 2H), 7.84 (s, 1H), 8.14-8.19 (m, 2H), 13.59 (s, 1H). LCMS RtK=0.71 min, [M+H]+=366.4.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][CH3:20])[CH:13]=2)=[N:4][CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.CCOC(C)=O>CO>[NH2:8][C:6]1[CH:7]=[C:2]([CH3:1])[C:3]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][CH3:20])[CH:13]=2)=[N:4][CH:5]=1
Reactant: CCCc1cccc(Oc2ncc([N+](=O)[O-])cc2C)c1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCc1cccc(Oc2ncc(N)cc2C)c1
Yield: 80.1 %

Procedure:
To a solution of 3-methyl-5-nitro-2-{[3-(2-methylethyl)phenyl]oxy}-pyridine (Intermediate 24, 279 mg, 1.03 mmol) in MeOH (20 mL) and EtOAc (20 mL) Pd/C (10%, 28 mg, 0.1 wet. e.q.) was added and the flask was evacuated and backfilled with H2. The resulting mixture was stirred at r. t. under H2 atmosphere overnight and filtered through a pad of Celite. The filtrate was concentrated in vacuo to afford the title compound (200 mg) as a grey solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.O[C:29]1[CH:39]=[CH:38][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:36]([O:35][C:33](=[O:34])[C:32]1[CH:38]=[CH:39][C:29]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[CH:30][CH:31]=1)[CH3:37]
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 55 %

Procedure:
To the solution of 0.3 g (0.77 mmol) 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) in 3 mL tetrahydrofuran, 0.13 g (0.84 mmol) ethyl 4-hydroxybenzoate and 0.22 g (084 mmol) triphenylphosphine were added. The solution was cooled to 0° C., 0.15 g (0.84 mmol) diethyl azodicarboxylate dissolved in 2 mL tetrahydrofuran were added dropwise and the reaction stirred at room temperature for 18 h. The reaction was adsorbed on silica gel and purified by silica gel column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 100:40 v/v) to yield the title compound as a white foam (55%). MS (Turbo Spray): m/z=539.2 [M+H].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][C:3]=1[O:12][CH2:13][O:14][CH3:15].C([Li])CCC.[Si:21]([O:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[CH2:40][CH2:39][C:38](=[O:41])[CH2:37][CH2:36]2)=[CH:31][CH:30]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>O1CCCC1>[Si:21]([O:28][C:29]1[CH:30]=[CH:31][C:32]([CH:35]2[CH2:40][CH2:39][C:38]([C:2]3[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][C:3]=3[O:12][CH2:13][O:14][CH3:15])([OH:41])[CH2:37][CH2:36]2)=[CH:33][CH:34]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C2CCC(=O)CC2)cc1
Reactant: COCOc1ccc(Br)c(OCOC)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOc1ccc(C2(O)CCC(c3ccc(O[Si](C)(C)C(C)(C)C)cc3)CC2)c(OCOC)c1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 25.3 %

Procedure:
A round bottomed flask equipped with magnetic stirrer was charged with 1-bromo-2,4-bis(methoxymethoxy)benzene (277 mg, 1.00 mmol) and anhydrous tetrahydrofuran (5 ml). The stirred solution was cooled to −78° C. and N,N,N′N′-tetramethylethylene diamine (0.32 ml, 2.10 mmol) was added followed by dropwise addition of n-butyl lithium (0.88 ml, 2.10 mmol, 2.40M solution in cyclohexanes). The resulting solution was stirred for 40 min at −78° C., then 4-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanone (304 mg, 1.00 mmol) was added via syringe as a solution in anhydrous tetrahydrofuran (2 ml) and the reaction mixture stirred for 30 min at −78° C., then allowed to warm to room temperature over 3 hr. The reaction was quenched with aqueous hydrochloric acid (5 ml, 0.10M), then poured into a separating funnel containing ethyl acetate (50 ml) and water (10 ml). The layers were separated and the aqueous phase extracted with ethyl acetate (3×5 ml). The combined organic layers were washed with brine (10 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting oil was purified via flash column chromatography (SiO2, ethyl acetate/petroleum ether, 3:7, v/v) furnishing the title compound as a white solid (127 mg, 25%) and a mixture of diastereoisomers. δH(CDCl3) 0.19 (6H, s), 0.98 (6H, s), 1.63 (2H, m), 1.84 (2H, m), 1.96 (2H, m), 2.56 (2H, m), 2.70 (1H, m), 3.48 (3H, s), 3.49 (3H, s), 3.85 (1H, s), 5.15 (2H, s), 5.24 (2H, s), 6.68 (1H, dd), 6.73 (2H, d), 6.85 (1H d), 7.05 (2H, d), 7.33 (1H, d).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17]CC3C=CC=CC=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd]>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc3c(ccn3Cc3ccccc3)c2)cc1
Agent: [Pd]
Product: Oc1ccc2c(ccn2Cc2ccccc2)c1
Reaction time: 72 h
Yield: 63.2 %

Procedure:
A slurry of 0.98 g (3.12 mmol) 1-benzyl-5-benzyloxy-1H-indole, 0.20 g 20% Palladium on carbon, and 1.51 g (24 mmol) NH4CHO was heated to reflux with stirring for 3 days. The reaction was allowed to cool and an additional 0.20 g 20% Palladium on carbon and 1.33 g NH4CHO was added. The reaction was refluxed for an additional 24 hours upon which time the reaction was complete by TLC. The reaction was filtered through paper and concentrated. The residue was chromatographed on silica using 25-40% EtOAc-hexane to afford 0.44 g 1-benzyl-5-hydroxy-1H-indole as a solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=2[OH:11])[CH2:3][CH2:2]1.ClC1C=CC=CC=1Cl.[OH-].[Na+].[OH:22][C:23]1[CH:28]=[C:27]([Cl:29])[N:26]=[N:25][C:24]=1Cl>C(O)(C)(C)C>[Cl:29][C:27]1[N:26]=[N:25][C:24]([O:11][C:5]2[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:4]=2[CH:1]2[CH2:3][CH2:2]2)=[C:23]([OH:22])[CH:28]=1
Reactant: Oc1cc(Cl)nnc1Cl
Reactant: Cc1cccc(C2CC2)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: Clc1ccccc1Cl
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
To a mixture of 12.8 g (86.4 mmol) of 2-cyclopropyl-6-methylphenol and 1,2-dichlorobenzene (78.3 mL) was added 3.64 g (86.4 mmol) of 95% sodium hydroxide at room temperature. The resultant mixture was heated to 180° C. and subjected to azeotropic dehydration under reflux while stirring for 30 minutes. To the resultant solution was added dropwise the preliminarily prepared solution of 5.00 g (purity: 95%; 28.8 mmol) of 4-hydroxy-3,6-dichloropyridazine in t-butanol (95.0 g) at 160° C. over 2 hours. (The t-butanol was distilled off simultaneously with the dropwise addition of the solution.) After stirring at 180° C. for another 30 minutes, the reaction mixture was cooled to room temperature, and 78.7 g of pure water was added to the cooled mixture and stirred for 30 minutes, and an organic phase containing 2-cyclopropyl-6-methylphenol added in an excess amount was separated. 50.0 g of toluene was added to the resultant aqueous phase and stirred at room temperature for 30 minutes, and an organic phase containing 2-cyclopropyl-6-methylphenol was separated. This operation was repeated twice. Then, the resultant aqueous solution containing a sodium salt of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol was quantitatively determined by an HPLC internal standard analysis method, which showed that 6.10 g of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 77%) and 39 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.5%) were obtained.
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28]1([CH3:38])[CH:33]=[CH:32][CH:31]=[C:30]([S:34]([NH2:37])(=[O:36])=[O:35])[CH:29]=1>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:37][S:34]([C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([CH3:38])[CH:29]=3)(=[O:35])=[O:36])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccc(S(N)(=O)=O)c1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2cccc(C)c2)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and m-toluenesulfonamide (Synlett, 1997, 375) in accordance with Procedure 1, Method B described hereinabove. Yield (24%); 1H NMR (CDCl3) δ 7.86 (m, 2H), 7.50 (d, J=15.7 Hz, 1H), 7.42-7.07 (m, 14H), 6.86 (d, J=8.4 Hz, 2H), 6.27 (d, J=15.7 Hz, 1H), 2.47 (q, J=7.3 Hz, 2H), 2.41 (s, 3H), 0.93 (t, J=7.3 Hz, 3H); APcI m/z: 508 (M+H+).
Reaction SMILES: Cl[Si](C)(C)C.[CH2:6]([O:8][C:9]([C:11]1[CH:12]=[N:13][N:14]([C:16]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=2)=[N:17][C:18](OCC)=[O:19])[CH:15]=1)=[O:10])[CH3:7].CN(C=O)C>O>[CH2:6]([O:8][C:9]([C:11]1[CH:12]=[N:13][N:14]([C:16]2[NH:17][C:18](=[O:19])[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=2)[CH:15]=1)=[O:10])[CH3:7]
Reactant: CCOC(=O)N=C(Nc1ccc(OC)c(OC)c1)n1cc(C(=O)OCC)cn1
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnn(-c2nc3cc(OC)c(OC)cc3c(=O)[nH]2)c1
Temperature: 80 °C

Procedure:
Chlorotrimethylsilane (1.26 mL, 10.0 mmol) was added to a solution of 1-[(3,4-dimethoxy-phenylamino)-ethoxycarbonylimino-methyl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.39 g, 1.0 mmol) and DMF (3 mL), and the resulting mixture was heated to 80° C. for 16 h in a sealed tube. The reaction mixture was cooled and water (2 mL) was added. The crude reaction mixture was concentrated under reduced pressure and the resulting aqueous mixture was adjusted to pH 7 using 2M aqueous NH4OH. The residue was triturated well and collected by vacuum filtration. The titled compound was purified by preparative reverse-phase HPLC (0.28 g, 81%). MS (ESI): mass calcd. for C16H16N4O5, 344.4; m/z found, 345.7 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 13.06-12.23 (br m, 1H), 8.97 (s, 1H), 8.28 (s, 1H), 7.47 (s, 1H), 7.21 (s, 1H), 4.29 (q, J=7.1 Hz, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 1.32 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([F:21])[C:5]([Cl:20])=[C:6]([C@:8]2([CH3:19])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:29](O)=[O:30])=[N:27][CH:28]=1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C(OCC)(=O)C>CN(C=O)C>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:17])([F:16])[F:15])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29](=[O:30])[C:26]3[CH:25]=[CH:24][C:23]([Cl:22])=[CH:28][N:27]=3)[CH:3]=[C:4]([F:21])[C:5]=2[Cl:20])([CH3:19])[N:9]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: C[C@@]1(c2cc(N)cc(F)c2Cl)C[C@@H](C(F)(F)F)OC(N)=N1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@]1(c2cc(NC(=O)c3ccc(Cl)cn3)cc(F)c2Cl)C[C@@H](C(F)(F)F)OC(N)=N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.4 %

Procedure:
To a mixture of (4S,6S)-4-(5-amino-2-chloro-3-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (0.060 g, 0.184 mmol) and 5-chloropicolinic acid (0.035 g, 0.221 mmol) in DMF (1.5 mL) at 0° C. was added 1-propanephosphonic acid cyclic anhydride, 50% solution in ethyl acetate (0.130 mL, 0.221 mmol). The reaction was gradually warmed to rt and stirred for 2 h. The reaction mixture was partitioned between EtOAc and saturated solution of NaHCO3. The organic layer was separated, washed twice with water, then washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude was purified by flash chromatography on silica gel (12 g, 0-100% EtOAc/DCM in 15 min). The fractions were combined and concentrated in vacuo. The resulting white solid was dissolved in MeOH and purified by reverse phase prep HPLC: 10-80% MeCH in Water (with 0.1% TFA). The fractions were collected and neutralized with solid Na2CO3, extracted with DCM three times. The organic solution was dried over sodium sulfate and concentrated in vacuo to give N-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-chloro-5-fluorophenyl)-5-chloropicolinamide (20 mg, 23.3% yield). MS m/z=465 [M+H]+. Calculated for C18H14Cl2F4N4O2: 465.2.
Reaction SMILES: [CH2:1]([N:3]1[C:8]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[C:7]([OH:14])[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[S:4]1(=[O:20])=[O:19])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>CN(C)C=O>[CH2:27]([N:11]1[N:12]=[N:13][C:9]([C:8]2[N:3]([CH2:1][CH3:2])[S:4](=[O:19])(=[O:20])[C:5]3[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=3[C:7]=2[OH:14])=[N:10]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: CCN1C(c2nnn[nH]2)=C(O)c2ccccc2S1(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1C(c2nnn(Cc3ccccc3)n2)=C(O)c2ccccc2S1(=O)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
A mixture of 2-ethyl-4-hydroxy-3-(tetrazol-5-yl)-1,2-benzothiazine 1,1-dioxide (0.5 g), potassium carbonate (0.120 g) and benzylbromide (0.21 ml) in dimethylformamide was stirred at room temperature for 16 hours, then poured into water (30 ml). The resulting solids were filtered off, washed with water and dried in vacuo to give crude product (0.638 g), which was recrystallized from toluene to afford the title compound (0.457 g, 70%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([C:16](=[O:18])[CH3:17])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Br-:20].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>O1CCCC1>[C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([C:16](=[O:18])[CH2:17][Br:20])[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)c1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(C(=O)CBr)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
2-{[4-Acetyl-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (15.90 g) obtained in Example 8 was dissolved in tetrahydrofuran (150 mL), phenyltrimethylammonium tribromide (21.81 g) was added by small portions over 15 min, and the mixture was stirred at room temperature overnight. The precipitated solid was filtered off, the solvent was evaporated, and the residue was dissolved in ethyl acetate (200 mL). The solution was washed successively with water and saturated aqueous sodium chloride solution (each 100 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by column chromatography (Yamazen HI-FLASH™ COLUMN size 3 L, elution solvent: hexane/ethyl acetate-90/10-50/50, performed in 5 times) to give the title compound (12.28 g).
Reaction SMILES: [ClH:1].Cl.[C:3]1([C:9]2[CH:10]=[C:11]([O:15][CH2:16][C@H:17]3[CH2:21][CH2:20][CH2:19][NH:18]3)[CH:12]=[N:13][CH:14]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C=O.[CH:24](O)=O.Cl>CCOCC>[ClH:1].[ClH:1].[C:3]1([C:9]2[CH:10]=[C:11]([O:15][CH2:16][C@H:17]3[CH2:21][CH2:20][CH2:19][N:18]3[CH3:24])[CH:12]=[N:13][CH:14]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=CO
Reactant: c1ccc(-c2cncc(OC[C@H]3CCCN3)c2)cc1
Agent: C=O
Agent: Cl
Solvent: CCOCC
Product: CN1CCC[C@@H]1COc1cncc(-c2ccccc2)c1

Procedure:
To 5-phenyl-3-(2-(R)-pyrrolidinylmethoxy)pyridine from Example 52 (150 mg, 0.59 mmol) was added formalin (38%, 5.0 mL) and formic acid (88%, 2.5 mL), and the mixture was refluxed for 16 hours. The reaction was quenched by the addition of saturated aqueous NaHCO3. The mixture was extracted with CHCl3, which was dried over MgSO4, filtered and concentrated. The residue was chromatographed on a silica gel column, eluting with CHCl3 /MeOH 10:1.5 to afford the base. The salt was prepared by treatment with HCl in ether, as described above, to give the title compound. mp. 89°-90 ° C. MS (DCI/NH3) m/z 269 (M+H)+. 1H NMR (D2O, 300 MHz) δ: 2.05-2.29 (m, 2H), 2.38-2.47 (m, 1H), 3.07 (s, 3H), 3.23-3.32 (m, 1H), 3.64-3.82 (m, 1H), 3.92-4.00 (m, 1H), 4.44 (dd, J=7.7, 11.0 (1H), 4.61 (dd, J=3.0, 11.2, 1H), 7.51-7.62 (m, 3H), 7.70-7.74 (m, 2H), 7.88 (s, 1H), 8.36 (br s, 1H), 8.56 (br s, 1H). Anal. Calcd for C17H20N2OCl·2 HCl·0.5 H2O: C, 58.29; H, 6.62; N, 8.00. Found: C, 58.16; H, 6.76; N, 8.18. [α]25D =+9.2° (c 0.39, MeOH).
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].[CH:6]1[C:19]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[O:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[CH:6]1[C:19]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:3](=[O:4])[CH2:2][Br:1])[CH:16]=3)[O:11][C:10]=2[CH:9]=[CH:8][C:7]=1[C:3](=[O:4])[CH2:2][Br:1]
Reactant: c1ccc2c(c1)Cc1ccccc1O2
Reactant: O=C(Cl)CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CBr)c1ccc2c(c1)Cc1cc(C(=O)CBr)ccc1O2
Temperature: 25 °C
Reaction time: 72 h
Yield: 36.7 %

Procedure:
Referring to Scheme 5, bromoacetyl chloride (4.59 ml, 54.9 mmol) was added dropwise to a solution of 9H-xanthene (5 g, 27.4 mmol) and AlCl3 (8.05 g, 60.4 mmol), DCM (100 mL) at 0° C. The reaction mixture was allowed to warm up to rt and left to stir for 72 h. The reaction mixture was poured onto ice (400 mL), extracted with DCM (2×200 mL). The combined organic phase was washed with brine (400 mL), dried over MgSO4, filtered and evaporated to dryness. The crude material was precipitated in EtOAc and filtered to give 1,1′-(9H-xanthene-2,7-diyl)bis(2-bromoethanone) (5-2) as a white solid (4.27 g, 36.7% yield). LC-MS (ESI): m/z 425.9 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([CH2:14][CH3:15])[CH2:12][CH2:11][CH2:10][CH:9]1[CH:16]([OH:40])[C@@H:17]([N:25](CC1C=CC=CC=1)CC1C=CC=CC=1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[OH-].[Pd+2].[OH-]>[C:1]([O:5][C:6]([N:8]1[CH:13]([CH2:14][CH3:15])[CH2:12][CH2:11][CH2:10][CH:9]1[CH:16]([OH:40])[C@@H:17]([NH2:25])[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: CCC1CCCC(C(O)[C@H](Cc2ccccc2)N(Cc2ccccc2)Cc2ccccc2)N1C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCC1CCCC(C(O)[C@@H](N)Cc2ccccc2)N1C(=O)OC(C)(C)C
Yield: 95 %

Procedure:
Stir 2-((2S)-2-dibenzylamino-1-hydroxy-3-phenylpropyl)-6-ethylpiperidine-1-carboxylic acid tert-butyl ester-Isomer 2 (0.7 g, 1.23 mmol) and 20% palladium hydroxide (0.2 g, 50% wet) in methanol (10 mL) under a balloon of hydrogen gas at room temperature for 2 days. Filter the suspension through a pad of filtering agent, wash with methanol and concentrate to give the title compound (0.4 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH:16]2[O:18][CH2:17]2)=[CH:6][CH:7]=1.[C:19]([NH2:23])([CH3:22])([CH3:21])[CH3:20]>CO>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH:16]([OH:18])[CH2:17][NH:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2ccccc2OCC2CO2)nn1
Reactant: CC(C)(C)N
Solvent: CO
Product: CC(C)(C)NCC(O)COc1ccccc1-c1ccc(Cl)nn1

Procedure:
A mixture of 3-chloro-6-(2-epoxypropoxyphenyl)pyridazine (0.7 g.), methanol (7 ml.) and t-butylamine (1.7 ml.) was stirred and heated under reflux for 1.25 hours. The mixture was evaporated under reduced pressure at 50° and the residue was recrystallized from toluene to give 3-chloro-6-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]pyridazine, m.p. 136.5°-137.5°. A sample of this product was treated with hydrochloric acid (1.0 N, 3.62 ml.), the solution was extracted with dichloromethane and the aqueous solution was evaporated under reduced pressure and the residue was recrystallized from ethanol/ether to give the monohydrochloride salt, m.p. 193.5°-194.5°.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:18]=[C:17]([F:19])[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([Cl:20])[CH:10]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:8][C:9]1[CH:18]=[C:17]([F:19])[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([Cl:20])[CH:10]=1
Reactant: COC(=O)c1c(F)cc(NC(=O)OC(C)(C)C)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1c(F)cc(N)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.7 %

Procedure:
To a solution of methyl 4-(tert-butoxycarbonylamino)-2-chloro-6-fluoro-benzoate (6.53 g, 21.5 mmol) in dichloromethane (40 mL) was added TFA (9.94 mL). The mixture was stirred at room temperature for 4 hours. The mixture was then concentrated. Water (30 mL) was added to the residue, and pH was adjusted 10 with 25% NaOH. The resulting suspension was extracted with EtOAc (3×). The combined organics were dried (Na2SO4), filtered and concentrated to give the title compound (4.41 g, quantitative yield) as an off-white solid. 1H NMR (400 MHz, CD2Cl2) δ 6.54 (s, 1H), 6.34 (dd, J=11.6, 2.1 Hz, 1H), 4.19 (s, 2H), 3.90 (s, 3H). LCMS (ESI) m/z 204.0 [M+H+].