Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]([CH2:39][CH2:40][CH2:41][CH2:42][O:43][CH3:44])[C:9]([C:11]([N:13]([CH2:35][CH:36]([CH3:38])[CH3:37])[C@H:14]3[CH2:19][C@@H:18]([C:20]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[O:21])[CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]3)=[O:12])=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C.[ClH:51]>>[ClH:51].[ClH:51].[F:1][C:2]1[C:7]2[N:8]([CH2:39][CH2:40][CH2:41][CH2:42][O:43][CH3:44])[C:9]([C:11]([N:13]([CH2:35][CH:36]([CH3:37])[CH3:38])[C@H:14]3[CH2:19][C@@H:18]([C:20]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[O:21])[CH2:17][NH:16][CH2:15]3)=[O:12])=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nc2cccc(F)c21
Agent: Cl
Solvent: CCOC(C)=O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](C(=O)N3CCOCC3)C2)nc2cccc(F)c21
Temperature: 25 °C
Reaction time: 10 h

Procedure:
tert-Butyl (3S,5R)-3-{{{7-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (160 mg) was dissolved in 2M hydrogen chloride-ethyl acetate (3 ml), and the mixture was stirred at room temperature for 10 hr. The reaction mixture was concentrated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC, and a fraction eluted with water-acetonitrile (9:1-6:4) was collected, basified (pH 10) with saturated aqueous potassium carbonate solution, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in 1M hydrogen chloride-ethyl acetate (1 ml), and the reaction mixture was concentrated under reduced pressure to give the object product (104 mg).
Reaction SMILES: O=[C:2]1[C:6]2[NH:7][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:9][C:5]=2[CH2:4][CH2:3]1.[F:14][C:15]1[CH:16]=[C:17]([Mg]Br)[CH:18]=[CH:19][CH:20]=1>[Pd]>[F:14][C:15]1[CH:20]=[C:19]([CH:2]2[C:6]3[NH:7][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:9][C:5]=3[CH2:4][CH2:3]2)[CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1cc2c([nH]1)C(=O)CC2
Reactant: Fc1cccc([Mg]Br)c1
Agent: [Pd]
Product: COC(=O)c1cc2c([nH]1)C(c1cccc(F)c1)CC2

Procedure:
The title compound was synthesized in two steps. First, methyl 6-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (447 mg, 2.5 mmol) was reacted with (3-fluorophenyl)magnesium bromide (0.5 M in hexanes, 13 mL, 6.3 mmol) according to General Procedure 3. The resulting crude product was converted to the title compound by hydrogenation according to General Procedure 6 (with 5% Pd/C). The crude product was purified by chromatography, eluting with heptane-EtOAc, gradient 0 to 40% EtOAc. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.24-2.35 (m, 1H), 2.61-2.71 (m, 1H), 2.71-2.81 (m, 1H), 2.87-2.98 (m, 1H), 3.81 (s, 3H), 4.24 (t, J=7.54 Hz, 1H), 6.71 (d, J=1.51 Hz, 1H), 6.81 (dt, J=9.81, 1.85 Hz, 1H), 6.88-6.93 (m, 2H), 7.25 (s, 1H), 8.60 (br. s, 1H).
Reaction SMILES: Cl.[C:2]1([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([CH2:12][CH:13]2[CH2:18][CH:17]3[CH2:19][CH2:20][N:14]2[CH2:15][CH2:16]3)[C:9]([OH:11])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[C:29]1(C(C2C=CC=CC=2)(CC2CC3CCN2CC3)C(O)=O)C=CC=CC=1.S([O-])(OC)(=O)=O>CO>[C:21]1([C:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)([CH2:12][CH:13]2[CH2:18][CH:17]3[CH2:19][CH2:20][N:14]2[CH2:15][CH2:16]3)[C:9]([O:11][CH3:29])=[O:10])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)C(CC1CC2CCN1CC2)(c1ccccc1)c1ccccc1
Agent: COS(=O)(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(CC1CC2CCN1CC2)(c1ccccc1)c1ccccc1

Procedure:
6.5 Parts of 2,2-diphenyl-3-(1-azabicyclo[2.2.2]-oct-2-yl)propionic acid hydrochloride is dissolved in 47 parts methanol. Then a solution of 0.7 part sodium hydroxide in 12 parts methanol is added, followed by 0.9 part 2,2-diphenyl-3-(1-azabicyclo[2.2.2]oct-2-yl)propionic acid and a solution of 2.7 parts methyl sulfate in 12 parts methanol. The resulting mixture is then refluxed for 20 minutes, cooled and stripped in vacuo. The gummy residue is partitioned between 90 parts by volume of a 2% sodium hydroxide solution and ethyl ether. The ether layer is separated, dried over anhydrous sodium sulfate and stripped in vacuo to afford as a gummy residue, methyl 2,2-diphenyl-3-(1-azabicyclo[2.2.2]oct-2-yl)propionate. The aqueous layer is adjusted to pH 7.9 with dilute hydrochloric acid, saturated with sodium chloride and extracted 6 times with portions of chloroform. The chloroform extracts are combined, dried over anhydrous sodium sulfate and stripped in vacuo to give 2,2-diphenyl- 3-(1-azabicyclo[2.2.2]oct-2-yl)propionic acid (starting material). This solid is refluxed with 2.0 parts methyl sulfate and 35 parts methanol for 18 minutes and then worked up as before to afford a second yield of the desired methyl 2,2-diphenyl-3-(1-azabicyclo[2.2.2]oct-2-yl)propionate.
Reaction SMILES: C(=O)(O)[O-:2].[Na+].Cl.NO.[CH3:9][C:10]1[N:15]=[C:14]([C:16]#[N:17])[CH:13]=[C:12]([O:18][CH:19]([CH3:24])[C:20]([F:23])([F:22])[F:21])[CH:11]=1>C(O)C>[CH3:9][C:10]1[N:15]=[C:14]([C:16]([NH2:17])=[O:2])[CH:13]=[C:12]([O:18][CH:19]([CH3:24])[C:20]([F:23])([F:21])[F:22])[CH:11]=1
Reactant: O=C([O-])O
Reactant: Cc1cc(OC(C)C(F)(F)F)cc(C#N)n1
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(OC(C)C(F)(F)F)cc(C(N)=O)n1
Reaction time: 8 h
Yield: 94 %

Procedure:
To 6 ml of ethanol were added 0.53 g of sodium bicarbonate and 0.44 g of hydroxylamine hydrochloride, and the mixture was heated to reflux for 1 hour. After allowing to cool, 0.72 g of 6-methyl-4-(2,2,2-trifluoro-1-methylethoxy)pyridine-2-carbonitrile was added at room temperature, and the mixture was stirred for 8 hours, and concentrated. To the residue was added water, the resultant solution was extracted with ethyl acetate three times, and the organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was washed with hexane three times to obtain 0.73 g of 6-methyl-4-(2,2,2-trifluoro-1-methylethoxy)pyridine-2-carboxamide=oxime.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[C:22]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[C:15](=[N:23]O)[C:14]=4[CH:13]=[CH:12][CH:11]=3)[NH:7][C:6]=2[CH:25]=1>[Ni].C(O)C.O1CCCC1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[C:22]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[CH:15]([NH2:23])[C:14]=4[CH:13]=[CH:12][CH:11]=3)[NH:7][C:6]=2[CH:25]=1
Reactant: ON=C1c2ccccc2-c2c1cccc2-c1nc2ccc(O)cc2[nH]1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: NC1c2ccccc2-c2c(-c3nc4ccc(O)cc4[nH]3)cccc21
Yield: 80.4 %

Procedure:
Carry out the procedure as in Example 6, starting from 500 mg of 4-(6-hydroxy-1H-benzimidazol-2-yl)-fluoren-9-one oxime (Z,E), obtained in Example 107, and 5 mg of Raney Nickel in 25 ml of ethanol and 25 ml of tetrahydrofuran for 5 hours at 60° C. under a hydrogen pressure of 1 bar. After purification by making a paste in diisopropyl ether, we obtain 385 mg of 4-(6-hydroxy-1H-benzimidazol-2-yl)-fluoren-9(R,S)-ylamine, in the form of a brown powder, with the following characteristics:
Reaction SMILES: [CH2:1]=[CH2:2].[CH:3]([C:6]1[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=1[O:8][CH:9]([C:13]([OH:15])=O)[C:10]([OH:12])=[O:11])([CH3:5])[CH3:4]>>[OH:15][C:13]1[CH:2]=[C:1]([C:6]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:7]=2)[O:12][C:10](=[O:11])[C:9]=1[O:8][C:7]1[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=1[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)c1ccccc1OC(C(=O)O)C(=O)O
Reactant: C=C
Product: CC(C)c1ccccc1Oc1c(O)cc(-c2ccccc2)oc1=O

Procedure:
The title compound was prepared by Method A using 1-phenyl-1-trimethylsilyloxy)ethylene (2.62 g, 13.6 mmol) and diethyl ester of 2-(isopropyl)phenoxy propanedioic acid (2.0 g, 6.8 mmol). 1 H NMR (250 MHz, DMSO-d6) δ 1.25 (d, 6H), 3.44 (m, 1H), 6.67 (d, 1H), 6.89 (s, 1H), 7.0 (t, 1H), 7.09 (t, 1H), 7.29 (d, 1H), 7.53 (m, 3H), 7.83 (m, 2H).
Reaction SMILES: C(OC([N:8]([C:39](OC(C)(C)C)=O)[C:9](=[O:38])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[CH:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([CH3:36])=[CH:34][C:33]([CH3:37])=[CH:32][N:31]=2)[CH2:26][CH2:25]1)=[O:23])=O)(C)(C)C.[N:46]1[CH:51]=[CH:50][CH:49]=[C:48](CN)[CH:47]=1>>[CH3:36][C:35]1[C:30]([N:27]2[CH2:28][CH2:29][N:24]([C:22]([C:11]3[CH:12]=[CH:13][C:14]([N:16]4[CH2:20][CH2:19][CH2:18][C:17]4=[O:21])=[CH:15][C:10]=3[C:9]([NH:8][CH2:39][C:48]3[CH:47]=[N:46][CH:51]=[CH:50][CH:49]=3)=[O:38])=[O:23])[CH2:25][CH2:26]2)=[N:31][CH:32]=[C:33]([CH3:37])[CH:34]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)c(C)c1
Reactant: NCc1cccnc1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C(=O)NCc3cccnc3)CC2)c(C)c1

Procedure:
Using N,N-di-tert-butyloxycarbonyl-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-5-(2-oxopyrrolidin-1-yl)benzamide (187 mg) described in Example 769 and C-pyridin-3-yl-methylamine (36 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (111 mg) was obtained.
Reaction SMILES: [NH2:1][C@@:2]([C@@H:13]1[CH2:17][CH2:16][NH:15][CH2:14]1)([CH2:6][CH2:7][CH2:8][CH2:9][B:10]([OH:12])[OH:11])[C:3]([OH:5])=[O:4].C(N(CC)CC)C.CN(C)C=O.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]=[C:38]=[S:39])=[CH:33][CH:32]=1>Cl>[ClH:30].[ClH:30].[NH2:1][C:2]([C@H:13]1[CH2:17][CH2:16][N:15]([C:38](=[S:39])[NH:37][C:34]2[CH:35]=[CH:36][C:31]([Cl:30])=[CH:32][CH:33]=2)[CH2:14]1)([CH2:6][CH2:7][CH2:8][CH2:9][B:10]([OH:12])[OH:11])[C:3]([OH:5])=[O:4]
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: N[C@@](CCCCB(O)O)(C(=O)O)[C@@H]1CCNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(CCCCB(O)O)(C(=O)O)[C@H]1CCN(C(=S)Nc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.7 %

Procedure:
A solution of (R)-2-amino-6-borono-2-((R)-pyrrolidin-3-yl)hexanoic acid (200 mg, 0.8 mmol) and triethylamine (700 mg, 6 mmol) in N,N-dimethylformamide (4 mL, 50 mmol) was treated with 4-chlorophenyl isothiocyanate (300 mg, 1.8 mmol) in a single portion. After stirring at room temperature for 30 min, the reaction was diluted with 1 N HCl (20 mL) and washed with ethyl acetate (20 mL). The aqueous solution was concentrated and purified by HPLC to give 2-amino-6-borono-2-((S)-1-(4-chlorophenylcarbamothioyl)pyrrolidin-3-yl)hexanoic acid hydrochloride hydrochloride (81 mg, 20%). 1H NMR (400 MHz, D2O, Mixture of diastereoisomers) δ 7.40-7.23 (m, 4H), 4.29-3.46 (m, 4H), 2.95-2.81 (m, 1H), 2.41-1.76 (m, 4H), 1.58-1.40 (br. m, 2H), 1.36-1.20 (br, m, 1H), 0.90-0.80 (br. m, 2H); MS ESI found for C17H25BClN3O4S m/z (M-water+H)+396.2; MS (ESI−) m/z (M−H)− 412.3, (M-water-H)− 394.3
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13](=[O:16])[CH2:14][Br:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)C>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C@@H:13]([OH:16])[CH2:14][Br:15])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O[C@@H](CBr)c1ccc(OCc2ccccc2)cc1
Temperature: -25 °C
Reaction time: 4 h
Yield: 56.3 %

Procedure:
A solution of 23 g of (+)-diisopinocamphenylchloroborane dissolved in 30 ml of tetrahydrofuran was cooled to -25° C. Thereto was added 12 g of 4-benzyloxyphenacyl bromide. The resulting mixture was stirred for 4 hours at -20° to -15° C. The reaction mixture was added to a mixture of 150 ml of diethyl ether and 100 ml of ice water. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: hexane:toluene=1:2) to obtain 6.8 g of (R)-1-(4-benzyloxyphenyl)-2-bromoethanol.
Reaction SMILES: [ClH:1].Cl.Cl.S1C(C2C=CN=C([NH:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)N=2)=CC2C=CC=CC1=2.[Br:30][C:31]1[CH:32]=[CH:33][C:34]2[CH:38]=[C:37]([C:39]3[C:44]([CH3:45])=[CH:43][N:42]=[C:41]([Cl:46])[N:40]=3)[S:36][C:35]=2[CH:47]=1.NCCCN1CCN(C)CC1>>[ClH:46].[ClH:1].[ClH:46].[Br:30][C:31]1[CH:32]=[CH:33][C:34]2[CH:38]=[C:37]([C:39]3[C:44]([CH3:45])=[CH:43][N:42]=[C:41]([NH:15][CH2:16][CH2:17][CH2:18][N:19]4[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]4)[N:40]=3)[S:36][C:35]=2[CH:47]=1
Reactant: CN1CCN(CCCNc2nccc(-c3cc4ccccc4s3)n2)CC1
Reactant: Cc1cnc(Cl)nc1-c1cc2ccc(Br)cc2s1
Agent: CN1CCN(CCCN)CC1
Agent: Cl
Product: Cc1cnc(NCCCN2CCN(C)CC2)nc1-c1cc2ccc(Br)cc2s1

Procedure:
Using the method of [4-(benzo[b]thiophen-2-yl)-pyrimidin-2-yl]-[3-(4-methylpiperazin-1-yl)-propyl]-amine tri-hydrochloride, the title compound is prepared from 4-(6-bromobenzo[b]thiophen-2-yl)-2-chloro-5-methylpyrimidine and 1-(3-aminopropyl)-4-methylpiperazine and isolated as a solid. ES+(m/z) 460 (79Br) and 462 (81Br) [M+H].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([OH:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])=[CH:17][CH:16]=2)[C@H:10]([O:33][CH2:34][C@H:35]2[CH2:39][O:38][C:37]([CH3:41])([CH3:40])[O:36]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:43][C:44]1[CH:45]=[C:46]([O:54][CH3:55])[C:47]2[C:52]([CH:53]=1)=[CH:51][CH:50]=[CH:49][CH:48]=2>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([O:14][CH2:43][C:44]2[CH:45]=[C:46]([O:54][CH3:55])[C:47]3[C:52](=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH:53]=2)[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])=[CH:17][CH:16]=2)[C@H:10]([O:33][CH2:34][C@H:35]2[CH2:39][O:38][C:37]([CH3:41])([CH3:40])[O:36]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(CCl)cc2ccccc12
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)[C@@H](c2ccc(OCCCOc3ccccc3Cl)cc2)[C@H](OC[C@H]2COC(C)(C)O2)C1
Product: COc1cc(CO[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H](OC[C@H]3COC(C)(C)O3)[C@@H]2c2ccc(OCCCOc3ccccc3Cl)cc2)cc2ccccc12

Procedure:
In analogy to the procedure described in example 1) (f) the (3S,4R,5R)-4-[4-[3-(2-chloro-phenoxy)-propoxy]-phenyl]-3-[(4S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]5-hydroxy-piperidine-1-carboxylic acid tert-butyl ester was reacted with the 3-chloromethyl-1-methoxy-naphthalene [example 1) (α)] to yield the (3S,4R,5R)-4-[4-[3-(2-chloro-phenoxy)-propoxy]-phenyl]-3-[(4S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester as colorless oil; MS: 762.3 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:13]([NH2:17])[CH2:14][CH2:15][CH3:16].[BH4-].[Na+]>CO.Cl>[CH2:13]([NH:17][CH2:9][C:8]1[CH:11]=[CH:12][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCN
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCNCc1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Yield: 76.1 %

Procedure:
0.5 ml of 4-tert-butylbenzaldehyde (3 mmol) and 0.20 ml of butylamine (2 mmol) were dissolved in 5 ml methanol at rt and then refluxed for 17 h. After cooling down to rt, 113 mg (3 mmol) of sodium borohydride were added and the reaction mixture was then refluxed for 3 h. After cooling down to rt, the reaction mixture was treated with 4 drops 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:1) to give 334 mg colorless oil (51%). MS (ISP) 220.4 (M+H)+.
Reaction SMILES: [CH:1]1([C:4](=O)[CH2:5][NH:6][C:7]2[C:8]([CH3:16])=[CH:9][C:10]([F:15])=[C:11]([CH:14]=2)[C:12]#[N:13])[CH2:3][CH2:2]1.[S-:18][C:19]#[N:20].[K+]>C(O)(=O)C>[CH:1]1([C:4]2[N:20]=[C:19]([SH:18])[N:6]([C:7]3[C:8]([CH3:16])=[CH:9][C:10]([F:15])=[C:11]([CH:14]=3)[C:12]#[N:13])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(F)c(C#N)cc1NCC(=O)C1CC1
Reactant: N#C[S-]
Agent: [K+]
Solvent: CC(=O)O
Product: Cc1cc(F)c(C#N)cc1-n1cc(C2CC2)nc1S
Temperature: 110 °C
Yield: 85.3 %

Procedure:
5-(2-Cyclopropyl-2-oxoethylamino)-2-fluoro-4-methylbenzonitrile (14.19 g, 61.2 mmol) was dissolved in glacial acetic acid (300 mL). Potassium thiocyanate (11.9 g, 122.4 mmol) was added as a solid with stirring. The reaction mixture was heated to 110° C. for 4 hours at which time the solvent was removed under reduced pressure. The residue was taken up in dichloromethane (200 mL) and washed with 200 mL water. The aqueous extract was extracted with (2×200 mL) additional dichloromethane, the organic extracts combined and dried over magnesium sulfate. The solvent was removed under reduced pressure and the oily residue was re-dissolved in EA (50 mL) and 150 mL hexanes was added. A dark layer formed and a stir bar was added to the flask. Vigorous stirring caused the product to precipitate as a peach colored solid. The product was collected by filtration, to yield 5-(4-cyclopropyl-2-mercapto-1H-imidazol-1-yl)-2-fluoro-4-methylbenzonitrile, (14.26 g, 52.23 mmol). Anal. LC/MS (m/z: 274, M+1)
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:9]=[C:8]([C:10](OCC)=[O:11])[C:7]([N:15]([CH3:20])[S:16]([CH3:19])(=[O:18])=[O:17])=[CH:6][CH:5]=1>CN(C=O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[N:15]([CH3:20])[S:16](=[O:18])(=[O:17])[CH2:19][C:10](=[O:11])[C:8]=2[N:9]=1
Reactant: CCOC(=O)c1nc(Br)ccc1N(C)S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1c2ccc(Br)nc2C(=O)CS1(=O)=O
Reaction time: 0.08 h

Procedure:
To a three necked flask flushed with argon was added NaH (60%, 0.75 g, 18.7 mmol) followed by DMF (10 ml) and stirring was continued for 5 min followed by addition of a solution of ethyl 6-bromo-3-[methyl(methylsulfonyl)amino]pyridine-2-carboxylate (3.16 g, 9.37 mmol) in DMF (35 ml, rinsed with 2×2.5 ml) at ambient temperature giving a reddish solution under effervescence. After stirring for 1 hour the reaction mixture was concentrated under reduced pressure followed by addition of water and ethyl acetate then the phases were separated. The acqueous phase was made slightly acidic using H2SO4 (95-97%) followed by extraction with methylene chloride. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography eluting with ethyl acetate/heptane, gradient, afforded 6-bromo-1-methyl-2,2-dioxo-pyrido[3,2-c]thiazin-4-one as a yellow solid.
Reaction SMILES: C[O:2][C:3]1[C:4]2[CH:11]=[C:10]([O:12][CH2:13][CH2:14][O:15]C(=O)C)[CH:9]=[CH:8][C:5]=2[O:6][CH:7]=1.O.OS(O)(=O)=O.[Na+].[Cl-]>O1CCCC1.C(OCC)(=O)C>[OH:15][CH2:14][CH2:13][O:12][C:10]1[CH:9]=[CH:8][C:5]2[O:6][CH2:7][C:3](=[O:2])[C:4]=2[CH:11]=1
Reactant: COc1coc2ccc(OCCOC(C)=O)cc12
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1COc2ccc(OCCO)cc21
Temperature: 25 °C

Procedure:
751 mg (7.0 mmol) XXII were stirred under reflux for 12 h in a mixture of 40 ml tetrahydrofuran, 20 ml water and 0.5 ml conc. H2SO4. Ethyl acetate and saturated NaCl solution were added to the reaction mixture cooled to room temperature. After separation of the phases, the aqueous phase was extracted twice with ethyl acetate and the combined organic phases were dried over Na2SO4. After column filtration (50 g SiO2, n-hexane:ethyl acetate=1:1+1% acetic acid, applied with ethyl acetate), XXIII was obtained in a yield of 448 mg (2.3 mmol, 77%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=2)[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:35][C:36]([F:49])([F:48])[C:37]1[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][C:38]=1[NH2:39]>>[CH3:1][O:2][C:3](=[O:34])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:31])[F:32])[CH:24]=2)[CH:12]=[C:13]([NH:39][C:38]2[CH:40]=[C:41]([C:44]([F:46])([F:45])[F:47])[CH:42]=[CH:43][C:37]=2[C:36]([F:48])([F:49])[F:35])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: Nc1cc(C(F)(F)F)ccc1C(F)(F)F
Reactant: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(Cl)c(C(F)(F)F)c2)c1
Product: COC(=O)C(CC(C)C)c1cc(Nc2cc(C(F)(F)F)ccc2C(F)(F)F)cc(-c2ccc(Cl)c(C(F)(F)F)c2)c1
Yield: 35 %

Procedure:
The title compound was prepared in 35% yield from 2-(4′-chloro-5-trifluoromethanesulfonyloxy-3′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester and 2,5-bis-(trifluoromethyl)aniline under the conditions described in Example 37, step (b).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5](/[CH:6]=[N:7]/[S@@:8]([C:10]([CH3:13])([CH3:12])[CH3:11])=[O:9])=[CH:4][CH:3]=1.[C:16]1([Mg]Br)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([C@@H:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:7][S@:8]([C:10]([CH3:11])([CH3:12])[CH3:13])=[O:9])=[CH:4][CH:3]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CC(C)(C)[S@@](=O)/N=C/c1ccc(Br)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[S@](=O)N[C@H](c1ccccc1)c1ccc(Br)cc1
Temperature: -45 °C
Reaction time: 4 h
Yield: 63 %

Procedure:
(R,E)-N-(4-bromobenzylidene)-2-methylpropane-2-sulfinamide, 18-b, (10 g, 34.84 mmol) was dissolved in anhydrous THF (100 ml). The mixture was then cooled to −45° C. and PhMgBr (34.84 ml, 69.68 mmol) was added dropwise. After addition, the mixture was allowed to stir at −45° C. for additional 4 h and warm to room temperature for another 2 h. TLC monitored the reaction and the time was prolonged if necessary. The mixture was quenched with saturated NH4Cl followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/ethyl acetate=4/1) to provide the product, 22-a, (8 g, 63%). HPLC indicated that the diastereomer ratio is 96:4 after recrystallization once in hexane/ethyl acetate.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]2[O:13][CH2:12][CH2:11][C:10](=[O:14])[CH2:9][CH2:8]2)=[C:5]([N+:15]([O-:17])=[O:16])[CH:4]=[N:3]1.[BH4-].[Na+]>CO>[CH3:1][N:2]1[C:6]([CH:7]2[O:13][CH2:12][CH2:11][CH:10]([OH:14])[CH2:9][CH2:8]2)=[C:5]([N+:15]([O-:17])=[O:16])[CH:4]=[N:3]1
Reactant: Cn1ncc([N+](=O)[O-])c1C1CCC(=O)CCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1ncc([N+](=O)[O-])c1C1CCC(O)CCO1
Reaction time: 1 h

Procedure:
To a solution of 2-(2-methyl-4-nitro-pyrazol-3-yl)tetrahydropyran-4-one (300 mg, 1.33 mmol) in DCM (12 mL) at −70° C. was added boron trifluoride etherate (0.75 mL, 1.73 mmol) dropwise followed by a (trimethylsilyl)diazomethane solution (2 M in hexanes, 0.87 mL, 1.73 mmol). The reaction mixture was stirred at −70° C. for 90 min, quenched with water (10 mL), diluted with DCM (12 mL) and warmed to room temperature. The organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave 7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-one as a colourless solid (121 mg) and its regioisomer 2-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-one (151 mg). To a solution of 7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-one (121 mg, 0.51 mmol) in MeOH (5 mL) at 0° C. was added portionwise NaBH4 (23 mg, 0.61 mmol). Stirring continued for 1 hr and the reaction mixture was quenched with 1 M HCl (5 mL) and EtOAc (10 mL). The aqueous layer was extracted with EtOAc (3×20 mL) and the combined organic layers were washed with brine (30 mL), separated, dried over Na2SO4 and concentrated under reduced pressure to give 7-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-4-ol as a 1:1 mixture of diastereomers as a colourless oil (85 mg, 27% over two steps). The product was used without further purification as a 1/1 mixture of diastereoisomers. 1H NMR (400 MHz, CDCl3) δ 8.02 and 8.01 (s, 1H), 5.61-5.56 and 5.54-5.50 (m, 1H), 4.26-4.14 (m, 1H), 4.07 and 4.04 (s, 3H), 3.90-3.80 and 3.81-3.63 (m, 1H), 2.20-1.80 (m, 8H).