Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[C:13]([F:15])([F:14])[C:12]([CH3:17])([CH3:16])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[CH:25][C:26]([C:29](O)=[O:30])=[N:27][CH:28]=1>>[NH2:18][C:10]1[O:11][C:12]([CH3:16])([CH3:17])[C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29]([C:26]3[CH:25]=[CH:24][C:23]([C:22]([F:33])([F:21])[F:32])=[CH:28][N:27]=3)=[O:30])[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cn1
Reactant: CC1(C)OC(N)=N[C@](C)(c2cc(N)ccc2F)C1(F)F
Product: CC1(C)OC(N)=N[C@](C)(c2cc(NC(=O)c3ccc(C(F)(F)F)cn3)ccc2F)C1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-2) and 5-trifluoromethyl-pyridine-2-carboxylic acid following procedure I yielded the title compound as a white foam. MS (ISP): m/z=461.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:17][CH3:18])=[CH:9][C:10]([O:15][CH3:16])=[C:11]([CH:14]=2)[CH:12]=O)=[C:5]([CH3:19])[O:4][N:3]=1.[C:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1)(=[O:22])[CH3:21]>>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:17][CH3:18])=[CH:9][C:10]([O:15][CH3:16])=[C:11](/[CH:12]=[CH:21]/[C:20]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)=[O:22])[CH:14]=2)=[C:5]([CH3:19])[O:4][N:3]=1
Reactant: COc1cc(OC)c(-c2c(C)noc2C)cc1C=O
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Product: COc1cc(OC)c(-c2c(C)noc2C)cc1/C=C/C(=O)c1ccc(C(=O)O)cc1
Yield: 7 %

Procedure:
The title compound was prepared by condensing 5-(3,5-dimethyl-isoxazol-4-yl)-2,4-dimethoxy-benzaldehyde (Ex-33A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp>260° C., 7% yield. 1H-NMR (DMSO-d6) δ 8.15 (d, J=8 Hz, 2H), 8.04 (d, J=16 Hz, 1H), 8.02 (d, J=8 Hz, 2H), 7.89 (s, 1H), 7.81 (d, J=16 Hz, 1H), 6.79 (s, 1H), 4.00 (s, 3H), 3.97 (s, 3H), 2.23 (s, 3H) 2.05 (s, 3H) MS m/z=407 ([M]+, 60%), 376 (100%). HMRS (EI) calcd. for C23H21NO6: 407.1369; found: 407.1375.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[CH2:11][CH2:12][C:13]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:3]1=2.Cl[CH2:20][C:21]1[CH:22]=[C:23]([O:27][CH3:28])[CH:24]=[CH:25][CH:26]=1.[Cl-].[Na+]>C(N(CC)CC)C>[CH3:28][O:27][C:23]1[CH:22]=[C:21]([CH2:20][N:16]2[CH2:17][CH2:18][C:13]3([C:3]4[N:2]([CH3:1])[C:10]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=5[C:4]=4[CH2:11][CH2:12]3)[CH2:14][CH2:15]2)[CH:26]=[CH:25][CH:24]=1
Reactant: Cn1c2c(c3ccccc31)CCC21CCNCC1
Reactant: COc1cccc(CCl)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: COc1cccc(CN2CCC3(CCc4c3n(C)c3ccccc43)CC2)c1
Yield: 34.7 %

Procedure:
A solution of 1,4-dihydro4-methylspiro[cyclopent[b]indole-3(2H), 4′-piperidine] (2.5 g) and triethylamine (2.9 ml) in dichloromethanc (100 ml) and 3-(chloromethyl)anisole (1.95 g) was stirred overnight at ambient temperature, under nitrogen. Saturated sodium chloride solution was added and the mixture was extracted with dichloromethane. The extracts were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was flashed chromatographed (silica gel), eluting with 10% anhydrous acetone/dichloromethane. The appropriate fractions were collected and concentrated to give 1.3 g (35%) of product, mp 100-101° C.
Reaction SMILES: [CH:1](=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1.C(O)(C(F)(F)F)=O>C(Cl)Cl.C(O)(C)C>[CH3:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C@H:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:2][CH:1]=[O:10])=[CH:13]1
Reactant: Cn1ccc2ccccc21
Reactant: O=CC=Cc1ccccc1
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc([C@@H](CC=O)c2ccccc2)c2ccccc21
Yield: 83.5 %

Procedure:
Prepared according to the general procedure from cinnamaldehyde (190 μL, 1.50 mmol), 1-methyl-1H-indole (64 μL, 0.50 mmol), TFA (7.7 μL, 0.10 mmol) and (2S,5S)-5-benzyl-2-tert-butyl-3-imidazolidin-4-one (24.6 mg, 0.100 mmol) in CH2Cl2 (0.85 mL) and isopropanol (0.15 mL) at −55° C. for 45 h to provide, after silica gel chromatography (10:90 EtOAc/hexanes), the title compound as a colorless oil (110 mg, 84% yield, 90% ee). IR (film) 3051, 3026, 2945, 2888, 2822, 2733, 1722, 1616, 1604, 1547, 1474, 1429, 1376, 1331, 1245, 1225, 1156, 1131, 1013, 765, 740, 700 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.76 (dd, J=2.4, 2.4 Hz, 1H, CHO), 7.43 (dt, J=0.9, 8.1 Hz, 1H, ArH), 7.36-7.28 (m, 7H, ArH), 7.04 (ddd, J=1.2, 6.9, 8.1 Hz, 1H, ArH), 6.88 (s, 1H, NCH), 4.88 (t, J=7.5 Hz, 1H, ArCH), 3.76 (s, 3H, NCH3), 3.22 (ddd, J=2.7, 8.4, 16.5 Hz, 1H, CH2CO); 3.10 (ddd, J=2.7, 8.4, 16.5 Hz, 1H, CH2CO); 13C NMR (75 MHz, CDCl3) δ 201.8, 143.5, 137.3, 128.6, 127.6, 126.8, 126.6, 126.4, 121.9, 119.4, 119.0, 116.6, 109.3, 50.0, 37.4, 32.9; HRMS (CI) exact mass calcd for (C15H17NO) requires m/z 263.1310, found m/z 263.1306. [α]D=+30.9 (CHCl3). The enantiomeric ratio was determined by HPLC analysis of the alcohol, obtained by NaBH4 reduction of the aldehyde, using a Chiracel AD and AD guard column (3:97 ethanol/hexanes, 1 mL/min); S isomer tr=48.5 min and R isomer tr=38.9 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:21][C:6]2=[C:7]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[S:8][C:9]([S:10]([CH3:13])(=O)=O)=[C:5]2[C:4](=[O:22])[CH2:3]1.[OH-].[Na+].[CH2:26](S)[CH2:27]C>CCO>[CH3:1][C:2]1([CH3:23])[CH2:21][C:6]2=[C:7]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[S:8][C:9]([S:10][CH2:13][CH2:26][CH3:27])=[C:5]2[C:4](=[O:22])[CH2:3]1
Reactant: CC1(C)CC(=O)c2c(S(C)(=O)=O)sc(C(=O)N3CCCC3)c2C1
Reactant: CCCS
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCSc1sc(C(=O)N2CCCC2)c2c1C(=O)CC(C)(C)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 6,6-dimethyl-3-methanesulphonyl-1-(pyrrolidin-1-ylcarbonyl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (500 mg, 1.4 mmol) in EtOH (15 mL) was added NaOH (0.71 mL of a 4 M solution, 2.8 mmol) followed by propanethiol (255 μL, 2.8 mmol). The mixture was stirred at room temperature for 2 h then evaporated. The residue was partitioned between EtOAc (20 mL) and water (20 mL). The organic layer was separated, dried (Na2SO4) and evaporated. The residue was triturated with ether and the colourless solid (380 mg, 77%) collected by filtration. mp 117-119° C. C18H25NO2S2 requires: C, 61.50; H, 7.17; N, 3.98%. Found: C, 61.48; H, 7.02; N, 3.97%. 1H NMR (250 MHz, CDCl3) δ1.04 (6H, s), 1.10 (3H, t, J=7.3 Hz), 1.87 (2H, sextet, J=7.3 Hz), 1.93-1.99 (4H, m), 2.40 (2H, s), 2.83 (2H, s), 3.00 (2H, t, J=7.3 Hz), 3.57-3.63 (4H, m). MS (ES+) 352 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=O)[NH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:22])=O>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:22])=[N:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]cnc2cc(OCc3ccccc3)ccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2cc(OCc3ccccc3)ccc12
Yield: 90 %

Procedure:
A solution of the product from Step 2 (2.82 g, 11.2 mmol) in phosphorous oxychloride (20 mL) was heated at 100° C. for 16 hours. The reaction was concentrated and azeotroped once with dichlromethane. The residue was dissolved in EtOAc and washed with saturated sodium bicarbonate solution then saturated sodium chloride solution. The organic layer was dried over sodium sulfate and concentrated to provide 7-(benzyloxy)-4-chloroquinazoline (2.72 g, 90%) as a yellow solid. MS 271.2 (ES+).
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])[CH2:6]1)(=O)C.[OH-].[Na+].O>CO>[OH:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])[CH2:6]1
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@]12CC[C@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Yield: 94.1 %

Procedure:
A mixture of 5 (1 g, 3.00 mmol), NaOH 0.12 g (3.44 mmol) in methanol was refluxed for 10 min, cooled to room temperature and treated with water. The resulting precipitate was filtered off and washed with water to afford crude product 6 (0.82 g, 95%).
Reaction SMILES: N[C:2]([CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)([CH3:5])[C:3]#[N:4].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][S:23](Cl)(=[O:25])=[O:24])=[CH:18][CH:17]=1.N1(C2CCCCCCC2)CCCCCCN1>O1CCCC1.C(OCC)(=O)C>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:2]([S:23]([CH2:22][C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=2)(=[O:24])=[O:25])([CH3:5])[C:3]#[N:4])=[CH:9][CH:10]=1
Reactant: CC(N)(C#N)COc1ccc(Cl)cc1
Reactant: O=S(=O)(Cl)Cc1ccc(Cl)cc1
Agent: C1CCCC(N2CCCCCCN2)CCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C#N)(COc1ccc(Cl)cc1)S(=O)(=O)Cc1ccc(Cl)cc1

Procedure:
A solution of 2-amino-2-(4-chlorophenoxymethyl)-propionitrile (0.5 g, 0.24 mmol), 4-chlorophenyl-methylsulfonyl chloride (0.46 g, 2.4 mmol) and diazabicyclooctane (0.6 g, 2.4 mmol) in anhydrous tetrahydrofuran (20 ml) is stirred for about 16 hours. The reaction mixture is diluted with ethyl acetate and washed with brine. The organic phase is dried over magnesium sulfate and the raw product received as the residue is purified by flash chromato-graphy (eluent: ethyl acetate/hexanes 1:3) to give the 2-(4-chlorophenoxy-methyl)-2-(4-chlorophenyl-methylsulfonyl)-propionitrile in form of colorless crystals, m.p. 119-120° C.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH2:17][NH:18]C(=O)OC(C)(C)C)[CH:11]=2)=[CH:6][CH:5]=1)=[O:3].FC(F)(F)C(O)=O.C([O-])([O-])=O.[K+].[K+].C(Cl)(Cl)Cl>C(Cl)Cl>[NH2:18][CH2:17][CH2:16][C:12]1[CH:11]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:2]([NH2:1])=[O:3])=[CH:5][CH:6]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCCc1cccc(-c2ccc(C(N)=O)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: NCCc1cccc(-c2ccc(C(N)=O)cc2)c1

Procedure:
To a solution of 1,1-dimethylethyl {2-[4′-(aminocarbonyl)-3-biphenylyl]ethyl}-carbamate (1.81 g, 0.005 mol) in CH2Cl2 (50 mL) at room temperature was added trifluoroacetic acid (15 mL) in one portion. After 1 hr the mixture was cooled in an ice bath and 1M K2CO3 (200 mL) and chloroform were added. The aqueous phase was extracted several times with mixtures of ethyl acetate, dichloromethane and chloroform. Residual solids were collected by filtration, affording the title compound as a white solid; LC/MS (method A) 1.04 min; m/z 241 (M+H). Combined organic extracts were dried over Na2SO4 and concentrated in vacuo affording an additional batch of the title compound (combined with the solid collected above). This product was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)/[C:10](=[N:19]/[S:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)(=[O:22])=[O:21])/[CH:9]=2)=[N:5][N:4]=[N:3]1.[Cl:35]C1C=CC(S(/N=C2\C=C(Cl)C(=O)C3C\2=CC=CC=3)(=O)=O)=CC=1.SC1N=CNN=1>>[NH:4]1[CH:1]=[N:2][C:6]([S:7][C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)/[C:10](=[N:19]/[S:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:35])=[CH:25][CH:24]=3)(=[O:21])=[O:22])/[CH:9]=2)=[N:5]1.[CH3:1][N:2]1[C:6]([S:7][C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)/[C:10](=[N:19]/[S:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)(=[O:21])=[O:22])/[CH:9]=2)=[N:5][N:4]=[N:3]1
Reactant: O=C1C(Cl)=C/C(=N\S(=O)(=O)c2ccc(Cl)cc2)c2ccccc21
Agent: Cn1nnnc1SC1=C/C(=N\S(=O)(=O)c2ccc(-c3ccccc3)cc2)c2ccccc2C1=O
Agent: Sc1nc[nH]n1
Product: O=C1C(Sc2nc[nH]n2)=C/C(=N\S(=O)(=O)c2ccc(Cl)cc2)c2ccccc21

Procedure:
(E)-N-(3-(1H-1,2,4-triazol-3-ylthio)-4-oxonaphthalen-1(4H)-ylidene)-4-chlorobenzenesulfonamide (13af) was prepared according to the procedure for 13x except using 12e and 3-mercapto-1,2,4-triazole, affording 43.8 mg (57.4%) title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])=[C:12]([OH:21])[CH:11]=2)=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:35][CH2:36][CH2:37]Br>CN(C=O)C>[Br:35][CH2:36][CH2:37][O:21][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[CH:4]=1)=[O:22]
Reactant: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1OCCBr
Temperature: 50 °C
Reaction time: 18 h
Yield: 39 %

Procedure:
N-(4-Chloro-3-(pyridin-2-yl)phenyl)-3-hydroxy-4-(methylsulfonylmethyl)benzamide (1.00 g, 2.40 mmol) was dissolved in DMF (20 ml). Cesium carbonate (1.56 g, 4.8 mmol) and 1,2-dibromoethane (0.83 ml, 9.6 mmol) were added, and the reaction was stirred at 50° C. for 18 hours. The reaction was quenched with water, basified with 10% aqueous NaOH, and extracted with ethyl acetate twice. The ethyl extracts were washed with water once, brine once, dried with MgSO4, and evaporated to a crude oil which was purified by chromatography (25% hexanes in ethyl acetate) to yield 490 mg of 3-(2-bromoethoxy)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide as a yellow solid. 3-(2-Bromoethoxy)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide (100 mg, 0.19 mmol) was dissolved in DMF (2.0 ml), and potassium carbonate (32 mg, 0.23 mmol) and tert-butyl piperazine-1-carboxylate (38 mg, 0.21 mmol) were added. The reaction was stirred for 18 hours at room temperature, quenched in water, and extracted with ethyl acetate twice. The ethyl acetate extracts were washed with water once, brine once, dried with MgSO4, and evaporated to a crude oil. The oil was dissolved in dichloromethane (1 ml) and treated with trifluoroacetic acid (3 ml) for 1 hour. The reaction was evaporated to dryness, and the crude solid was purified on reverse phase HPLC to yield 63 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)-3-(2-(piperazin-1-yl)ethoxy)benzamide as a white solid. N-(4-Chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)-3-(2-(piperazin-1-yl)ethoxy)benzamide (30 mg, 0.047 mmol) was dissolved in dichloromethane (1.5 ml) and THF (1.0 ml). N-ethyl-N-isopropylpropan-2-amine (18 gut, 0.10 mmol) and methanesulfonyl chloride (4 μl, 0.051 mmol) were added, and the reaction stirred at room temperature for 72 hours. Additional N-ethyl-N-isopropylpropan-2-amine (9 μl, 0.051 mmol) and methanesulfonyl chloride (4 μl, 0.051 mmol) were added and the reaction stirred for 2 hours. After a further addition of methanesulfonyl chloride (4 IIl, 0.051 mmol), the reaction was stirred for 2 hours and evaporated to a crude solid which was purified on reverse phase HPLC to yield 8 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-3-(2-(4-(methylsulfonyl)piperazin-1-yl)ethoxy)-4-(methylsulfonylmethyl)benzamide. MS (Q1) 607 (M)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([S:13]([NH2:16])(=[O:15])=[O:14])[S:10][N:9]=1.S(Cl)(Cl)=O.[CH:21]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=O>>[N:23]1([CH:21]=[N:16][S:13]([C:11]2[S:10][N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[N:12]=2)(=[O:15])=[O:14])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: O=CN1CCOCC1
Reactant: Cc1ccccc1-c1nsc(S(N)(=O)=O)n1
Solvent: O=S(Cl)Cl
Product: Cc1ccccc1-c1nsc(S(=O)(=O)N=CN2CCOCC2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3.5 g of 3-(2-methylphenyl)-1,2,4-thiadiazole-5-sulfonamide in 18 ml of N-formylmorpholine at -5° C. was added 5 ml of thionyl chloride. The resulting mixture was stirred for 3 hours at room temperature, then poured into ice water and stirred for 30 minutes. The solid was collected, washed with water and sucked dry. The solid was then triturated with ether, ether/hexane (1:1) and hexane successively. The product was dried (P2O5) to give 4.52 g of solid, m.p. 151°-153° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH2:19][C@@H:18](O)[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C1C(COC(/N=N\C(OCC2C=CC(Cl)=CC=2)=O)=O)=CC=C(Cl)C=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH2:19][C@H:18]([O:8][C:4]2[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](O)C1
Reactant: Oc1cncc(Br)c1
Agent: O=C(/N=N\C(=O)OCc1ccc(Cl)cc1)OCc1ccc(Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CCC[C@H](Oc2cncc(Br)c2)C1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-7, 5-bromopyridin-3-ol was reacted with (R)-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester in presence of di-(4-chlorobenzyl)azodicarboxylate and triphenylphosphine to give the title compound as a light yellow oil. MS: 357.1 and 359.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[C:17](SC)=[N:16][CH:15]=[N:14][C:13]=3[N:12]([CH3:21])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.N>[Ni].O1CCOCC1>[NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([CH3:21])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1
Reactant: CSc1ncnc2c1c(C(=O)c1cncc(N)c1)cn2C
Agent: [Ni]
Agent: N
Solvent: C1COCCO1
Product: Cn1cc(C(=O)c2cncc(N)c2)c2cncnc21
Yield: 100 %

Procedure:
Raney nickel (10 g) was added to (5-aminopyridin-3-yl)[7-methyl-4-(methylthio)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (1.5 g, 5.0 mmol) and conc ammonia (150 mL) in 1,4 dioxane (150 mL). The mixture was refluxed for 6 hours then filtered. The filtrate was evaporated in vacuo and purified by prep HPLC (method 4) to afford the title compound as a brown solid in 100% yield, 1.9 g.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[Cl:6][C:7]([Cl:23])([Cl:22])[CH:8](Cl)[CH:9]([N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12].O>C(O)(=O)C>[Cl:23][C:7]([Cl:6])([Cl:22])[CH:8]([O:3][C:1](=[O:4])[CH3:2])[CH:9]([N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[C:10](=[O:15])[C:11]([CH3:13])([CH3:12])[CH3:14]
Reactant: CC(=O)[O-]
Reactant: CC(C)(C)C(=O)C(C(Cl)C(Cl)(Cl)Cl)n1cncn1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)OC(C(C(=O)C(C)(C)C)n1cncn1)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
16.4 g (0.2 mol) of anhydrous sodium acetate were added to 31.5 g (0.1 mol) of 1,1,1,2-tetrachloro-3-(1,2,4-triazol-1-yl)-5,5-dimethyl-hexan-4-one in 150 ml of glacial acetic acid. The mixture was stirred at room temperature overnight and then heated to 40° C. for about 4 hours. The reaction mixture was then added to 1,000 ml of water and extracted twice with 250 ml of chloroform each time. The combined organic phases were dried over sodium sulphate and concentrated by distilling off the solvent in vacuo. The solid residue was recrystallized from ethanol and rinsed with a little hexane. 27.8 g (77.8% of theory) of 1,1,1-trichloro-2-acetoxy-3-(1,2,4-triazol-1-yl)-5,5-dimethylhexan-4-one were obtained as a diastereomer mixture of melting point 115°-119° C.
Reaction SMILES: [OH:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:13]C.Br>C(Cl)Cl>[OH:13][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:2]=1[OH:1])[CH:6]=[O:7]
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: Br
Solvent: ClCCl
Product: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
17.1 g of 4-hydroxy-3-methoxy-5-nitrobenzaldehyde are treated with 170 ml of constant-boiling hydrobromic acid and heated under reflux for 3.5 hours. After cooling the separated precipitate is filtered under suction, washed twice with ice-water and taken up in ethyl acetate. The organic phase is washed twice with 50 ml of sodium chloride solution each time, dried over magnesium sulfate and evaporated in a water-jet vacuum. The crystals obtained are taken up in methylene chloride, whereupon the solution is filtered over a ten-fold amount of silica gel. The material obtained is crystallized from ethyl acetate/isopropyl ether. There is obtained 3,4-dihydroxy-5-nitrobenzaldehyde in the form of yellow crystals of m.p. 142°-143°.
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([S:43][CH:44]([C:69]#[N:70])[CH2:45][NH:46][C:47]([C:49]1[NH:50][C:51]2[C:56]([CH:57]=1)=[C:55]([CH3:58])[CH:54]=[CH:53][C:52]=2[N:59]([CH3:68])[S:60]([C:63]1[S:64][CH:65]=[CH:66][CH:67]=1)(=[O:62])=[O:61])=O)C1C=CC=CC=1.CSC.C(=O)([O-])O.[Na+]>C(#N)C>[C:69]([CH:44]1[S:43][C:47]([C:49]2[NH:50][C:51]3[C:56]([CH:57]=2)=[C:55]([CH3:58])[CH:54]=[CH:53][C:52]=3[N:59]([CH3:68])[S:60]([C:63]2[S:64][CH:65]=[CH:66][CH:67]=2)(=[O:62])=[O:61])=[N:46][CH2:45]1)#[N:70]
Reactant: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C(=O)NCC(C#N)SCc3ccccc3)cc12
Agent: O=C([O-])O
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CSC
Solvent: CC#N
Product: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C3=NCC(C#N)S3)cc12
Reaction time: 0.17 h
Yield: 66.4 %

Procedure:
To a mixture of triphenylphosphine oxide (2.35 g) and acetonitrile (20 mL) was slowly added trifluoromethanesulfonic anhydride (0.71 mL) at 0° C., and the mixture was stirred for 10 min. N-[2-(Benzylthio)-2-cyanoethyl]-4-methyl-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (1.10 g) and dimethylsulfide (0.46 mL) were added. The reaction mixture was stirred at 0° C. for 30 min, saturated aqueous sodium hydrogencarbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (0.58 g, yield 67%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (3:2, volume ratio). melting point 173-174° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([C:18]([NH:20][C:21]3[CH:22]=[C:23](/[CH:27]=[CH:28]/[C:29]([O:31]CC)=[O:30])[CH:24]=[CH:25][CH:26]=3)=[O:19])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=[CH:6][CH:7]=1.O[Li].O>>[OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([C:18]([NH:20][C:21]3[CH:22]=[C:23](/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30])[CH:24]=[CH:25][CH:26]=3)=[O:19])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1cccc(NC(=O)c2cc(-c3cccc(O)c3)cc3ccccc23)c1
Agent: [Li]O
Solvent: O
Product: O=C(O)/C=C/c1cccc(NC(=O)c2cc(-c3cccc(O)c3)cc3ccccc23)c1
Yield: 44 %

Procedure:
Compound 25a was synthesized from 24a (1.02 mmol) and LiOH.H2O (10.3 mmol) using procedure according to the Method E described above.