Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:22][CH2:23][O:24][CH3:25])[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])(=[O:14])=[O:13])[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>CO>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([N:9]1[CH2:8][CH2:7][C:6]([CH2:22][CH2:23][O:24][CH3:25])([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]1)(=[O:13])=[O:14]
Reactant: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCCC1(C(=O)O)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Temperature: 60 °C
Reaction time: 5 h
Yield: 111.8 %

Procedure:
1-(2-Chloro-benzenesulfonyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (0.5 g) was dissolved in MeOH (8 ml), 3M aqueous NaOH (6.41 ml) was added and the mixture was stirred at 5 h at 60° C. to complete the reaction. The solvent was evaporated off, the residue was acidified with 3M aqueous HCl and extracted with dichloromethane. The layers were separated, the organic phase was washed with brine, dried over sodium sulphate and concentrated to give the desired 1-(2-chloro-benzenesulfonyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid (0.519 g) as a light brown solid. MS (ESI): 360.1 (M-H)−.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[N:14]=[C:13]([C:18]4[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=4)/[CH:21]=[CH:22]/[C:23](O)=[O:24])[NH:12][C:11]=3[N:10]([CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:9]2=[O:36])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:39])=O>ClCCl>[CH:1]1([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[N:14]=[C:13]([C:18]4[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=4)/[CH:21]=[CH:22]/[C:23]([Cl:39])=[O:24])[NH:12][C:11]=3[N:10]([CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:9]2=[O:36])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)/C=C/c1cccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)/C=C/c1cccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)c1

Procedure:
A mixture of (E)-3-(1,3-bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl)cinnamic acid, from Example 31, (0.20 g, 0.41 mmol) in dichloromethane (5 ml) and thionyl chloride (Aldrich, 0.6 ml, 0.81 mmol) was refluxed for 1.5 hours. Volatiles were removed in vacuo to give (E)-3-(1,3-bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl)cinnamic acid chloride as a yellow solid which was used without further purification.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si]([O:26][CH2:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([F:53])=[C:33]([CH:52]=1)[CH2:34][N:35]1[CH2:51][CH2:50][C:38]2([O:43][CH2:42][CH2:41][N:40]([C:44](=[O:49])[C:45]([F:48])([F:47])[F:46])[CH2:39]2)[CH2:37][CH2:36]1)(C(C)(C)C)(C)C>C1COCC1>[F:48][C:45]([F:46])([F:47])[C:44]([N:40]1[CH2:39][C:38]2([CH2:50][CH2:51][N:35]([CH2:34][C:33]3[CH:52]=[C:29]([CH2:28][CH2:27][OH:26])[CH:30]=[CH:31][C:32]=3[F:53])[CH2:36][CH2:37]2)[O:43][CH2:42][CH2:41]1)=[O:49]
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc(F)c(CN2CCC3(CC2)CN(C(=O)C(F)(F)F)CCO3)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(N1CCOC2(CCN(Cc3cc(CCO)ccc3F)CC2)C1)C(F)(F)F
Reaction time: 18 h

Procedure:
TBAF (1M in THF, 16.4 mL) was added to a solution of 1-(9-(5-(2-(tert-butyldimethylsilyloxy)ethyl)-2-fluorobenzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-2,2,2-trifluoroethanone [Example 44, step a] (8.5 g) in THF (100 mL) and the resultant solution allowed to stand at 20° C. for 18 hours. The solvent was evaporated under reduced pressure and the residue was purified by flash silica chromatography, using 2% methanol in dichloromethane containing 1% triethylamine as solvent. Fractions containing the product were evaporated to dryness to afford the subtitled compound. Yield 4.2 g. m/z 405 (M+H)+ (APCI).
Reaction SMILES: [BrH:1].[CH2:2]([O:4][C:5](=[O:30])[C@H:6]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[NH:7][C:8](=[O:21])[CH2:9][NH:10]C(OCC1C=CC=CC=1)=O)[CH3:3].C(OCC)C>C(O)(=O)C>[CH2:2]([O:4][C:5](=[O:30])[C@H:6]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[NH:7][C:8](=[O:21])[CH2:9][NH2:10])[CH3:3].[BrH:1]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)CNC(=O)OCc1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)CN
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
250 ml of 25% HBr in glacial acetic acid was added to carbobenzoxyglycyl-L-tyrosine ethyl ester obtained above, and after the mixture was stirred for 30 minutes at room temperature, 5 l of absolute ethyl ether was added to the mixture to produce a precipitate. The precipitate was washed with ethyl ether to obtain glycyl-L-tyrosine ethyl ester·HBr.
Reaction SMILES: [N+:1]([C:4]1[CH:79]=[CH:78][C:7]([CH2:8][C:9]([CH2:68][C:69]2[CH:74]=[CH:73][C:72]([N+:75]([O-])=O)=[CH:71][CH:70]=2)([CH2:40][C:41](=[O:67])/[CH:42]=[CH:43]/[C:44]2[CH:49]=[CH:48][C:47]([O:50][C:51](=[O:66])[C:52]3[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH2:60][CH2:61][C:62]([F:65])([F:64])[F:63])=[CH:54][CH:53]=3)=[CH:46][CH:45]=2)[C:10]([C:13](=[O:39])/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23](=[O:38])[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][C:34]([F:37])([F:36])[F:35])=[CH:26][CH:25]=3)=[CH:18][CH:17]=2)([OH:12])[OH:11])=[CH:6][CH:5]=1)([O-])=O.CCCCCC>CN(C)C=O.O.[Zn]>[NH2:75][C:72]1[CH:73]=[CH:74][C:69]([CH2:68][C:9]([CH2:8][C:7]2[CH:78]=[CH:79][C:4]([NH2:1])=[CH:5][CH:6]=2)([CH2:40][C:41](=[O:67])/[CH:42]=[CH:43]/[C:44]2[CH:49]=[CH:48][C:47]([O:50][C:51](=[O:66])[C:52]3[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH2:60][CH2:61][C:62]([F:63])([F:64])[F:65])=[CH:54][CH:53]=3)=[CH:46][CH:45]=2)[C:10]([C:13](=[O:39])/[CH:14]=[CH:15]/[C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23](=[O:38])[C:24]3[CH:25]=[CH:26][C:27]([O:30][CH2:31][CH2:32][CH2:33][C:34]([F:37])([F:36])[F:35])=[CH:28][CH:29]=3)=[CH:20][CH:21]=2)([OH:11])[OH:12])=[CH:70][CH:71]=1
Reactant: O=C(/C=C/c1ccc(OC(=O)c2ccc(OCCCC(F)(F)F)cc2)cc1)CC(Cc1ccc([N+](=O)[O-])cc1)(Cc1ccc([N+](=O)[O-])cc1)C(O)(O)C(=O)/C=C/c1ccc(OC(=O)c2ccc(OCCCC(F)(F)F)cc2)cc1
Agent: [Zn]
Solvent: CCCCCC
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(CC(CC(=O)/C=C/c2ccc(OC(=O)c3ccc(OCCCC(F)(F)F)cc3)cc2)(Cc2ccc(N)cc2)C(O)(O)C(=O)/C=C/c2ccc(OC(=O)c3ccc(OCCCC(F)(F)F)cc3)cc2)cc1
Yield: 0.1 %

Procedure:
2.20 g (2.00 mol) of 2,2-bis(4-nitrobenzyl)-1,3 di[(2E)-3-{4-[(4-(4,4,4-trifluorobutoxy)benzoyl)oxy]phenyl}prop-2-enoyl] propanediol are dissolved in a mixture of 25 ml of N,N-dimethylformamide and 3 ml water. 3.25 g (12.01 mmol) ferric chloride hexahydrate are added. 1.31 g (20.02 mmol) Zinc powder are added portionwise within 40 min. The mixture is allowed to react for 2 hours. The reaction mixture is then partitioned between ethyl acetate and water and filtered. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. Chromatography of the residue on 100 g silica gel using toluene:ethyl acetate 1:1 as eluant and crystallization form ethylacetate:hexane mixture to yield 1.20 g 2,2-bis(4-aminobenzyl)-1,3 di[(2E)-3-{4-[(4-(4,4,4-trifluorobutoxy)benzoyl)oxy]phenyl}prop-2-enoyl] propanediol
Reaction SMILES: [C:1]([S@@:5](/[N:7]=[CH:8]/[C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])=[O:6])([CH3:4])([CH3:3])[CH3:2].[CH2:19]([Zn]CC)[CH3:20].CCCCCC.C([Mg]Br)C.C(OCC)C.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[C:1]([S@@:5]([NH:7][C@H:8]([C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])[CH2:19][CH3:20])=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cccc(/C=N/[S@@](=O)C(C)(C)C)c1
Reactant: CC[Zn]CC
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC[C@H](N[S@@](=O)C(C)(C)C)c1cccc(C(=O)OC)c1
Reaction time: 0.08 h

Procedure:
To a solution of 500 mg of methyl 3-[(E)-{[(S)-tert-butylsulfinyl]imino}methyl]benzoate in 12 ml of THF was added 0.50 ml of a 1 M diethylzinc/hexane solution at −78° C., followed by stirring at the same temperature for 5 minutes. 0.80 ml of a 3 M ethylmagnesium bromide/diethyl ether solution was added thereto at −78° C., followed by stirring at the same temperature for 2 hours. To the reaction mixture were added a saturated aqueous ammonium chloride solution and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 447 mg of methyl 3-[(1S)-1-{[(S)-tert-butylsulfinyl]amino}propyl]benzoate.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23]O)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[Br:1][C:2]1[C:3]([O:13][CH2:23][CH2:22][NH:21][C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: Oc1noc(-c2ccccc2)c1Br
Product: CC(C)(C)OC(=O)NCCOc1noc(-c2ccccc2)c1Br
Yield: 81.4 %

Procedure:
4-Bromo-3-hydroxy-5-phenylisoxazole (0.2 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.15 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 9(a) to obtain the title compound (0.26 g, 81%) as a colorless powder.
Reaction SMILES: O=C[C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[OH-].[Na+].OO.I([O-])(=O)(=O)=[O:17].[Na+]>O.C(O)(=O)C>[CH3:7][O:6][C:5]1[C:8](=[O:9])[CH:10]=[CH:11][C:3](=[O:17])[CH:4]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COc1cc(C=O)ccc1O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COC1=CC(=O)C=CC1=O
Temperature: 10 °C
Yield: 334.4 %

Procedure:
Vanillin (2.432 kg) was added to a solution of sodium hydroxide (640 g) in water (8 l) and cooled to 10° C. with an ice-bath. Then a solution of hydrogen peroxide (30%) (2.4 l) was added at a rate to keep the temperature of the reacting mixture below 30° C. The addition completed (about 2 hours), the reaction mixture was added over a period of 3 hours to a suspension of sodium periodate (880 g) in water (4 l) and acetic acid (640 ml) cooled with an ice-bath to 10° C. (the temperature of the reacting mixture was kept below 35° C.). The resulting precipitate was filtered, washed with cold water followed by ethanol/hexane (1:1) mixture and air-dried to afford the title compound (1.9 kg), m.p. 144°-147° C.
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:31]=[C:32]([O:34][CH3:35])[CH:33]=1)[C:8]([NH:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[C:22]([O:24][CH2:25][CH3:26])[C:21](F)=[C:20]([O:28][CH2:29][CH3:30])[CH:19]=2)[CH2:13][CH2:12]1)=[O:9])#[N:2].C(OC(=O)C1C=C(OCC)C([Cl:49])=C(OCC)C=1)C.ClC1C(OCC)=CC(CN2CCC(NC(=O)C3C=C(OC)C=C(CO)C=3)CC2)=CC=1OCC.C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[Cl:49][C:21]1[C:22]([O:24][CH2:25][CH3:26])=[CH:23][C:18]([CH2:17][N:14]2[CH2:15][CH2:16][CH:11]([NH:10][C:8](=[O:9])[C:7]3[CH:31]=[C:32]([O:34][CH3:35])[CH:33]=[C:5]([O:4][CH2:3][C:1]#[N:2])[CH:6]=3)[CH2:12][CH2:13]2)=[CH:19][C:20]=1[O:28][CH2:29][CH3:30]
Reactant: CCOC(=O)c1cc(OCC)c(Cl)c(OCC)c1
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(OCC#N)c3)CC2)cc(OCC)c1F
Agent: CCOc1cc(CN2CCC(NC(=O)c3cc(CO)cc(OC)c3)CC2)cc(OCC)c1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(OCC#N)c3)CC2)cc(OCC)c1Cl

Procedure:
In analogy to the procedure described in example 50k), 3-cyanomethoxy-5-methoxy-N-piperidin-4-yl-benzamide (example 245) was reacted with 4-chloro-3,5-diethoxy-benzaldehyde (example 219), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as off-white solid. MS: 502.2 (MH+).
Reaction SMILES: C(C1(NC([C@@H]2C[C@@H](S(C3C=CC=CC=3C(F)(F)F)(=O)=O)CN2C2N(C3C=CC=CC=3)N=C(C)C=2)=O)CC1)#N.COC([C@H]1C[C@@H](S(C2C=CC=CC=2C(F)(F)F)(=O)=O)CN1C(=O)CC(=O)C)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1.CC(C)CNN.[CH3:106][O:107][C:108]([C@H:110]1[CH2:114][C@@H:113]([S:115]([C:118]2[CH:123]=[CH:122][CH:121]=[CH:120][C:119]=2[C:124]([F:127])([F:126])[F:125])(=[O:117])=[O:116])[CH2:112][N:111]1[C:128]1[N:129]([CH2:134][CH:135]([CH3:137])[CH3:136])[N:130]=[C:131]([CH3:133])[CH:132]=1)=[O:109]>>[CH3:106][O:107][C:108]([C@@H:110]1[CH2:114][C@@H:113]([S:115]([C:118]2[CH:123]=[CH:122][CH:121]=[CH:120][C:119]=2[C:124]([F:127])([F:125])[F:126])(=[O:117])=[O:116])[CH2:112][N:111]1[C:128]1[N:129]([CH2:134][CH:135]([CH3:137])[CH3:136])[N:130]=[C:131]([CH3:133])[CH:132]=1)=[O:109]
Reactant: COC(=O)[C@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1CC(C)C
Agent: CC(C)CNN
Agent: COC(=O)[C@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=O)CC(C)=O
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1CC(C)C

Procedure:
In analogy to the procedure described in example 308d, a mixture of (2S,4R)-1-(3-oxo-butyryl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (example 192 f) and of (2R,4R)-1-(3-oxo-butyryl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with Lawesson's reagent (CAS Reg. No. 19172-47-5) and (2-methylpropyl)-hydrazine 4-methylbenzenesulfonate (CAS Reg. No. 112306-59-9) to give a mixture of the title compound and (2R,4R)-1-(2-isobutyl-5-methyl-2H-pyrazol-3-yl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester as yellow solid. MS (ESI): m/z=474.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1I>>[Br:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[S:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: Cc1ccc(S)cc1
Reactant: Fc1ccc(I)c(Br)c1
Product: Cc1ccc(Sc2ccc(F)cc2Br)cc1

Procedure:
Prepared from 4-methyl-benzenethiol and 2-bromo-4-fluoro-1-iodo-benzene.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([CH:16]4[CH2:18][CH2:17]4)[N:13]([CH3:19])[C:12]=3[CH:20]=2)[C:4](=[O:21])[CH:3]=1.[F:22][C:23]([F:32])([F:31])[C:24]1[S:25][CH:26]=[C:27]([CH2:29][OH:30])[N:28]=1.C1(C)C=CC=CC=1.CC(C)([O-])C.[K+]>O>[CH:16]1([C:14]2[N:13]([CH3:19])[C:12]3[CH:20]=[C:8]([N:5]4[CH:6]=[CH:7][C:2]([O:30][CH2:29][C:27]5[N:28]=[C:24]([C:23]([F:32])([F:31])[F:22])[S:25][CH:26]=5)=[CH:3][C:4]4=[O:21])[CH:9]=[CH:10][C:11]=3[N:15]=2)[CH2:18][CH2:17]1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(Br)cc3=O)cc21
Reactant: OCc1csc(C(F)(F)F)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4csc(C(F)(F)F)n4)cc3=O)cc21
Reaction time: 8 h
Yield: 22.4 %

Procedure:
To a mixture of 4-bromo-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (100 mg), (2-(trifluoromethyl)thiazol-4-yl)methanol (80 mg) and toluene (5 ml) was added potassium tert-butoxide (98 mg) at 100° C., and the mixture was stirred at the same temperature overnight. The mixture was poured into water, and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated in vacuo, and purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (29.0 mg) as a white solid.
Reaction SMILES: C(OC([N:11]([CH2:22][CH:23]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:32][CH:31]=1)[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])=O)C1C=CC=CC=1>C(O)C.[C].[Pd]>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([NH:11][CH2:22][CH:23]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:32][CH:31]=2)[C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)(=[O:13])=[O:14])=[CH:16][CH:17]=1
Reactant: CCOC(=O)COc1ccc(C(CN(C(=O)OCc2ccccc2)S(=O)(=O)c2ccc(Cl)cc2)c2cccnc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)COc1ccc(C(CNS(=O)(=O)c2ccc(Cl)cc2)c2cccnc2)cc1

Procedure:
In 10 ml of ethanol were suspended 0.23 g of the thus obtained ethyl 4-{2-[N-benzyloxycarbonyl-N-(4-chlorobenzenesulfonyl)amino]-1-(3pyridyl)ethyl}phenyloxyacetate and 0.14 g of 10% palladium-carbon. The thus prepared suspension was subjected to 14 hours of catalytic reduction reaction at ambient temperature and pressure. The resulting reaction mixture was filtered to collect filtrate, and the solvent in the filtrate was removed by distillation under a reduced pressure. Thereafter, the resulting residue was applied to silica gel preparative TLC and developed twice with methanol-methylene chloride (5:95 v/v) to obtain 0.12 g of ethyl 4-[2-(4-chlorobenzenesulfonamido)-1-(3-pyridyl)ethyl]phenyloxyacetate from the band at an Rf value of from 0.65 to 0.43.
Reaction SMILES: [OH:1][CH:2]1[CH:8]2[CH:9]=[CH:10][CH:3]1[CH:4]1[CH:7]2[N:6]=[N:5]1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]=[N+:19]=[N-:20])=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[N:19]=[N:20][CH:9]3[C:10]42[CH:2]([OH:1])[CH:8]3[CH:7]2[CH:4]([N:5]=[N:6]2)[CH2:3]4)=[CH:14][CH:13]=1
Reactant: OC1C2C=CC1C1N=NC21
Reactant: [N-]=[N+]=Nc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: OC1C2C3N=NC3CC13C2N=NN3c1ccc(Cl)cc1

Procedure:
30 parts of 9-hydroxy-3,4-diazatricyclo[4,2,1,02,5 ]-nona-3,7-diene and 34 parts of p-chlorophenyl azide in 100 parts of toluene were heated at 80° C. for 3 hours, while stirring. The mixture was evaporated down in a rotary evaporator at from 20° to 40° C. and under 20 mbar, after which the residue was digested successively with 100 parts of diethyl ether and 100 parts of petroleum ether, and the product was dried at 20° C. under 1 mbar. 59 parts (92 mole %) of 8-(4-chlorophenyl)-12-hydroxy-3,4,8,9,10-pentazatetracyclo[5,4,1,02,5,07,11 ]dodeca-3,9-diene of melting point 178° C. (decomposition) were obtained (Command No. 1). ##STR20##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:21])[C:11]=1[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH2:5][N:6]=[N+:7]=[N-:8].[C:22]([CH2:24][C:25]([NH2:27])=[O:26])#[N:23].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:23][C:22]1[N:6]([CH2:5][C:4]2[CH:3]=[C:2]([Cl:1])[C:11]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)=[C:10]([Cl:21])[CH:9]=2)[N:7]=[N:8][C:24]=1[C:25]([NH2:27])=[O:26]
Reactant: N#CCC(N)=O
Reactant: [N-]=[N+]=NCc1cc(Cl)c(C(=O)c2ccc(Cl)cc2)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)c1nnn(Cc2cc(Cl)c(C(=O)c3ccc(Cl)cc3)c(Cl)c2)c1N

Procedure:
3,5-dichloro-4-(4′-chlorobenzoyl)benzyl azide (858.D) (1 mole) is reacted with cyanoacetamide (1.69 mole) in hot Acetonitrile, and Potassium carbonate, (6.2 mole) to give 5-amino-1-(4-(4-chlorobenzoyl)-3,5-dichlorobenzyl)-1,2,3-triazole-4-carboxamide (858.E).
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][NH2:7])([CH3:3])[CH3:2].[CH:8]1([C:11]2[N:16]=[C:15]([C:17]([NH:19][C:20]3[CH:28]=[N:27][CH:26]=[CH:25][C:21]=3[C:22](O)=[O:23])=[O:18])[C:14]([NH:29][C:30]3[CH:31]=[N:32][CH:33]=[N:34][CH:35]=3)=[N:13][CH:12]=2)[CH2:10][CH2:9]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[CH:1]([O:4][CH2:5][CH2:6][NH:7][C:22]([C:21]1[CH:25]=[CH:26][N:27]=[CH:28][C:20]=1[NH:19][C:17]([C:15]1[C:14]([NH:29][C:30]2[CH:35]=[N:34][CH:33]=[N:32][CH:31]=2)=[N:13][CH:12]=[C:11]([CH:8]2[CH2:10][CH2:9]2)[N:16]=1)=[O:18])=[O:23])([CH3:3])[CH3:2]
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)cnc1Nc1cncnc1
Reactant: CC(C)OCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)OCCNC(=O)c1ccncc1NC(=O)c1nc(C2CC2)cnc1Nc1cncnc1
Reaction time: 24 h
Yield: 80.4 %

Procedure:
To a stirred mixture of 2-aminoethyl isopropyl ether (25 mg, 242 μmol) and 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-isonicotinic acid (101 mg, 267 μmol) at rt in THF (5 ml) under an argon atmosphere were added 4-methylmorpholine (123 mg, 134 μl, 1.21 mmol) and HATU (184 mg, 485 μmol). The mixture was heated to reflux and stirring was continued for 1 day. The reaction mixture was concentrated. The crude product was purified by silica gel chromatography using an EtOAc/MeOH gradient as eluent. After trituration with MeOH, the title compound (90 mg, 80%) was obtained as yellow solid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:4](=[O:15])(=[O:14])[N:3]1[CH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=1.[O:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH3:1][C@H:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[S:4](=[O:15])(=[O:14])[N:3]1[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([NH:32][CH:29]2[CH2:30][CH2:31][O:26][CH2:27][CH2:28]2)=[O:23])=[CH:24][CH:25]=1
Reactant: NC1CCOCC1
Reactant: C[C@H]1CCC(c2ccccc2)S(=O)(=O)N1Cc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H]1CCC(c2ccccc2)S(=O)(=O)N1Cc1ccc(C(=O)NC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To a solution of 4-[[(3S)-3-methyl-1,1-dioxo-6-phenyl-thiazinan-2-yl]methyl]benzoic acid Stereoisomer A (75 mg, 0.21 mmol), tetrahydropyran-4-amine (64 mg, 0.63 mmol) and triethylamine (0.12 mL, 0.83 mmol) in N,N-dimethylformamide (1.5 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (121 mg, 0.31 mmol) and the reaction was stirred at room temperature for 2 hours. The reaction was then partitioned between dichloromethane and saturated sodium bicarbonate in water. The organic layer was separated, concentrated and purified by preparative HPLC to give 4-(((3S)-3-methyl-1,1-dioxido-6-phenyl-1,2-thiazinan-2-yl)methyl)-N-(tetrahydro-2H-pyran-4-yl)benzamide Stereoisomer A (66.4 mg, 0.15 mmol, 72% yield). 1H NMR (400 MHz, DMSO) δ 8.27-8.19 (d, J=7.7 Hz, 1H), 7.85-7.77 (m, 2H), 7.50-7.43 (m, 4H), 7.43-7.34 (m, 3H), 4.64-4.53 (m, 1H), 4.47-4.33 (m, 2H), 4.18-4.06 (m, 1H), 4.06-3.93 (m, 1H), 3.91-3.81 (m, 2H), 3.46-3.33 (m, 2H), 2.48-2.37 (m, 1H), 2.17-2.08 (m, 1H), 1.92-1.69 (m, 3H), 1.70-1.50 (m, 3H), 1.11-1.02 (d, J=6.9 Hz, 3H); LCMS [M+1]+=443.2.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][C:22]([C:26]#[N:27])=[CH:23][CH:24]=3)[N:19]=[CH:18][C:17]2=[O:28])[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.C(Cl)(Cl)Cl>[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][C:22]([C:26]#[N:27])=[CH:23][CH:24]=3)[N:19]=[CH:18][C:17]2=[O:28])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)cnc3cc(C#N)ccc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)ncc(=O)n2CCN1CCC(N)CC1
Reaction time: 1 h
Yield: 87.9 %

Procedure:
To a solution of tert-butyl{1-[2-(6-cyano-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 198, 0.38 g) in methylene chloride (4 mL) was added at 0° C. TFA (2 mL). After 1 hour, the reaction was diluted with chloroform, washed with saturated solution of Na2CO3, dried (Na2SO4), filtered and concentrated yielding 0.25 g of crude product.