Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1([O:9][CH3:10])[CH:7]([CH3:8])[CH2:6][NH:5][CH2:4]1.C([O:13][C:14]([C:16]1[CH2:17][N:18]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=2[F:35])[C:19]2[C:24]([CH:25]=1)=[CH:23][C:22]([F:26])=[C:21](Cl)[N:20]=2)=[O:15])C.C(N(CC)CC)C>N1C=CC=CC=1>[CH3:1][O:2][C:3]1([O:9][CH3:10])[CH:7]([CH3:8])[CH2:6][N:5]([C:21]2[N:20]=[C:19]3[C:24]([CH:25]=[C:16]([C:14]([OH:15])=[O:13])[CH2:17][N:18]3[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[F:35])=[CH:23][C:22]=2[F:26])[CH2:4]1
Reactant: CCOC(=O)C1=Cc2cc(F)c(Cl)nc2N(c2ccc(F)cc2F)C1
Reactant: COC1(OC)CNCC1C
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: COC1(OC)CN(c2nc3c(cc2F)C=C(C(=O)O)CN3c2ccc(F)cc2F)CC1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 68.5 %

Procedure:
In a reaction similar to that of Step 1, Example 387, into oven-dried glassware maintained under dry N2 were placed 0.132 g (0.91 mmol) of 3,3-dimethoxy-4-methylpyrrolidine (from Step 5 Example 183), 0.300 g (0.78 mmol) of 7-chloro-6-fluoro-1-(2,4-difluorophenyl)-1,8-naphthyridine-3-carboxylic acid ethyl ester, 12 mL of dry pyridine and 0.437 mL (3.1 mmol) of triethylamine. The reaction was stirred at room temperature for 15 hours, then the solvent was removed in a rotary evaporator. The residue was dissolved in methylene chloride and the product purified by column chromatography over silica gel, eluting with 0.5% increasing to 3% methanol/methylene chloride which was evaporated to afford 0.240 g of the title compound. This material was taken directly to the next step.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][C:10]2[CH:14]=[CH:15][C:16]([CH2:18][C:19](OC(C)(C)C)=[O:20])=[N:17][C:9]1=2)=O)(C)(C)C.[BH4-].[Li+]>C1COCC1>[O:11]1[CH2:12][CH2:13][NH:8][C:9]2[N:17]=[C:16]([CH2:18][CH2:19][OH:20])[CH:15]=[CH:14][C:10]1=2
Reactant: CC(C)(C)OC(=O)Cc1ccc2c(n1)N(C(=O)OC(C)(C)C)CCO2
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCc1ccc2c(n1)NCCO2
Reaction time: 0.17 h
Yield: 94.9 %

Procedure:
To a solution of 6-tert-butoxycarbonylmethyl-2,3-dihydro-pyrido[3,2-b][1,4]oxazine-4-carboxylic acid tert-butyl ester (350 mg, 1mmol) in THF (4.0 ml) was added a solution of lithium borohydride (0.6 ml, 2.0 m in thf). The mixture was refluxed overnight, then cooled in an ice-bath. Aqueous solution of naoh (0.36 ml, 5%) was added. The ice-bath was removed. Additional h2o (0.36 ml) was added and the mixture stirred for 10 min. Celite and na2so4 were added. The mixture was filtered through celite, and the celite washed with etoac. The filtrate and washing were combined, dried over na2so4, concentrated, and flash chromatographed on silica gel, eluting with meoh/dcm (1, 2, 3, 4%) to give the product (171 mg, 94% yield) as a yellow oil. 1H NMR (CDCl3) δ 6.90 (d, 1H, J=7.8 Hz), 6.39 (d, 1H, J=7.7 Hz), 4.85 (bs, 1H), 4.20 (t, 2H, J=4.4 Hz), 3.91 (t, 2H, J=5.5 Hz), 3.69-3.52 (m, 2H), 2.78 (t, 2H, J=5.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2C(OC(C)(C)C)=O)=[O:10])=[CH:4][CH:3]=1>Cl.O1CCOCC1>[Cl-:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C@H:11]2[CH2:15][CH2:14][CH2:13][NH2+:12]2)=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)Nc1ccc(Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1ccc(Cl)cc1)[C@H]1CCC[NH2+]1
Product: [Cl-]
Reaction time: 2 h

Procedure:
4.00 g (12.3 mmol) of tert-butyl (R)-2-(4-chlorophenylcarbamoyl)pyrrolidine-1-carboxylate are dissolved in 20 ml of 4N HCl in dioxane and left at room temperature for 2 hours. The reaction mixture is evaporated and dried, giving (R)-2-(4-chlorophenylcarbamoyl)pyrrolidinium chloride as a slightly brownish solid; ESI 225.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(CC)CC.[NH2:30][C:31]1[N:32]=[CH:33][C:34]([C:41]2[CH:51]=[CH:50][C:44]([C:45]([N:47]([CH3:49])[CH3:48])=[O:46])=[CH:43][CH:42]=2)=[N:35][C:36]=1[C:37]([NH:39][NH2:40])=[O:38].[CH3:52][O:53][C:54]1[CH:58]=[CH:57][S:56][C:55]=1[C:59](O)=[O:60]>C(Cl)Cl.O>[NH2:30][C:31]1[N:32]=[CH:33][C:34]([C:41]2[CH:42]=[CH:43][C:44]([C:45]([N:47]([CH3:48])[CH3:49])=[O:46])=[CH:50][CH:51]=2)=[N:35][C:36]=1[C:37](=[O:38])[NH:39][NH:40][C:59]([C:55]1[S:56][CH:57]=[CH:58][C:54]=1[O:53][CH3:52])=[O:60]
Reactant: CN(C)C(=O)c1ccc(-c2cnc(N)c(C(=O)NN)n2)cc1
Reactant: COc1ccsc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccsc1C(=O)NNC(=O)c1nc(-c2ccc(C(=O)N(C)C)cc2)cnc1N
Temperature: 25 °C
Reaction time: 72 h

Procedure:
TBTU (160.4 mg, 0.4995 mmol) and Et3N (33.70 mg, 46.42 μL, 0.3330 mmol) were added to a solution of 4-(5-amino-6-(hydrazinecarbonyl)pyrazin-2-yl)-N,N-dimethylbenzamide (100 mg, 0.3330 mmol) and 3-methoxythiophene-2-carboxylic acid (52.67 mg, 0.3330 mmol) in CH2Cl2 (2.000 mL) and the resulting solution stirred at room temperature for 72 h. The reaction mixture was diluted with dichloromethane (5 mL) and water (5 mL) and the layers separated. The aqueous layer was extracted further with dichloromethane (3×5 mL), and the combined organic extracts dried over MgSO4, filtered and concentrated in vacuo to leave 4-[5-amino-6-[[(3-methoxythiophene-2-carbonyl)amino]carbamoyl]pyrazin-2-yl]-N,N-dimethyl-benzamide as a yellow oil. POCl3 (1.788 g, 1.087 mL, 11.66 mmol) was added to 4-[5-amino-6-[[(3-methoxythiophene-2-carbonyl)amino]carbamoyl]pyrazin-2-yl]-N,N-dimethyl-benzamide and the resulting mixture heated at 100° C. for 2 h. The reaction mixture was cooled to room temperature and ice/water added carefully with vigorous stirring between additions. The mixture was left to stir at room temperature for 20 min and then diluted with dichloromethane (10 mL) and the layers separated. The aqueous layer was extracted further with dichloromethane (2×5 mL) and combined organics dried over MgSO4 and concentrated in vacuo. Solid obtained is re-dissolved in CH2Cl2 and purified by column chromatography on the ISCO column companion system (12 g column, 0-5% MeOH/CH2Cl2). Product fractions were combined and concentrated in vacuo. This was purified further by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The product fractions were combined and freeze dried to give the product as a yellow solid (33.0 mg, 23% yield) 1H NMR (400 MHz, DMSO) d 2.98 (s, 3H), 3.01 (s, 3H), 4.07 (s, 3H), 7.30 (d, 1H), 7.56 (d, 2H), 7.70 (br s, 2H), 7.96 (d, 1H), 8.14 (d, 2H) and 8.97 (s, 1H) ppm; MS (ES+) 423.19
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14](=[O:32])[N:15]2[CH2:18][CH2:19][CH2:20][C:21]2([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].[F:39][C:40]1[CH:41]=[C:42]([S:46][CH2:47][CH2:48]Br)[CH:43]=[CH:44][CH:45]=1>O.C(OCC)(=O)C>[F:39][C:40]1[CH:41]=[C:42]([S:46][CH2:47][CH2:48][N:24]2[CH2:25][CH2:26][C:21]([CH2:20][CH2:19][CH2:18][N:15]3[C:16]4[C:11](=[CH:10][CH:9]=[C:8]([O:7][CH3:6])[CH:17]=4)[CH:12]=[CH:13][C:14]3=[O:32])([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:22][CH2:23]2)[CH:43]=[CH:44][CH:45]=1
Reactant: CCOC(=O)C1(CCCn2c(=O)ccc3ccc(OC)cc32)CCNCC1
Reactant: Fc1cccc(SCCBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C1(CCCn2c(=O)ccc3ccc(OC)cc32)CCN(CCSc2cccc(F)c2)CC1
Temperature: 60 °C
Reaction time: 4 h
Yield: 67.2 %

Procedure:
To 2.5 mL of an N,N-dimethylformamide solution containing 0.10 g of ethyl 4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)piperidine-4-carboxylate, 74 mg of potassium carbonate and 69 mg of 1-(3-fluorophenyl)thio-2-bromoethane were added at room temperature, and stirred at 60° C. for 4 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and water were added. The organic layer was separated, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=10:1], to give 95 mg of ethyl 1-(2-((3-fluorophenyl)thio)ethyl)-4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)piperidine-4-carboxylate as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=1[CH3:13].Br[CH2:15]/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1>>[F:24][C:21]1[CH:22]=[CH:23][C:18](/[CH:17]=[CH:16]/[CH2:15][O:1][C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=2[CH3:13])=[CH:19][CH:20]=1
Reactant: Cc1cc(O)c(C)c(C)c1NC=O
Reactant: Fc1ccc(/C=C/CBr)cc1
Product: Cc1cc(OC/C=C/c2ccc(F)cc2)c(C)c(C)c1NC=O
Yield: 52 %

Procedure:
By using N-(4-hydroxy-2,3,6-trimethylphenyl)formamide and 1-[(E)-3-bromo-1-propenyl]-4-fluorobenzene, the title compound was synthesized according to Reference Example 17a.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[O:6]1C2[CH:11]=[CH:12][C:13](C=NC3CCCCC3)=[CH:14][C:9]=2[O:8][CH2:7]1.C(I)C.[OH2:26]>CCCCCC.C1COCC1>[CH2:3]([C:2]1[C:1]2[O:6][CH2:7][O:8][C:9]=2[CH:14]=[CH:13][C:12]=1[CH:11]=[O:26])[CH3:4]
Reactant: O
Reactant: [Li]CCCC
Reactant: C(=NC1CCCCC1)c1ccc2c(c1)OCO2
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCI
Product: CCc1c(C=O)ccc2c1OCO2

Procedure:
n-Butyl lithium in hexane (1.6M, 320 ml) was added under nitrogen to a stirred solution of N-(1,3-benzodioxol-5-ylmethylene)cyclohexanamine (100 g) in dry THF (500 ml) at -78°. After 15 min ethyl iodide (50 ml) was added and the mixture was allowed to warm slowly to -50°. Water was then added and the mixture was extracted with ether. The extracts were concentrated in vacuo and the concentrate heated in 2N hydrochloric acid (250 ml) on a steam bath for 20 min. The resultant solution was diluted with water and extracted with ether. The extracts were dried and evaporated to give the title compound (38 g) as a pale yellow oil. T.l.c. (ether:hexane, 1:9) Rf 0.3.
Reaction SMILES: [F-].[K+].[C:3]1([N:9]2[C:13](=[O:14])[CH2:12][C:11]([CH3:15])=[N:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:17][N:18]1[C:22](=[O:23])[C:21]2[C:24]([CH:30]([CH3:32])[CH3:31])=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:20]=2[S:19]1(=[O:34])=[O:33].O.C(OCC)(=O)C>CN(C=O)C>[CH:30]([C:24]1[C:21]2[C:22](=[O:23])[N:18]([CH2:17][O:14][C:13]3[N:9]([C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)[N:10]=[C:11]([CH3:15])[CH:12]=3)[S:19](=[O:34])(=[O:33])[C:20]=2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=1)([CH3:32])[CH3:31]
Reactant: CC1=NN(c2ccccc2)C(=O)C1
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CCl)C2=O
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COc1cc(C)nn1-c1ccccc1)C2=O
Reaction time: 0.08 h
Yield: 7.5 %

Procedure:
To a mixture of 460 mg (7.9 mmol) of KF in DMF (25 ml) was added under nitrogen at room temperature 2,4-dihydro-2-phenyl-5-methyl-3H-pyrazol-3-one (1.38 g; 7.98 mmol) with stirring (5 minutes) followed by 2-chloromethyl-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (1.1 g, 3.63 mmol) and the resulting mixture was stirred at room temperature for 6 hours and then poured into water/ethyl acetate. The above mixture was extracted with ethyl acetate (3×75 ml) and the organic layer was dried over magnesium sulfate, and concentrated in vacuo. The residue (yellow foam, 1.3 g) was purified by flash chromatography (silica gel; 10-20% ethyl acetate in hexane) to afford 120 mg of 4-isopropyl-6-methoxy-2-(1-phenyl-3-methylpyrazol-5-yl-oxymethyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =Ph; R2 =CH3 ; R3 =H; R4 =CH(CH3)2 ; R5 =6-OCH3) as a white foam, m.p. 65°-670° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[N:3]=1.[NH2:28][C:29]1[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][C:30]=1[C:31]([NH:33][CH3:34])=[O:32]>>[C:39]([C:36]1[CH:37]=[CH:38][C:29]([NH:28][C:2]2[C:7]([C:8]([F:10])([F:9])[F:11])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([CH2:17][P:18](=[O:25])([O:19][CH2:20][CH3:21])[O:22][CH2:23][CH3:24])=[CH:26][CH:27]=3)[N:3]=2)=[C:30]([C:31](=[O:32])[NH:33][CH3:34])[CH:35]=1)#[N:40]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Reactant: CNC(=O)c1cc(C#N)ccc1N
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(C#N)cc3C(=O)NC)n2)cc1)OCC
Yield: 21.8 %

Procedure:
The title compound was prepared using the procedure from Example 102 (Diethyl (4-{[4-{[4-fluoro-2-(methylcarbamoyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-benzyl)phosphonate) with diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (10.0 mg, 0.0236 mmol) and 2-amino-5-cyano-N-methylbenzamide (Compound 150A, 8.3 mg, 0.0472 mmol). The crude mixture was purified by MDP to obtain the title compound as white solid (2.9 mg, 22% yield). 1H NMR (400 MHz, CD3OD) δ=1.28 (t, J=7.1 Hz, 6H), 2.92 (s, 3H), 3.26 (d, J=21.5 Hz, 2H), 4.07 (qd, J=7.3, 7.1 Hz, 4H), 7.28 (dd, J=8.8, 2.5 Hz, 2H), 7.56 (d, J=6.3 Hz, 2H), 7.76 (d, J=8.6 Hz, 1H), 8.04 (d, J=1.8 Hz, 1H), 8.42 (s, 1H), 8.88 (br. s., 1H). MS (ES+): m/z 563.17 (100) [MH+]; HPLC: tR=1.04 min (UPLC, purity).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:10][C:9]=1[N+:18]([O-])=O)(=[O:7])=[O:6].Cl>O.C(O)C.[Fe]>[OH:1][CH2:2][CH2:3][CH2:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH2:17])(=[O:15])=[O:16])=[CH:10][C:9]=1[NH2:18])(=[O:6])=[O:7]
Reactant: NS(=O)(=O)c1ccc(S(=O)(=O)CCCO)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1cc(S(N)(=O)=O)ccc1S(=O)(=O)CCCO

Procedure:
A mixture of 4-(3-hydroxypropylsulfonyl)-3-nitrobenzenesulfonamide (4.0 g, 0.012 mol), iron powder (11 g), and 12M HCl (0.6 ml) in 10 ml water and 40 ml ethanol was refluxed on a steam bath for about 2 hours. The reaction mixture was filtered hot, and the solvent evaporated. The residue was taken up in ethyl acetate, washed with water, saturated sodium bicarbonate, water, then brine. After drying, evaporation of solvent left a residue that quickly crystallized. The solid was washed with water and collected. Recrystallization from butanol left 2.0 g of a white solid. M.p.=136.5°-138° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]([N:16]2[CH:20]=[CH:19]N=C2)=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N)C.CCN(C(C)C)C(C)C>C1COCC1.CCOC(C)=O>[CH2:20]([NH:16][C:14]([O:13][C@H:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9]1)=[O:15])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OC(=O)n2ccnc2)C1
Agent: CCN
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCNC(=O)O[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 60 °C

Procedure:
To a solution of [(35)-1-tert-butoxycarbonylpyrrolidin-3-yl]imidazole-1-carboxylate (173 mg, 0.61 mmol) in THF (2.5 mL) at room temperature under an atmosphere of nitrogen was added a solution of ethanamine (369 mg, 461 μL of 2 M, 0.9 mmol) in THF followed by the addition of DIEA (119 mg, 161 μL, 0.9 mmol). The reaction mixture was heated at 60° C. for 1.5 h, cooled to room temperature and diluted with EtOAc. The organic layer was washed with 5 mL of 1M HCl solution, dried over MgSO4, filtered and concentrated under reduced pressure to obtain tert-butyl (35)-3-(ethylcarbamoyloxy)pyrrolidine-1-carboxylate. LC/MS m/z 259.2 [M+H]+.
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42](O)=[O:43])[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH:48]([NH:51][CH3:52])([CH3:50])[CH3:49]>>[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42]([N:51]([CH:48]([CH3:50])[CH3:49])[CH3:52])=[O:43])[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:4])([CH3:3])[CH3:5]
Reactant: CNC(C)C
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(C)C(C)C)CC1

Procedure:
In a manner analogous to the method described in examples 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride (example 94) was coupled with isopropyl-methyl-amine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C39H51Cl2N6O3 [(M+H)+] 721.3394, observed 721.3399.
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[CH2:8][CH2:7][CH:6]([N:9]2[CH2:14][CH2:13][N:12]([S:15]([CH2:18][CH2:19][CH2:20][C@@H:21]3[CH2:25][CH2:24][CH2:23][N:22]3C(OC(C)(C)C)=O)(=[O:17])=[O:16])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1.C(OCC)(=O)C.C(OCC)C>CO>[ClH:1].[CH3:2][N:3]1[CH2:8][CH2:7][CH:6]([N:9]2[CH2:14][CH2:13][N:12]([S:15]([CH2:18][CH2:19][CH2:20][C@@H:21]3[CH2:25][CH2:24][CH2:23][NH:22]3)(=[O:17])=[O:16])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1
Reactant: CN1CCC(N2CCN(S(=O)(=O)CCC[C@@H]3CCCN3C(=O)OC(C)(C)C)CC2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CO
Product: CN1CCC(N2CCN(S(=O)(=O)CCC[C@@H]3CCCN3)CC2)CC1
Reaction time: 1 h

Procedure:
Hydrogen chloride in methanol (5 ml, 1.25 mol/l) was added to (S)-tert-butyl 2-(3-(4-(1-methylpiperidin-4-yl)piperazin-1-ylsulfonyl)propyl)pyrrolidine-1-carboxylate (0.27 g, 0.589 mmol) and the mixture was refluxed. After 1 h ethyl acetate (10 ml) and diethyl ether (20 ml) were added to the suspension, the mixture was stirred in an ice bath for 1 h and the precipitate was filtered out with suction, washed with diethyl ether and dried in vacuo. Yield: 0.22 g (79%)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH2:11][CH3:12].C([Li])(C)(C)C.CCCCC.CN(C)[CH:25]=[O:26]>C1COCC1>[CH2:11]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([CH:25]=[O:26])[CH:3]=2)[NH:7][N:6]=1)[CH3:12]
Reactant: CN(C)C=O
Reactant: CCc1n[nH]c2ccc(Br)cc12
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCc1n[nH]c2ccc(C=O)cc12

Procedure:
A solution of 6.90 g (30.7 mmol) 5-bromo-3-ethyl-1H-indazole (Example 7A) in THF (300 ml) was cooled to −78° C. At this temperature, a 1.7 M solution of tert-butyllithium in n-pentane (63.1 ml, 107 mmol) was slowly added. The mixture was stirred at −78° C. for 30 minutes before N,N-dimethylformamide (80.0 ml) was slowly added. The cooling bath was removed, and stirring was continued until room temperature was reached. Then, water (250 ml) was added carefully. The mixture was extracted several times with ethyl acetate (500 ml). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure to yield 4.5 g (84% of th.) of the crude title compound which was used in the next step without further purification.
Reaction SMILES: [C:1]1([CH:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([CH2:19][NH:20][C:21](=[O:32])[N:22]([CH3:31])[CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:42][C@H:43]1[C@@H:47]([O:48]C(=O)C)[C@H:46](OC(=O)C)[O:45][C@@H:44]1[CH2:56][O:57]C(=O)C)(=O)C.C[Si](OS(C(F)(F)F)(=O)=O)(C)C.C(OCC)(=O)C>ClC(Cl)(Cl)C>[NH3:9].[OH:48][C@@H:47]1[C@H:43]([OH:42])[C@@H:44]([CH2:56][OH:57])[O:45][C@H:46]1[N:14]1[CH:13]=[N:12][C:11]2[C:15]1=[N:16][C:17]([CH2:19][NH:20][C:21](=[O:32])[N:22]([CH3:31])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[N:18][C:10]=2[NH:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CN(CCc1ccccn1)C(=O)NCc1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CN(CCc1ccccn1)C(=O)NCc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Product: N
Temperature: 25 °C
Reaction time: 4 h
Yield: 0.1 %

Procedure:
N,O-Bistrimethylsilylacetamide (0.5 ml, 2.02 mmol) was added to a suspension of N′-({6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl)-N-methyl-N-[2-(2-pyridinyl) ethyl]urea (0.16 g, 0.31 mol) (Preparation 26) in 1,1,1-trichloroethane (15 ml). The suspension was heated to reflux. When all suspended solid had dissolved the reaction mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure. The residue was twice dissolved in toluene (50 ml) and the solvent was removed under reduced pressure. The residue was then dissolved in toluene (15 ml) and (2R,3R,4R,5S)-4,5-bis(acetyloxy)-2-[(acetyloxy)methyl]tetrahydro-3-furanyl acetate (0.112 g, 0.36 mol) was added. The solution was stirred at room temperature and trimethylsilyltrifluoromethanesulphonate (0.17 ml, 0.94 mmol) was added. The resulting solution was heated under reflux for 2 hours and then allowed to cool to room temperature. The reaction mixture was diluted by the addition of ethyl acetate (75 ml) and then washed with saturated aqueous sodium hydrogen carbonate solution (two portions of 30 ml) and saturated aqueous sodium chloride solution (30 ml). The organic layer was dried over anhydrous magnesium sulphate. The solvent was removed under reduced pressure to give a solid that was purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 concentrated aqueous ammonia (97:3:0.5 by volume). This material was dissolved in methanol (50 ml) and a stream of ammonia gas was passed through the solution until it was saturated. The solution was allowed to stand at room temperature for 4 hours. The solvent was removed under reduced pressure to give a residue that was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:0.88 concentrated aqueous ammonia (90:10:1 by volume) to give the title compound (0.05 g) as a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([CH3:10])=[O:9].CC(C)=O.[N-:15]=[N+:16]=[N-:17].[Na+]>O>[N:15]([CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([CH3:10])=[O:9])=[N+:16]=[N-:17]
Reactant: CC(=O)c1sccc1CBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)c1sccc1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of methyl 3-bromomethyl-2-thienyl ketone (5 g., 0.023 mole) in 42 ml. of acetone and 4 ml. of water was added sodium azide (1.56 g., 0.024 mole) with caution (exothermic!). The resulting solution was stirred at room temperature for 2.5 hours, the acetone evaporated, the residue diluted with water and extracted with diethyl ether. The combined extracts were washed with water, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate and the dried extracts evaporated to dryness to obtain 4.0 g. (97%) of yellow oil. 1H--NMR (CDCl3), ppm. (δ): 7.5 (d, J=5, aromatic-H), 7.2 (d, J=5, aromatic-H), 4.75 (s, CH2N3), 2.5 (s, CH3); IR spectrum (film, cm.-1 : 3100, 2100 (N3), 1660, 1525 and 1420.