Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[NH:17][CH2:16][CH2:15][CH2:14]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:28]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH2:38]I)=[CH:32][CH:31]=1)#[N:29]>CN(C)C=O>[C:28]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH2:38][N:17]2[C:18]3[C:13](=[CH:12][C:11]([NH:10][S:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)(=[O:9])=[O:8])=[CH:20][CH:19]=3)[CH2:14][CH2:15][CH2:16]2)=[CH:32][CH:31]=1)#[N:29]
Reactant: N#Cc1ccc(CCCI)cc1
Reactant: O=S(=O)(Nc1ccc2c(c1)CCCN2)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(CCCN2CCCc3cc(NS(=O)(=O)c4ccccc4)ccc32)cc1
Temperature: 45 °C
Reaction time: 5 h

Procedure:
1.73 g 6-phenylsulphonamido-1,2,3,4-tetrahydro-quinoline are dissolved with 0.7 g triethylamine in 10 ml of dimethylformamide and combined with 1.62 g of 3-(4-cyanophenyl)propyliodide in 15 ml of dimethylformamide and stirred for 5 hours at 40-50° C. Then the mixture is evaporated down, the residue is dissolved in ethyl acetate/water, the organic phase is dried and concentrated by evaporation in vacuo. The product is chromatographed with methylene chloride/ethyl acetate (19:1) over a silica gel column.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH3:19])[C:11]3[N:12]([C:14]([C:17]#[CH:18])=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.[OH:20][CH2:21][C:22]([NH:25][S:26]([C:29]1[CH:30]=[N:31][CH:32]=[C:33](Br)[CH:34]=1)(=[O:28])=[O:27])([CH3:24])[CH3:23]>>[OH:20][CH2:21][C:22]([NH:25][S:26]([C:29]1[CH:30]=[N:31][CH:32]=[C:33]([C:18]#[C:17][C:14]2[N:12]3[CH:13]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH:9]=[C:10]([CH3:19])[C:11]3=[N:16][CH:15]=2)[CH:34]=1)(=[O:28])=[O:27])([CH3:24])[CH3:23]
Reactant: C#Cc1cnc2c(C)cc(-c3ccc(Cl)cc3)cn12
Reactant: CC(C)(CO)NS(=O)(=O)c1cncc(Br)c1
Product: Cc1cc(-c2ccc(Cl)cc2)cn2c(C#Cc3cncc(S(=O)(=O)NC(C)(C)CO)c3)cnc12

Procedure:
The title compound was prepared from 6-(4-chloro-phenyl)-3-ethynyl-8-methyl-imidazo[1,2-a]pyridine (example C.21) (270 mg, 1 mmol) and 5-bromo-pyridine-3-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.2) (282 mg, 0.9 mmol) according to general procedure II. Obtained as a light yellow solid (180 mg, 35%). MS (ISP) 495.0 [(M+H)+], 497 [(M+2+H)+]; mp 215–217° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[C:12]1[N:20]=[C:19]2[C:15]([N:16]=[C:17]([CH2:22][N:23]3[CH2:28][CH2:27][CH:26]([C:29]([OH:34])([CH2:32][CH3:33])[CH2:30][CH3:31])[CH2:25][CH2:24]3)[N:18]2[CH3:21])=[C:14]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[N:13]=1>>[CH3:21][N:18]1[C:17]([CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]([OH:34])([CH2:30][CH3:31])[CH2:32][CH3:33])[CH2:25][CH2:24]2)=[N:16][C:15]2[C:19]1=[N:20][C:12]([N:3]1[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=[C:2]1[CH3:1])=[N:13][C:14]=2[N:35]1[CH2:36][CH2:37][O:38][CH2:39][CH2:40]1
Reactant: CCC(O)(CC)C1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3n2C)CC1
Reactant: Cc1nc2ccccc2[nH]1
Product: CCC(O)(CC)C1CCN(Cc2nc3c(N4CCOCC4)nc(-n4c(C)nc5ccccc54)nc3n2C)CC1

Procedure:
Following General Procedure I for Buchwald coupling, 2-methylbenzimidazole and 3-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)pentan-3-ol were reacted to give 316. LCMS m/z: 533.3 (MH+)
Reaction SMILES: C([O:5][C:6](=[O:85])[C@H:7]([CH2:76][CH2:77][C:78]([O:80]C(C)(C)C)=[O:79])[NH:8][C:9](=[O:75])[CH2:10][NH:11][C:12](=[O:74])[CH2:13][NH:14][C:15](=[O:73])[C@H:16]([CH2:62][CH2:63][CH2:64][NH:65]C(OC(C)(C)C)=O)[NH:17][C:18](=[O:61])[CH2:19][CH2:20][S:21][CH2:22][CH:23]([O:43][C:44](=[O:60])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[CH2:24][O:25][C:26](=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])(C)(C)C.[ClH:86]>C(O)(=O)C>[ClH:86].[C:44]([O:43][CH:23]([CH2:24][O:25][C:26](=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:22][S:21][CH2:20][CH2:19][C:18]([NH:17][C@H:16]([C:15]([NH:14][CH2:13][C:12]([NH:11][CH2:10][C:9]([NH:8][C@H:7]([C:6]([OH:85])=[O:5])[CH2:76][CH2:77][C:78]([OH:80])=[O:79])=[O:75])=[O:74])=[O:73])[CH2:62][CH2:63][CH2:64][NH2:65])=[O:61])(=[O:60])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59]
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)N[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)NCC(=O)NCC(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)OC(=O)CCCCCCCCCCCCCCC
Agent: Cl
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)N[C@@H](CCCN)C(=O)NCC(=O)NCC(=O)N[C@@H](CCC(=O)O)C(=O)O)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 17 h
Yield: 100 %

Procedure:
To N(alpha)-(6,7-bis(palmitoyloxy)-4-thiaheptanoyl)-N(delta)-(t-butyloxycarbonyl)ornitylglycylglycylglutamic acid di-t-butyl ester as obtained in Example 13 (180 mg), a 4N solution of hydrochloric acid (4 ml) in acetic acid was added, followed by stirring at room temperature for 17 hours. The solvent was distilled off to yield the title compound (150 mg, yield 100%) as a colorless crystal.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:28])[CH2:4][NH:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:21])[C:10]=2[C:9]([NH:22][CH2:23][CH:24]([OH:27])[CH2:25]Cl)=[CH:8][CH:7]=1.[OH-].[Na+]>CO>[O:27]1[CH2:25][CH:24]1[CH2:23][NH:22][C:9]1[C:10]2[C:11](=[O:21])[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18](=[O:20])[C:19]=2[C:6]([NH:5][CH2:4][CH:3]2[O:28][CH2:2]2)=[CH:7][CH:8]=1
Reactant: O=C1c2ccccc2C(=O)c2c(NCC(O)CCl)ccc(NCC(O)CCl)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1c2ccccc2C(=O)c2c(NCC3CO3)ccc(NCC3CO3)c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.4 %

Procedure:
To a solution of 1,4-Bis-(3-chloro-2-hydroxylpropylamino)-9, 10-anthracenedione (8.3 g, 19.8 mmoles) in MeOH (500 mL) at 60° C. was added NaOH (3.5 g). The resulting blue solution was stirred at room temperature for 4 hours, and the solvent was removed under reduced pressure. The residual solid was then purified by flash column chromatography (silica gel, CH2Cl2 : MeOH/25:1). Recrystalization from CH2Cl2 :hexanes yielded the title compound 1,4-Bis-(2,3-epoxypropylamino)-9, 10-anthracenedione, (6.2 g, 89.37%), mp 189°-190° C.: 1H NMR (CDCl3) δ 2.74 (m, 1H, CH2), 2.87 (m, 1H, CH2), 3.26 (m, 1H, CH) 3.57 (m, 1H, CH2), 3.78 (m, 1H, CH2), 7.32 (s, 2H, Ar 2, 3)), 7.71 (dd, J=3.2 Hz, 5.5 Hz, 2H, Ar 6, 7)), 8.34 (dd, J=3.2 Hz, 5.5 Hz, 2H, Ar (5,8)), 10.76 (s, 2H, NH). Anal. Calcd for C20H18O4N2 ×0.25 H2O: C, 67.66: H, 5.25; N, 7.93. Found: C, 67.72; H, 5.55; N, 7.54. IR: 3400, 3070, 2910, 1640, 1220, 900.
Reaction SMILES: [H-].[Na+].[CH:3](OCC)=[O:4].[CH3:8][O:9][C:10]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][C:15]2=[O:21].Cl>C1COCC1.O.CO>[F:20][C:17]1[CH:18]=[CH:19][C:10]([O:9][CH3:8])=[C:11]2[C:16]=1[C:15](=[O:21])[CH:14]([CH:3]=[O:4])[CH2:13][CH2:12]2
Reactant: COc1ccc(F)c2c1CCCC2=O
Reactant: CCOC=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(F)c2c1CCC(C=O)C2=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 113.1 %

Procedure:
Sodium hydride (12.7 g) (50% dispersion, washed with hexane) was suspended in dry THF under nitrogen. Ethyl formate (27 g) was added and the mixture was stirred for 20 minutes in an ice/water bath. 5-Methoxy-8-fluoro-1-tetralone (J. Med. Chem. (1973) 1003) (17 g) dissolved in THF was added and the mixture was allowed to warm to room temperature. The mixture was stirred under nitrogen for 24 hours. Methanol was added followed by water. The mixture was poured into water, acidified with conc. HCl (aq) and extracted into CHCl3. The organic phase was dried (MgSO4), filtered and concentrated to give a dark oil (22 g) which solidified on standing. This material was recrystallised from ethyl acetate/hexane to give the above compound, m.p. 66°-68° C.
Reaction SMILES: ClCCl.[C:4]([Si:8]([CH3:11])([CH3:10])Cl)([CH3:7])([CH3:6])[CH3:5].[N:12]([C@@H:15]1[CH2:20][C@H:19]([OH:21])[C@@H:18]([CH2:22][OH:23])[O:17][CH2:16]1)=[N+:13]=[N-:14].C(N(CC)CC)C>C(Cl)(Cl)Cl>[N:12]([C@@H:15]1[CH2:20][C@H:19]([OH:21])[C@@H:18]([CH2:22][O:23][Si:8]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:11])[CH3:10])[O:17][CH2:16]1)=[N+:13]=[N-:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: [N-]=[N+]=N[C@H]1CO[C@H](CO)[C@@H](O)C1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H]1OC[C@H](N=[N+]=[N-])C[C@@H]1O
Temperature: 25 °C
Reaction time: 50 h
Yield: 89 %

Procedure:
A dichloromethane (4 ml) solution of tert-butyldimethylchlorosilane (381 mg, 2.54 mmol) was added to a dichloromethane (10 ml) solution of 1,5-anhydro-2-azido-2,3-dideoxy-D-ribo-hexitol (440 mg, 2.54 mmol) and triethylamine (0.46 ml, 3.30 mmol) under ice cooling. After stirring at room temperature for 50 hours, the reaction mixture was diluted with chloroform and the organic layer was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, then the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography [n-hexane:ethyl acetate=10:1→4:1 (v/v)] to give 650 mg (89%) of the title compound as a colorless oil.
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Br:11])=[CH:6][C:5]=1[CH2:12]Br.[F:15][C:16]([F:26])([F:25])[C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Br:11][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([Cl:10])[CH:8]=1)[C:3](=[O:14])[N:22]([CH2:21][C:20]1[CH:19]=[CH:18][C:17]([C:16]([F:15])([F:25])[F:26])=[CH:24][CH:23]=1)[CH2:12]2
Reactant: COC(=O)c1c(Cl)cc(Br)cc1CBr
Reactant: NCc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=C1c2c(Cl)cc(Br)cc2CN1Cc1ccc(C(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 34.2 %

Procedure:
A mixture of 4-bromo-2-bromomethyl-6-chloro-benzoic acid methyl ester (1.4 g, 4.0 mmol), 4-trifluoromethyl-benzylamine (0.770 mL, 5.4 mmol), and K2CO3 (1.1 g, 8.0 mmol) in toluene (10 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-bromo-7-chloro-2-(4-trifluoromethyl-benzyl)-2,3-dihydro-isoindol-1-one (0.553 g, 35%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.23 (s, 2H), 4.83 (s, 2H), 7.28-7.64 (m, 6H). GC-MS: m/z 405 (M+1)+, 336 (M−68)+.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]([NH2:15])[CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH2:28][C:29](O)=[O:30])[CH:21]=[CH:22][C:23]=1[C:24]([O:26][CH3:27])=[O:25]>>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH2:28][C:29]([NH:15][CH:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH3:14])=[O:30])[CH:21]=[CH:22][C:23]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: CC(N)c1ccccc1N1CCCCC1
Reactant: COC(=O)c1ccc(CC(=O)O)cc1OC
Product: COC(=O)c1ccc(CC(=O)NC(C)c2ccccc2N2CCCCC2)cc1OC

Procedure:
Prepared from 1-(2-piperidino-phenyl)-1-ethylamine and 3-methoxy-4-methoxycarbonyl-phenylacetic acid.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:22])=[C:16]2[C:21]=1[N:20]=[CH:19][CH:18]=[CH:17]2)(=[O:10])=[O:9].N(OC(C)(C)C)=O.C(O)(=O)C>C1COCC1>[CH3:22][C:15]1[CH:14]=[C:13]2[C:12](=[C:21]3[C:16]=1[CH:17]=[CH:18][CH:19]=[N:20]3)[NH:11][S:8](=[O:10])(=[O:9])[C:3]1[C:4]2=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: Cc1ccc(NS(=O)(=O)c2ccccc2N)c2ncccc12
Agent: CC(C)(C)ON=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cc2c(c3ncccc13)NS(=O)(=O)c1ccccc1-2
Reaction time: 2 h
Yield: 35.2 %

Procedure:
In a similar fashion using route 16 general procedure 31, 2-amino-N-(5-methylquinolin-8-yl)-benzenesulfonamide (Intermediate 176) (150 mg, 0.48 mmol), tert-butyl nitrite (0.12 ml, 0.88 mmol), acetic acid (28 μl, 0.48 mmol) and THF (5 ml), at 0° C. for 2 h then at room temperature for 2 h, gave the title compound (50 mg, 53%) after purification by column chromatography using silica basified with TEA with n-hexane/EtOAc (1:1) followed by DCM/MeOH (1:0-199:1) gradient elution.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:44]=[CH:43][C:12]([O:13][CH2:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([CH3:32])[C:26]=4[CH3:33])=[CH:20][C:19]=3[N:34]([CH3:42])C(=O)OC(C)(C)C)=O)=[CH:11][CH:10]=2)[S:3]1.[ClH:45].O1CCOCC1>>[ClH:45].[OH:31][C:28]1[CH:29]=[CH:30][C:25]([O:24][C:21]2[CH:22]=[CH:23][C:18]3[N:17]=[C:15]([CH2:14][O:13][C:12]4[CH:43]=[CH:44][C:9]([CH2:8][CH:4]5[S:3][C:2](=[O:1])[NH:6][C:5]5=[O:7])=[CH:10][CH:11]=4)[N:34]([CH3:42])[C:19]=3[CH:20]=2)=[C:26]([CH3:33])[C:27]=1[CH3:32]
Reactant: Cc1c(O)ccc(Oc2ccc(NC(=O)COc3ccc(CC4SC(=O)NC4=O)cc3)c(N(C)C(=O)OC(C)(C)C)c2)c1C
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(O)ccc(Oc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3c2)c1C
Temperature: 25 °C
Reaction time: 44 h

Procedure:
A mixture of t-butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(4-hydroxy-2,3-dimethylphenoxy)phenyl}-N-methylcarbamate (2.35 g) and 4N hydrogen chloride/dioxane (20 ml) was stirred at ambient temperature for 44 hours. The solvent of the reaction mixture was evaporated to dryness. To the residue was added ethyl acetate and insoluble product was collected by filtration and washed with ethyl acetate to give the title compound (1.82 g).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[NH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][NH:27][CH2:26]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[NH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][N:27]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[C:9]([NH2:17])[C:10]=1[F:16])[CH2:26]2
Reactant: Nc1ccc2c(c1)CNC2
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Nc1ccc2c(c1)CN(c1c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)C2
Yield: 42.3 %

Procedure:
200 mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 99 mg of 5-aminoisoindoline, 200 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 117 mg of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=1.[CH2:16]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH2:29][C@@H:28]([C:32](Cl)=[O:33])[CH2:27]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(OCC)(=O)C>ClCCl.CN(C)C1C=CN=CC=1.CCCCCC>[CH2:16]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH2:29][C@@H:28]([C:32](=[O:33])[NH:15][C:11]2[CH:10]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[N:14]=[CH:13][N:12]=2)[CH2:27]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Reactant: COc1ccccc1-c1cc(N)ncn1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: COc1ccccc1-c1cc(NC(=O)[C@@H]2CCCN(C(=O)OCc3ccccc3)C2)ncn1
Reaction time: 2 h
Yield: 66.8 %

Procedure:
To a solution of 6-(2-methoxy-phenyl)-pyrimidin-4-ylamine (XXIV) (5.80 g, 28.5 mmol) in 60 ml of dichloromethane was added 4-dimethylaminopyridine (4.16 g, 34.2 mmol) followed by dropwise addition of (R)-3-chlorocarbonyl-piperidine-1-carboxylic acid benzyl ester (XXIX) (8.00 g, 28.5 mmol) at room temperature. The reaction mixture was stirred for 2 hours and washed with water. The organic layer was separated, dried over sodium sulfate and concentrated. The obtained crude residue was passed through a pad of silica gel eluting with 25% ethyl acetate in hexane to provide (R)-3-[6-(2-methoxy-phenyl)-pyrimidin-4-ylcarbamoyl]-piperidine-1-carboxylic acid benzyl ester (XXX) (8.5 g, 67%).
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][C:6]1([CH3:19])[C:11]2[NH:12][C:13]3[C:18]([C:10]=2[CH2:9][CH2:8][O:7]1)=[CH:17][CH:16]=[CH:15][CH:14]=3)C.CO.[OH-].[K+]>O>[CH3:19][C:6]1([CH2:5][C:4]([OH:20])=[O:3])[C:11]2[NH:12][C:13]3[C:18]([C:10]=2[CH2:9][CH2:8][O:7]1)=[CH:17][CH:16]=[CH:15][CH:14]=3
Reactant: CCOC(=O)CC1(C)OCCc2c1[nH]c1ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(CC(=O)O)OCCc2c1[nH]c1ccccc21
Reaction time: 8 h

Procedure:
Hydrolysis of this ester to the title compound is effected as follows: The ester is dissolved in 230 ml. of methanol. To this is added 10 g. of KOH in 30 ml. of H2O and the solution is allowed to stand at room temperature overnight. The methanol is evaporated, water added and the solution washed with benzene. The aqueous phase is acidified with 6N HCl, and extracted with benzene. This organic phase is washed with water, dried over sodium sulfate and evaporated to dryness to give an oil, which is crystallized from benzen containing a trace of petroleum ether to afford the title compound, m.p. 150° - 152° C., νmaxCHCl3 3325 and 1705 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:23][CH3:24])=[C:8]([S:10]([C:13]2[CH:21]=[C:20]([Br:22])[C:16]3[N:17]=[CH:18][NH:19][C:15]=3[CH:14]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4].CI.[C:27]([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:23][CH3:24])=[C:8]([S:10]([C:13]2[CH:21]=[C:20]([Br:22])[C:16]3[N:17]=[CH:18][N:19]([CH3:27])[C:15]=3[CH:14]=2)(=[O:11])=[O:12])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(S(=O)(=O)c2cc(Br)c3nc[nH]c3c2)c(SC)s1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(S(=O)(=O)c2cc(Br)c3ncn(C)c3c2)c(SC)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.7 %

Procedure:
To a solution of 4-(7-bromo-3H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester (as prepared in Example 38, step e) (100 mg, 0.22 mmol) in dimethylformamide (2 mL) was added MeI (13.9 μL, 0.22 mmol) and K2CO3 (61.8 mg, 0.45 mmol), then stirred overnight at room temperature. The solvents were removed in vacuo and the residue was diluted with ethyl acetate (100 mL). The ethyl acetate layer was washed with water (15 mL) and brine (25 mL), and dried over MgSO4. The solvent was removed in vacuo to afford 20 mg (19%) of 4-(7-bromo-3-methyl-3H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester and 4-(7-bromo-1-methyl-1H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester as a mixture. This mixture was used directly in the following step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:13](=[O:14])[CH:12]=[C:11]([NH:15][CH3:16])[N:10]=[CH:9]2)=[CH:5][CH:4]=1.[CH3:19][CH:20]([C:26]([O:28]CC)=O)[C:21]([O:23]CC)=O>C1(OC2C=CC=CC=2)C=CC=CC=1>[OH:28][C:26]1[C:12]2[C:13](=[O:14])[N:8]([CH2:7][C:6]3[CH:17]=[CH:18][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:9]=[N:10][C:11]=2[N:15]([CH3:16])[C:21](=[O:23])[C:20]=1[CH3:19]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: CNc1cc(=O)n(Cc2ccc(OC)cc2)cn1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1ccc(Cn2cnc3c(c(O)c(C)c(=O)n3C)c2=O)cc1
Temperature: 240 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
3-(4-Methoxybenzyl)-6-(methylamino)pyrimidin-4(3H)-one (14.8 g, 60.2 mmol, 1 eq, compound 8A) and diethyl methylmalonate (61.6 mL, 361 mmol, 6 eq) were mixed in phenyl ether (25 mL) and heated at 240° C. for 2 days. The solution was allowed to RT and left standing overnight. The tan precipitate which formed was collected and washed with ether to give 15.2 g of the title compound as a tan solid (78%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.89 (s, 3H) 3.55 (s, 3H) 3.74 (s, 3H) 5.14 (s, 2H) 6.93 (d, J=8.59 Hz, 2H) 7.37 (d, J=8.59 Hz, 2H) 8.89 (s, 1H) 11.82 (s, 1H). %). [M+H] calc'd for C17H17N3O4, 328; found, 328.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][NH:6][CH:7]=1)#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+].Br[CH2:17][CH2:18][C@@:19]([CH3:29])([S:25]([CH3:28])(=[O:27])=[O:26])[C:20]([O:22]CC)=[O:21].[OH-].[Li+]>C(#N)C>[C:1]([C:3]1[CH:4]=[N:5][N:6]([CH2:17][CH2:18][C@@:19]([CH3:29])([S:25]([CH3:28])(=[O:27])=[O:26])[C:20]([OH:22])=[O:21])[CH:7]=1)#[N:2]
Reactant: CCOC(=O)[C@@](C)(CCBr)S(C)(=O)=O
Reactant: N#Cc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Product: C[C@@](CCn1cc(C#N)cn1)(C(=O)O)S(C)(=O)=O
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a solution of 4-cyanopyrazole (0.150 g, 1.61 mmol, 1 eq) in acetonitrile (10 mL) was added cesium carbonate (1.31 g, 4.03 mmol, 2.5 eq), sodium iodide (0.048 mg, 0.322 mmol, 0.2 eq) and (R)-ethyl 4-bromo-2-methyl-2-(methylsulfonyl)butanoate (0.555 g, 1.93 mmol, 1.2 eq). The mixture was heated at 50° C. overnight. The reaction mixture was cooled to room temperature and was filtered via Buchner funnel, and eluted with EtOAc. The filtrate was concentrated under reduced pressure and was diluted with up in tetrahydrofuran (5 mL) and water (5 mL). Lithium hydroxide (0.116 g, 4.83 mmol, 3 eq) was added, and the reaction mixture was allowed to stir at room temperature for four hours. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (10 mL), and concentrated again. This yielded (2R)-4-(4-cyano-1H-pyrazol-1-yl)-2-methyl-2-(methylsulfonyl)butanoic acid as a yellow oil, which was carried on crude in the next step. LC-MS M+H+272.2.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9]C)=O.[NH2:11][C:12](N)=[O:13].[OH-].[Na+]>CN(C)C=O>[NH:1]1[C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7](=[O:9])[NH:11][C:12]1=[O:13]
Reactant: NC(N)=O
Reactant: COC(=O)c1sccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=c1[nH]c(=O)c2sccc2[nH]1
Temperature: 190 °C
Reaction time: 12 h
Yield: 60.8 %

Procedure:
Methyl 3-aminothiophene-2-carboxylate (4.9 g, 31.3 mmol) and urea (19 g, 187 mmol) were dissolved in N,N-dimethylformamide (10 mL), the reaction temperature was raised to 190° C., followed by stirring for 12 hours. After the reaction was complete, the reaction mixture was added to 1N NaOH aqueous solution, cooled to room temperature and filtered under a reduced pressure to remove the insoluble precipitate. The filtrate was acidified (pH 2) with 2N HCl aqueous solution, and the resulting solid was filtered under a reduced pressure with washing using distilled water. The resulting solid was dried under a reduced pressure to obtain the title compound (yield: 3.2 g, 61.5%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([OH:19])[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]1.[H-].[Na+].I[CH2:23][CH2:24][CH2:25][CH3:26]>CN(C)C=O>[CH2:23]([O:19][C:8]1([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH2:9][N:10]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:11]1)[CH2:24][CH2:25][CH3:26]
Reactant: CC(C)(C)OC(=O)N1CC(O)(c2ccccc2F)C1
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCOC1(c2ccccc2F)CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 80.4 %

Procedure:
135 mg (0.4 mmol) of 3-(2-fluorophenyl)-3-hydroxy-1-(tert-butoxycarbonyl)azetidine at 80% in 2 ml of dimethylformamide are added to a suspension of 65 mg (1.6 mmol) of sodium hydride at 60% in 1.5 ml of dimethylformamide, under nitrogen, at 0° C. After stirring for 20 minutes at 0° C., 0.2 ml (1.5 mmol) of iodobutane are added. The reaction medium is stirred at ambient temperature for 1 h 30 and is then hydrolysed with water and with a saturated aqueous solution of ammonium chloride and extracted with a 1/2 heptane/ethyl acetate mixture. The organic phases are combined, washed with water, dried over magnesium sulphate, filtered and evaporated. The crude product is purified by silica gel chromatography, elution being carried out with an 8/2 heptane/ethyl acetate mixture. 104 mg of 3-butoxy-3-(2-fluorophenyl)-1-(tert-butoxycarbonyl)azetidine are obtained in the form of a yellow oil with a yield of 79%.