Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](O)=[O:25])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:60][CH2:61][C:62]([NH:64][C:65]1[CH:79]=[CH:78][C:68]([CH2:69][NH:70][C:71](=[O:77])[O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[CH:67][CH:66]=1)=[O:63]>C(Cl)Cl>[C:73]([O:72][C:71]([NH:70][CH2:69][C:68]1[CH:67]=[CH:66][C:65]([NH:64][C:62](=[O:63])[CH2:61][NH:60][C:24](=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][NH:18][C:16](=[O:17])[O:15][CH2:14][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[CH:79][CH:78]=1)=[O:77])([CH3:74])([CH3:75])[CH3:76]
Reactant: CC(C)(C)OC(=O)NCc1ccc(NC(=O)CN)cc1
Reactant: O=C(O)CCCCCNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccc(NC(=O)CNC(=O)CCCCCNC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}hexanoic acid (2.66 g, 7.53 mmol, 1.0 eq.) in dry DCM (50 mL) at 0° C. was added N,N-diisopropylethylamine (1.93 g, 15.1 mmol, 2.0 eq) and 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 2.86 g, 7.53 mmol, 1.0 eq.). The mixture was stirred at 0° C. for 30 min and #B119 (2.1 g, 7.53 mmol, 1.0 eq.) was added in one portion. The mixture was stirred at room temperature overnight. The mixture was filtered and solid was washed with DCM and dried in vacuo to afford #B120 (4 g, 86.4%) as a white solid. 1H NMR (400 Hz, DMSO-d6): δ 9.91 (s, 1H), 8.11 (br, 1H), 7.90 (d, 2H), 7.69 (d, 2H), 7.51 (d, 2H), 7.41 (m, 2H), 7.33 (m, 3H), 7.17 (d, 2H), 4.28 (m, 3H), 4.06 (d, 2H), 3.86 (br, 2H), 2.97 (m, 2H), 2.15 (m, 2H), 1.51 (m, 2H), 1.38 (m, 12H); LCMS (Protocol I): m/z 637.1 (M+Na]+, retention time=1.18 minutes.
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[N:28][C:27]([C:30]([OH:38])([CH3:37])[CH2:31]OS(C)(=O)=O)=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[N:28][C:27]([C:30]([OH:38])([CH3:37])[CH2:31][N:43]4[CH2:44][CH2:45][CH:40]([OH:39])[CH2:41][CH2:42]4)=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CCNCC1
Reactant: CC(O)(COS(C)(=O)=O)c1cnc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(O)(CN1CCC(O)CC1)c1cnc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)cn1
Yield: 24.1 %

Procedure:
Methanesulfonic acid 2-[4-(4-benzyl-phthalazin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-yl]-2-hydroxy-propyl ester (64 mg, 0.120 mmol) is combined with 4-hydroxy piperidine (61 mg, 0.600 mmol), diisoproylethylamine (63 μL, 0.360 mmol), and acetonitrile (1 mL). The mixture is heated to reflux for 16 h. Concentrate the crude mixture in vacuo. The residue is purified by flash chromatography on silica gel (MeOH/CH2Cl2) to afford the title compound (15.6 mg, 24%).
Reaction SMILES: [CH2:1]1[N:11]2[C:12]3[C:8]([C@@H:9]4[CH2:16][NH:15][CH2:14][CH2:13][C@@H:10]42)=[CH:7][CH:6]=[CH:5][C:4]=3[O:3][CH2:2]1.[NH2:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C:25](=[O:30])[CH2:26][CH2:27][CH2:28]Cl>>[NH2:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C:25](=[O:30])[CH2:26][CH2:27][CH2:28][N:15]1[CH2:14][CH2:13][C@@H:10]2[N:11]3[CH2:1][CH2:2][O:3][C:4]4[CH:5]=[CH:6][CH:7]=[C:8]([C:12]3=4)[C@@H:9]2[CH2:16]1
Reactant: Nc1cc(F)ccc1C(=O)CCCCl
Reactant: c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCO2
Product: Nc1cc(F)ccc1C(=O)CCCN1CC[C@H]2[C@@H](C1)c1cccc3c1N2CCO3

Procedure:
The title compound was prepared by the method of Example 355 Step B as a yellow oil (172 mg, 57%) from (6bR,10aS)-1,2,6b,7,8,9,10,10a-octahydro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole (165 mg, 0.76 mmol) and 1-(2-amino-4-fluorophenyl)-4-chloro-1-butanone (329 mg, 1.5 mmol). The title compound was spectroscopically identical to Example 529.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]([C:19]3[S:23][C:22]([C:24]([O:26]C)=O)=[C:21]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]([F:39])([F:38])[F:37])[CH:20]=3)[CH:17]=[N:18][C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:40]>CO>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]([C:19]3[S:23][C:22]([C:24]([NH2:40])=[O:26])=[C:21]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]([F:37])([F:39])[F:38])[CH:20]=3)[CH:17]=[N:18][C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)c1sc(-n2cnc3cc(CO[Si](C)(C)C(C)(C)C)ncc32)cc1OCc1ccccc1C(F)(F)F
Reactant: N
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCc1cc2ncn(-c3cc(OCc4ccccc4C(F)(F)F)c(C(N)=O)s3)c2cn1
Temperature: 120 °C
Reaction time: 3.5 h

Procedure:
A mixture of 1.05 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3H-imidazo[4,5-c]pyridin-3-yl]-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxylate (compound B2a) and 100 ml of a saturated solution of ammonia in methanol was stirred in an autoclave at 120° C. for 3.5 h. The reaction mixture was allowed to cool down to room temperature, concentrated to dryness, dissolved in dichloromethane and filtered through a plug of silica gel (eluents: dichloromethane/ethyl acetate) to yield the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][C:22]([C:25]([F:26])([F:28])[F:27])=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1NCCc2ccc(C(F)(F)F)cc21
Product: CC1c2cc(C(F)(F)F)ccc2CCN1C(=O)c1cc2ncc(Cl)cn2n1
Yield: 16 %

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-7-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:13]=3[C:12](=[O:19])[O:11][C:10]=2[CH:20]=1.[C:21]([NH:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)(=[O:23])[CH3:22].C(N(CC)CC)C>O1CCCC1>[C:21]([NH:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[C:14]4[CH2:15][CH2:16][CH2:17][CH2:18][C:13]=4[C:12](=[O:19])[O:11][C:10]=3[CH:20]=2)[CH2:27][CH2:26]1)(=[O:23])[CH3:22]
Reactant: O=c1oc2cc(OCCCBr)ccc2c2c1CCCC2
Reactant: CC(=O)NC1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NC1CCN(CCCOc2ccc3c4c(c(=O)oc3c2)CCCC4)CC1

Procedure:
A mixture of 17.3 g. (0.051 mole) 3-(3-bromopropoxy)-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran-6-one, 7.3 g. (0.051 mole) 4-acetamidopiperidine, 5.2 g. triethylamine and 100 ml. tetrahydrofuran is heated under reflux for 14 hours and then cooled and filtered. The precipitate obtained is washed with tetrahydrofuran and water and dried in a vacuum. There are obtained 11.3 g. (55% of theory) of the desired compound (m.p. 167°-168° C.) which is identical to the compound of Example 23.
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C1(C)C=CC(S(O[CH2:23][CH2:24][CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH2:28][CH2:27]2)(=O)=O)=CC=1>C(O)C.O>[CH2:35]([O:34][C:32]([N:29]1[CH2:30][CH2:31][CH:26]([CH2:25][CH2:24][CH2:23][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])[CH2:27][CH2:28]1)=[O:33])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(CCCC1CCN(C(=O)OCc2ccccc2)CC1)C(=O)OCC

Procedure:
To a solution of sodium (5.8 g) in ethanol (300 ml) are added diethyl malonate (40 g) and 3-(1-benzyloxycarbonyl-4-piperidyl)propyl p-toluenesulfonate (90.5 g). The resulting mixture is refluxed for 2 hours with stirring, cooled, diluted with water (1 l) and extracted with ethyl acetate (500 ml). The extract is dried over magnesium sulfate and evaporated in vacuo to give ethyl 5-(1-benzyloxycarbonyl-4-piperidyl)-2-ethoxycarbonylvalerate as an oil. To the stirred solution of this oil in ethanol (200 ml) is added dropwise a solution of sodium hydroxide (34 g) in water (200 ml). After the addition is complete, the mixture is diluted with water (300 ml) and extracted with a mixture of ether and petroleum ether (1:1, 300 ml). The aqueous layer is acidified with concentrated hydrochloric acid and extracted with ethyl acetate (500 ml). The extract is washed with water, dried over anhydrous magnesium sulfate and evaporated in vacuo to yield 5-(1-benzyloxycarbonyl-4-piperidyl)-2-carboxyvaleric acid as an oil. This oil is heated at 160°-170° C. for 45 minutes with stirring to give 5-(1-benzyloxycarbonyl-4-piperidyl)valeric acid (50 g) as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.ClCCCl.[Cl:12][C:13]1[C:14]2[N:15]([C:19]([CH:23]3[CH2:26][C:25](=O)[CH2:24]3)=[N:20][C:21]=2[I:22])[CH:16]=[CH:17][N:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Cl:12][C:13]1[C:14]2[N:15]([C:19]([CH:23]3[CH2:26][CH:25]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[CH2:24]3)=[N:20][C:21]=2[I:22])[CH:16]=[CH:17][N:18]=1
Reactant: O=C1CC(c2nc(I)c3c(Cl)nccn23)C1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CN1CCN(C2CC(c3nc(I)c4c(Cl)nccn34)C2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-Methyl piperazine (5.75 mL, 0.0514 mol) in 1,2-dichloroethane (1096.7 mL, 13.892 mol) was added to 3-(8-chloro-1-iodo-imidazo[1,5-a]pyrazin-3-yl)-cyclobutanone (17.00 g, 0.04892 mol) and sodium triacetoxyborohydride (21.8 g, 0.0978 mol). The reaction stirred at rt for 3 h. The reaction was concentrated, dissolved in CH2Cl2, and then washed with saturated NaHCO3 solution and brine. The product was dried over sodium sulfate, filtered, and concentrated in vacuo. The product was flushed through a quick silica gel plug (wetted with 100% CHCl3, eluted with 8% (7N NH3) MeOH in CHCl3), to afford the title compound; 1H NMR (CDCl3, 400 MHz) δ 7.63 (1H, d), 7.30 (1H, d), 3.42 (1H, m), 2.94 (1H, m), 2.65 (4H, m), 2.44 (8H, m), 2.32 (3H, s); MS (ES+): m/z 431.85/433.87 (100/45) [MH+]; HPLC: tR=1.82 min. (OpenLynx, polar—5 min.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Cl)[N:9]=[C:10]=[O:11])=[CH:4][CH:3]=1.[C:13]1([CH:19]2[CH2:24][C:23](=[O:25])[CH:22]=[C:21]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=3)[CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:22]3[C:23](=[O:25])[CH2:24][CH:19]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:20][C:21]=3[N:26]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:35])[F:36])[CH:28]=3)[C:10](=[O:11])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C1C=C(Nc2cccc(C(F)(F)F)c2)CC(c2ccccc2)C1
Reactant: O=C=NC(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Product: O=C1CC(c2ccccc2)CC2=C1C(c1ccc(Br)cc1)NC(=O)N2c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A solution of 1-bromo-4-(chloro(isocyanato)methyl)benzene (201 mg, 0.815 mmol) in dichloromethane (3 mL) is added to a solution of 5-phenyl-3-(3-(trifluoromethyl)phenyl-amino)cyclohex-2-enone (intermediate 14, 270 mg, 0.815 mmol) in dichloromethane (7 mL), and the mixture is heated at reflux for 4 h and cooled to room temperature. After 2 d the mixture is concentrated under reduced pressure and the residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 90:10 to 60:40). Yield: 195 mg; ESI mass spectrum: [(79Br)-M+H]+=541, [(81Br)-M+H]+=543; Retention time HPLC: 1.42 min, 1.44 min (1:1 mixture of diastereomers) (Z002—002).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:19][C:20](=[O:22])[CH3:21])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9](N2CCOCC2)[N:8]=1.Cl.[C:24](N)(=N)C>>[CH3:1][C:2]1[N:3]=[C:4]([NH:19][C:20](=[O:22])[CH3:21])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH3:24])[N:8]=1
Reactant: CC(=O)Nc1nc(C)c(-c2ccnc(N3CCOCC3)n2)s1
Reactant: CC(=N)N
Agent: Cl
Product: CC(=O)Nc1nc(C)c(-c2ccnc(C)n2)s1

Procedure:
The titled compound is prepared by an analogous procedure to N-[4-Methyl-5-(2-morpholin-4-yl-pyrimidin-4-yl)-thiazol-2-yl]-acetamide (25e) by replacing morpholinoformamidine hydrobromide (part 25c) with acetamidine hydrochloride.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([NH2:10])[CH2:7][CH2:8][CH3:9]>ClCCl.C(Cl)(Cl)Cl>[CH2:6]([NH:10][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:7][CH2:8][CH3:9]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCN
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCCCNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
Methanesulfonyl chloride (6.76 ml., 87.3 mmole, 1.0 eq.) was dissolved in distilled dichloromethane (44 ml., 0.5M). The solution was cooled in an ice bath and treated dropwise with n-butylamine (17.3 ml., 175 mmole, 2.0 eq.). After the addition was complete, the clear solution was stirred overnight at room temperature. The mixture was diluted with chloroform (200 ml.), dried, washed with 0.5N HCl (2×200 ml.) and saturated NaCl solution (200 ml.), dried (MgSO4) and freed of solvent in vacuo leaving an oil. This was purified by distillation to give N-butylmethanesulfonamide (11.4 g., 86%,. b.p. 106°-110°/0.5 mm) which solidified on standing.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].[Br:10]Br>C(O)(=O)C>[Br:10][C:6]1[C:5]([CH3:8])=[CH:4][C:3]([OH:9])=[C:2]([F:1])[CH:7]=1
Reactant: BrBr
Reactant: Cc1ccc(F)c(O)c1
Solvent: CC(=O)O
Product: Cc1cc(O)c(F)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
2-fluoro-5-methylphenol (23.8 g, 0.19 mol) and bromine (9.7 ml, 0.19 mol) are combined in 50 ml of glacial acetic acid and stirred at RT for one hour. Acetic acid was removed under vacuum. The liquid was diluted with ethyl acetate and washed with water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford 4-bromo-2-fluoro-5-methylphenol (38 g, 98% yield) as a colorless liquid. No [M+H] peak by LCMS. 1H NMR (400 MHz, CHLOROFORM-d) ppm 1.98 (s, 1H) 2.22 (s, 3H) 6.81 (dd, J=9.15, 0.54 Hz, 1H) 7.17 (d, J=9.88 Hz, 1H)
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:9](Br)=[N:10][C:11]([CH:14]2[CH2:19][N:18]([CH3:20])[C:17](=[O:21])[N:16]([CH3:22])[CH2:15]2)=[CH:12][CH:13]=1)(C)(C)C.[CH3:25][C:26]1([CH3:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[NH2:7][C:8]1[C:9]([N:29]2[CH2:30][CH2:31][C:26]([CH3:32])([CH3:25])[CH2:27][CH2:28]2)=[N:10][C:11]([CH:14]2[CH2:15][N:16]([CH3:22])[C:17](=[O:21])[N:18]([CH3:20])[CH2:19]2)=[CH:12][CH:13]=1
Reactant: CN1CC(c2ccc(NC(=O)OC(C)(C)C)c(Br)n2)CN(C)C1=O
Reactant: CC1(C)CCNCC1
Product: CN1CC(c2ccc(N)c(N3CCC(C)(C)CC3)n2)CN(C)C1=O
Temperature: 25 °C

Procedure:
The title compound is prepared from [2-bromo-6-(1,3-dimethyl-2-oxo-hexahydro-pyrimidin-5-yl)-pyridin-3-yl]-carbamic acid tert-butyl ester (as prepared in the previous step) and 4,4-dimethylpiperidine (US 2003236247) following the literature procedure of Buchwald (Org. Lett., 4, 2885-8 (2002)). The residue obtained is purified by silica gel chromatography with an appropriate solvent mixture. After isolation, removal of the BOC protecting group from the resulting intermediate is carried out by stirring at RT in TFA-DCM (1:2), monitoring by TLC for completion, and then concentration in vacuo.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9]([CH3:13])[CH:8]([CH3:14])[N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.[CH3:21]N(C)C(=O)C.IC.[H-].[Na+]>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:21])[C:10](=[O:12])[CH:9]([CH3:13])[CH:8]([CH3:14])[N:7]([CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19]3)[C:6]=2[N:20]=1
Reactant: CC1C(=O)Nc2cnc(Cl)nc2N(C2CCCC2)C1C
Reactant: CC(=O)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CC1C(=O)N(C)c2cnc(Cl)nc2N(C2CCCC2)C1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.09 g (0.0003 mole) of (rac)-2-chloro-9-cyclopentyl-7,8-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-41), 1 mL of N,N-dimethylacetamide and 0.028 mL (0.00045 mole) of iodomethane at 0 degrees was added 0.027 g (0.00045 mole) of 60% sodium hydride in oil. The mixture was stirred at ambient temperature for 1 hour, then 20 mL of water was added. The precipitate was collected by filtration to give 0.092 g of (rac)-2-chloro-9-cyclopentyl-5,7,8-trimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-41) as an yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].C(Cl)CCl.Cl.[CH3:33][N:34]([CH3:57])[CH2:35][CH2:36][N:37]([C:42]1[CH:43]=[C:44]2[C:48](=[CH:49][CH:50]=1)[C:47](=[O:51])[N:46]([CH2:52][C:53](O)=[O:54])[C:45]2=[O:56])[S:38]([CH3:41])(=[O:40])=[O:39]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:53](=[O:54])[CH2:52][N:46]1[C:45](=[O:56])[C:44]2[C:48](=[CH:49][CH:50]=[C:42]([N:37]([CH2:36][CH2:35][N:34]([CH3:33])[CH3:57])[S:38]([CH3:41])(=[O:39])=[O:40])[CH:43]=2)[C:47]1=[O:51]
Reactant: CN(C)CCN(c1ccc2c(c1)C(=O)N(CC(=O)O)C2=O)S(C)(=O)=O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: CN(C)CCN(c1ccc2c(c1)C(=O)N(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.6 %

Procedure:
To a solution of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (180 mg, 0.428 mmol), DMAP (52.3 mg, 0.428 mmol) and EDC (164 mg, 0.857 mmol) in DCM (10 ml), 2-(5-(N-(2-(dimethylamino)ethyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetic acid hydrochloride (191 mg, 0.471 mmol) was added portion wise within 4 hours, and the reaction was stirred at room temperature for 24 hours. The solvent was evaporated and the crude was purified by flash silica gel chromatography (DCM/MeOH 10/0.2) affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5-(N-(2-(dimethylamino)ethyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetoxy)ethyl)pyridine 1-oxide as a white solid (253 mg, 0.328 mmol, 77% yield). MS/ESI+ 771.15 [MH]+, [αD]=−32.18, c=0.353, DCM). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.43 (s, 2H), 7.93-8.00 (m, 2H), 7.89 (dd, 1H), 7.19 (d, 1H), 7.09 (d, 1H), 6.97 (dd, 1H), 7.08 (t, 1H), 6.02 (dd, 1H), 4.43 (s, 2H), 3.92-4.05 (m, 2H), 3.88 (t, 2H), 3.39 (dd, 1H), 3.23 (dd, 1H), 3.13 (s, 3H), 2.31 (t, 2H), 2.10 (s, 6H), 1.07-1.33 (m, 1H), 0.49-0.71 (m, 2H), 0.27-0.49 (m, 2H)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]([CH3:14])[CH2:8][C:9](OCC)=[O:10])=[CH:3][CH:2]=1.[NH3:15]>>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]([CH3:14])[CH2:8][C:9]([NH2:15])=[O:10])=[CH:3][CH:2]=1
Reactant: CCOC(=O)CC(C)c1ccncc1
Reactant: N
Product: CC(CC(N)=O)c1ccncc1
Yield: 47 %

Procedure:
A solution of ethyl 3-(pyridin-4-yl)butanoate (0.50 g, 2.59 mmol) in methanolic ammonia (10 ml) was heated to 100° C. in a pressure bomb for 48 h. The solvent was evaporated under reduced pressure to afford the crude compound, which was washed with n-pentane and dried under reduced pressure to afford 0.2 g (47%) of 3-(pyridin-4-yl)butanamide as an off-white solid.
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:2]12.Cl[C:12]1[N:13]=[CH:14][C:15]([C:18]([NH:20][C:21]2[NH:22][N:23]=[C:24]([CH2:26][CH2:27][C:28]3[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[CH:29]=3)[CH:25]=2)=[O:19])=[N:16][CH:17]=1>CS(C)=O>[CH2:1]1[CH:2]2[CH2:10][CH2:9][CH2:8][CH2:7][N:3]2[CH2:4][CH2:5][N:6]1[C:12]1[N:13]=[CH:14][C:15]([C:18]([NH:20][C:21]2[NH:22][N:23]=[C:24]([CH2:26][CH2:27][C:28]3[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[CH:29]=3)[CH:25]=2)=[O:19])=[N:16][CH:17]=1
Reactant: COc1cc(CCc2cc(NC(=O)c3cnc(Cl)cn3)[nH]n2)cc(OC)c1
Reactant: C1CCN2CCNCC2C1
Solvent: CS(C)=O
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4CCN5CCCCC5C4)cn3)[nH]n2)cc(OC)c1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
2,3,4,6,7,8,9,9a-Octahydro-1H-pyrido[1,2-a]pyrazine (477 mg, 3.40 mmol) was added in one portion to 5-chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide (659 mg, 1.70 mmol) in anhydrous dimethylsulfoxide (1.70 ml) at 25° C. The resulting solution was stirred at 100° C. for 18 h. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH to afford impure material. The concentrated eluant was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% formic acid) and MeCN as eluents. The sample was then put through a basic HPLC system to obtain the free base. Fractions containing the desired compound were evaporated to dryness to afford the title compound (395 mg, 47%) as a cream solid.
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].[CH2:17]([CH:19]1[O:21][CH2:20]1)Cl>>[CH3:3][C:2]([C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH:19]2[CH2:20][O:21]2)=[CH:14][CH:15]=1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:1]
Reactant: CC(C)(c1ccccc1)c1ccc(O)cc1
Reactant: ClCC1CO1
Product: CC(C)(c1ccccc1)c1ccc(OCC2CO2)cc1

Procedure:
The title compound was prepared from 4-(1-methyl-1-phenyl-ethyl)-phenol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.
Reaction SMILES: [CH:1]1([O:6][C:7](=[O:43])[C@H:8]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](=[O:41])[NH:32][O:33]C(OCC(C)C)C)=[CH:19][CH:18]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>C(Cl)Cl.O1CCOCC1>[CH:1]1([O:6][C:7](=[O:43])[C@H:8]([NH:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](=[O:41])[NH:32][OH:33])=[CH:21][CH:22]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)COC(C)ONC(=O)CCCCCCC(=O)Nc1ccc(CN[C@@H](C(=O)OC2CCCC2)c2ccccc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(CCCCCCC(=O)Nc1ccc(CN[C@@H](C(=O)OC2CCCC2)c2ccccc2)cc1)NO

Procedure:
(R)-{4-[7-(1-Isobutoxy-ethoxycarbamoyl)-heptanoylamino]-benzylamino}-phenyl-acetic acid cyclopentyl ester (50 mg, 0.08 mmol, 1 eq) was dissolved in DCM (0.5 mL) and stirred with 4M HCl in dioxane (0.2 mL) for 30 min. The resulting salt was concentrated, dissolved in methanol and purified by preparative HPLC to yield compound (83). LCMS purity 94%, m/z 496 [M++H]+, 1H NMR (300 MHz, MeOD), δ: 1.41-1.95 (16H, m, 8×CH2), 2.15-2.17 (2H, m, CH2), 2.40 (2H, t, J=7.2 Hz, CH2), 4.16 (2H, q, J=13.5 Hz, CH2), 5.12 (1H, s, CH), 5.27-5.30 (1H, m, CH), 7.40 (2H, d, J=8.7 Hz, Ar—H), 7.50-7.56 (5H, m, Ar—H), 7.67 (2H, d, J=8.7 Hz, Ar—H).