Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[CH2:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1.Cl>N1C=CC=CC=1>[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([N:9]2[C:10](=[O:12])[CH2:11][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]2=[O:13])=[O:20])=[CH:17][CH:16]=1
Reactant: O=C1CN(c2ccccc2)C(=O)N1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CN(c2ccccc2)C(=O)N1C(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 24.6 %

Procedure:
In accordance with the synthesis process (B), 500 mg (2.84 mmol) of 1-phenyl-imidazolidin-2,4-dione were dissolved in 20 ml of pyridine. To the solution, 500 mg (2.86 mmol) of p-chlorobenzoyl chloride were added dropwise while chilling with ice water. The resultant mixture was stirred at 0°-5° C. for 2 hours, and dilute hydrochloric acid was then added to the reaction mixture. Crystals deposited were collected by filtration by means of suction. These crude crystals were recrystallized from n-hexane/ethyl acetate, thereby obtaining 220 mg (yield: 25%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[C:5]([Cl:22])=[CH:4][N:3]=1.[CH2:23]([N:25]1[CH2:31][CH2:30][C:29]2[CH:32]=[C:33]([NH2:36])[CH:34]=[CH:35][C:28]=2[CH2:27][CH2:26]1)[CH3:24].Cl.C(=O)([O-])[O-]>COCCO.O1CCOCC1>[Cl:22][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])=[N:7][C:2]([NH:36][C:33]2[CH:34]=[CH:35][C:28]3[CH2:27][CH2:26][N:25]([CH2:23][CH3:24])[CH2:31][CH2:30][C:29]=3[CH:32]=2)=[N:3][CH:4]=1
Reactant: CCN1CCc2ccc(N)cc2CC1
Reactant: O=C(N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCO
Solvent: C1COCCO1
Product: CCN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NC(=O)C(F)(F)F)n3)cc2CC1
Temperature: 120 °C
Reaction time: 7 h
Yield: 45 %

Procedure:
N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-2,2,2-trifluoro-acetamide (204 mg, 0.571 mmol) was added into a Vial, followed by a solution of 3-Ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (106 mg, 0.557 mmol) in 2-Methoxyethanol (7 mL). 4 M of Hydrogen chloride in 1,4-Dioxane (0.2 mL) was added and the reaction was heated at 120° C. After 7 h, the reaction was cooled to room temperature, Macroporous carbonate resin (3.16 mmol/g loading; 530 mg, 1.68 mmol) was added and stirred 30 min. The polymer was filtered off, and the solvent removed in vacuo. The residue was dissolved in DCM, then chromatographed (2×12 g SiO2, ISCO, 0-10% MeOH:DCM) to afford N-{(1R,2R)-2-[5-Chloro-2-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-2,2,2-trifluoro-acetamide (128 mg, 45%) as a beige solid. m.p.=165° C.; LCMS (m/e) 511 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.98 (s, 1H), 7.94 (s, 1H), 7.32 (m, 2H), 7.08 (d, 1H, J=8.1 Hz), 6.93 (s, 1H), 5.27 (d, 1H, J=7.4 Hz), 3.99 (m, 1H), 3.87 (m, 1H), 3.68 (m, 3H), 3.11 (m, 2H), 2.7-2.9 (m, 4H), 2.30 (d, 1H, J=11.4 Hz), 2.16 (d, 1H, J=11.7 Hz), 1.8-1.9 (m, 2H), 1.2-1.6 (m, 8H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12][CH:13](O)[CH3:14].Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH:13]([CH3:14])[CH3:12])=[O:10]
Reactant: CC(C)O
Reactant: O=C(O)Cc1ccccc1I
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)Cc1ccccc1I
Temperature: 25 °C

Procedure:
A solution of 2-(2-iodophenyl)acetic acid (0.50 g) and propan-2-ol (0.142 ml) in dry dimethylformamide (10 ml) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.458 g) with stirring at ambient temperature under an atmosphere of argon. After 18 hours the reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (3×50 ml) and brine. The aqueous layers were back-extracted with ethyl acetate (50 ml) and the organic layers were combined, dried (MgSO4) and evaporated. The residue was purified by chromatography on silica gel (Varian Band Elut S1 silica gel) eluting with dichloromethane to give 2-propyl 2-(2-iodophenyl)acetate (232 mg) as a yellow oil, NMR: 1.2(6H, d), 3.8(2H, s), 4.9(1H, m), 7.0(1H, m), 7.4(2H, d) and 7.85(1H, d).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][C@@H:12]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:13]([CH3:17])[C:14](O)=[O:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[O:36][NH2:37]>C(Cl)Cl>[OH:36][NH:37][C:14](=[O:15])[C@@H:13]([CH3:17])[C@@H:12]([S:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C[Si](C)(C)ON
Reactant: COc1ccc(S[C@@H](CCCCc2ccccc2)[C@H](C)C(=O)O)cc1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccc(S[C@@H](CCCCc2ccccc2)[C@H](C)C(=O)NO)cc1OC
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 92.9 %

Procedure:
(2R,3S)-3-(3,4-Dimethoxyphenylsulfanyl)-2-methyl-7-phenylheptanoic acid (0.46 g, 1.2 mmol) is dissolved in CH2Cl2 (4.5 mL) and cooled to 0° C. and to this is added 2 M oxalyl chloride in CH2Cl2 (1.9 mL, 3.8 mmol) over 5 minutes. The ice bath is removed and the reaction allowed to warm to room temperature. After 1.5 hours, the reaction is concentrated in vacuo and azeotroped with chloroform several times. The crude residue is dissolved in CH2Cl2 (4 mL) and O-trimethylsilylhydroxylamine (0.4 g, 3.6 mmol) is added slowly. After 5 minutes, the reaction is diluted with CH2Cl2 (20 mL) and washed with 2 N HCl (15 mL). The aqueous layer is back-extracted with CH2Cl2 (10 mL) and the combined organic layers are washed with water (50 mL), dried over MgSO4 and concentrated in vacuo. The crude residue is azeotroped with ether/petroleum ether and triturated with a large volume of petroleum ether to give (+)-(2R,3S)-3-(3,4-dimethoxyphenylsulfanyl)-2-methyl-7-phenylheptanoic acid hydroxyamide (0.45 g, 94%): [a]D23 +22° (c=1.0, CHCl3); 1H NMR (300 MHz, CD3OD) δ 7.25-7.21 (m, 2H), 7.15-7.10 (m, 3H), 7.05-6.98 (m, 2H), 6.87 (d, J=8.2 Hz, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.17-3.14 (m,1H), 2.58-2.52 (m, 2H), 2.35-2.30 (m, 1H), 1.75-1.65 (m, 1H), 1.60-1.40 (m, 5H), 1.17 (d, J=7.0 Hz, 3H); MS (ion spray) m/e 404 (M+H)+ ; Anal. (C22H29NO4S) C, H, N.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[CH:17]=2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[OH-].[Na+].C(OCC)(=O)C>C1COCC1.Cl>[NH2:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[C:15]([NH:14][CH2:13][CH2:12][CH2:11][CH2:10][NH:9][C:3]1[C:2]([Br:1])=[CH:7][N:6]=[C:5]([Cl:8])[N:4]=1)=[O:25]
Reactant: O=C(NCCCCNc1nc(Cl)ncc1Br)c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1cccc(C(=O)NCCCCNc2nc(Cl)ncc2Br)c1
Reaction time: 21 h

Procedure:
A solution of 568 mg (1.32 mmol) of N-[4-(5-bromo-2-chloro-pyrimidin-4-ylamino)-butyl]-3-nitro-benzamide in 15 ml of THF is mixed at room temperature with 9 ml of a 15% solution of Ti(III)Cl in approximately 10% hydrochloric acid. After 21 hours, the batch is made basic with 2N NaOH solution, mixed with ethyl acetate and filtered on Celite. The filter cake is rewashed with ethyl acetate. The organic phase of the filtrate is filtered through a Whatman filter and concentrated by evaporation. 447 mg (1.12 mmol, corresponding to 85% of theory) of the product is obtained.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:21])=[C:4]([C:14]([OH:20])=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=1)[C:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].C([O-])([O-])=O.[K+].[K+].[CH:28]1[CH:33]=[CH:32][C:31]([CH2:34]Br)=[CH:30][CH:29]=1>CC(C)=O>[CH2:34]([O:20][C:14]1[C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:2]([F:1])=[C:3]([CH3:21])[C:4]=1[C:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6])[C:31]1[CH:32]=[CH:33][CH:28]=[CH:29][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: Cc1c(F)cc([N+](=O)[O-])c(O)c1C(=O)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1c(F)cc([N+](=O)[O-])c(OCc2ccccc2)c1C(=O)Oc1ccccc1
Yield: 98.7 %

Procedure:
A 30 L 4-neck flask equipped with mechanical stirrer, thermometer, addition funnel and gas inlet was charged with a solution of compound 64 (1423 g, 4.89 mol) in acetone (17 L). K2CO3 (1350 g, 9.8 mol) and KI (81 g, 0.49 mol) were added to the stirring reaction mixture and the resulting suspension was degassed with N2 for 5 min prior to adding BnBr (878.2 g, 5.13 mol) at 27˜29° C. over 8 mM. After the addition, the brown suspension was refluxed for 2.5 h, then allowed to cool to 20˜30° C. The suspension was filtered, and the filter cake was washed with acetone (3×900 mL). The filtrate was concentrated under reduced pressure and the residual oil was dissolved in MTBE (7.0 L) and successively washed with water (5×1.0 L) and brine (4×1.0 L). The organic layer was dried over Na2SO4 filtered then concentrated to dryness under reduced pressure to afford 1840 g of crude compound 65 (98.7% yield) as brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:12]1[C:16]2[CH:17]=[CH:18][C:19]([S:21]([N:24]([CH2:29][C@H:30]3[O:34][C:33]([CH3:36])([CH3:35])[N:32]([C:37]([O:39][C@@H:40]4[C@H:47]5[C@H:43]([O:44][CH2:45][CH2:46]5)[O:42][CH2:41]4)=[O:38])[C@H:31]3[CH2:48][C:49]3[CH:54]=[CH:53][C:52](O)=[CH:51][CH:50]=3)[CH2:25][CH:26]([CH3:28])[CH3:27])(=[O:23])=[O:22])=[CH:20][C:15]=2[O:14][CH2:13]1>>[O:12]1[C:16]2[CH:17]=[CH:18][C:19]([S:21]([N:24]([CH2:29][C@H:30]3[O:34][C:33]([CH3:36])([CH3:35])[N:32]([C:37]([O:39][C@@H:40]4[C@H:47]5[C@H:43]([O:44][CH2:45][CH2:46]5)[O:42][CH2:41]4)=[O:38])[C@H:31]3[CH2:48][C:49]3[CH:50]=[CH:51][C:52]([O:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:53][CH:54]=3)[CH2:25][CH:26]([CH3:27])[CH3:28])(=[O:23])=[O:22])=[CH:20][C:15]=2[O:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: CC(C)CN(C[C@H]1OC(C)(C)N(C(=O)O[C@H]2CO[C@H]3OCC[C@H]32)[C@H]1Cc1ccc(O)cc1)S(=O)(=O)c1ccc2c(c1)OCO2
Product: CC(C)CN(C[C@H]1OC(C)(C)N(C(=O)O[C@H]2CO[C@H]3OCC[C@H]32)[C@H]1Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1)S(=O)(=O)c1ccc2c(c1)OCO2

Procedure:
According to example 135 (with the exception that N-(tert-butoxycarbonyl)ethanolamine was used instead of phenethyl alcohol), (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (4S,5R)-5-{[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]methyl}-4-(4-hydroxybenzyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate was converted to the desired compound. MS(ESI): 798(M+Na).
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][CH:6]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]=1.[CH3:12][NH:13][CH3:14]>C(OCC)C>[CH3:12][N:13]([CH2:2][C:3]1[S:7][CH:6]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]=1)[CH3:14]
Reactant: CNC
Reactant: COC(=O)c1csc(CCl)c1
Solvent: CCOCC
Product: COC(=O)c1csc(CN(C)C)c1

Procedure:
A solution of methyl 5-(chloromethyl)-3-thiophene-carboxylate (1.9 g) in dry diethylether (100 ml) was treated with anhydrous dimethylamine (5 ml). After 6 hours the solvent was removed in vacuo and the residue was dissolved in 5 M hydrochloric acid (20 ml). The aqueous solution was washed with diethylether, basified with 5 M sodium hydroxide (30 ml) and extracted with ether. The ethereal extracts were evaporated to give an oily residue which was distilled to yield the title compound as a colourless oil (1.6 g) b.p. 120°-130°/0.5 mm.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:23][O:24][C:25]1[CH:26]=[CH:27][C:28]2[NH:34][C:33](=[O:35])[N:32]([CH:36]3[CH2:41][CH2:40][N:39]([C:42]4[N:47]=[CH:46][N:45]=[C:44]([C:48]([OH:50])=O)[CH:43]=4)[CH2:38][CH2:37]3)[CH2:31][CH2:30][C:29]=2[CH:51]=1.Cl.[Br:53][C:54]1[CH:55]=[N:56][C:57]2[CH2:58][CH2:59][NH:60][CH2:61][C:62]=2[CH:63]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C=O)C.CO>[Br:53][C:54]1[CH:55]=[N:56][C:57]2[CH2:58][CH2:59][N:60]([C:48]([C:44]3[N:45]=[CH:46][N:47]=[C:42]([N:39]4[CH2:40][CH2:41][CH:36]([N:32]5[CH2:31][CH2:30][C:29]6[CH:51]=[C:25]([O:24][CH3:23])[CH:26]=[CH:27][C:28]=6[NH:34][C:33]5=[O:35])[CH2:37][CH2:38]4)[CH:43]=3)=[O:50])[CH2:61][C:62]=2[CH:63]=1
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)ncn3)CC1)C(=O)N2
Reactant: Brc1cnc2c(c1)CNCC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CCc5ncc(Br)cc5C4)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
90 mg (0.24 mmol) TBTU were added to 80 mg (0.20 mmol) 6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 70 mg (0.28 mmol) 3-bromo-5,6,7,8-tetrahydro-1,6-naphthyridine-hydrochloride and 120 μL (0.86 mmol) triethylamine in 0.9 mL DMF and the mixture was stirred overnight at RT. The reaction mixture was combined with 1 mL methanol, 1 mL saturated sodium hydrogen carbonate solution and 8 mL ice water. The precipitate was suction filtered, washed with water and diethyl ether and dried.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:12]=[C:11]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH:24][C@H:25]3[CH2:29][NH:28][CH2:27][C@H:26]3[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[C:37](Cl)(=[O:39])[CH3:38]>>[C:37]([N:28]1[CH2:29][C@H:25]([NH:24][S:21]([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][C:11]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[N:4]=[C:3]([CH3:2])[CH:12]=3)=[CH:16][CH:17]=2)(=[O:23])=[O:22])[C@H:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27]1)(=[O:39])[CH3:38]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CNC[C@H]3C(=O)OC(C)(C)C)cc2)c2ccccc2n1
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N1C[C@H](NS(=O)(=O)c2ccc(OCc3cc(C)nc4ccccc34)cc2)[C@H](C(=O)OC(C)(C)C)C1
Yield: 39.2 %

Procedure:
According to the procedure of Example 17, Step 3, the reaction of 320.4 mg of tert-butyl cis-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]pyrrolidine-3-carboxylate hydrochloride with 57 mg of acetyl chloride provided 127 mg (39% yield) of tert-butyl cis-1-acetyl-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]pyrrolidine-3-carboxylate. MS: 540.1(M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9](C(=O)C)[CH2:10][CH2:11][N:12]=2)=[C:6]([Cl:16])[N:5]=[C:4]([NH2:17])[N:3]=1>C(O)(=O)C>[Cl:16][C:6]1[C:7]([C:8]2[NH:9][CH2:10][CH2:11][N:12]=2)=[C:2]([Cl:1])[N:3]=[C:4]([NH2:17])[N:5]=1
Reactant: CC(=O)N1CCN=C1c1c(Cl)nc(N)nc1Cl
Solvent: CC(=O)O
Product: Nc1nc(Cl)c(C2=NCCN2)c(Cl)n1

Procedure:
4.0 g 4,6-dichloro-5-(1-acetyl-2-imidazolin-2-yl)-aminopyrimidine are kept in 80 ml 50% acetic acid for 2 days at 60° C. Then the solution is concentrated, the residue taken up in water and extracted with chloroform, whereby the starting material and the byproducts are separated. Subsequently, the aqueous phase is alkalized, and the reaction product is extracted with chloroform. After concentration, 1.4 g (41%) 4,6-dichloro-5-(2-imidazolin-2-yl)-aminopyrimidine, melting point 197°-198° C., is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:19](=[O:30])[NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=3)=[C:11]([C:15]([CH3:18])([CH3:17])[CH3:16])[NH:12]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:31]([N:12]1[C:13]2[C:9](=[CH:8][CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:14]=2)[C:10]([C:19](=[O:30])[NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[C:11]1[C:15]([CH3:18])([CH3:17])[CH3:16])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)(C)C)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)(C)C)n(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of ethyl2-tert-butyl-3-(3,4-difluorobenzylcarbamoyl)-1H-indole-6-carboxylate (Compound 115, 33 mg, 0.080 mmol) in DMF (1 ml) was added benzyl bromide (47 μl, 0.40 mmol) and K2CO3 (33 mg, 0.24 mmol). The mixture was stirred at room temperature for 24 h, diluted with EtOAc, washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→30% EtOAc-hexanes) followed by PTLC (5% MeOH—CH2Cl2) to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[N:5]=[C:4]([C:13]([NH:15][C:16]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)[N:18]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)[N:17]=2)=[O:14])[CH:3]=1.[O:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]1[N:40]1[C:44]([C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=2)=[CH:43][C:42]([C:52](O)=[O:53])=[N:41]1.[I-].ClC1C=CC=C[N+]=1C.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[O:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]1[N:40]1[C:44]([C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=2)=[CH:43][C:42]([C:52]([NH:1][C:2]2[N:6]([CH:7]3[CH2:12][CH2:11][CH2:10][CH2:9][O:8]3)[N:5]=[C:4]([C:13](=[O:14])[NH:15][C:16]3[CH:20]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=4)[N:18]([CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][O:29]4)[N:17]=3)[CH:3]=2)=[O:53])=[N:41]1
Reactant: Cc1ccc(-c2cc(NC(=O)c3cc(N)n(C4CCCCO4)n3)nn2C2CCCCO2)cc1
Reactant: Cc1ccc(-c2cc(C(=O)O)nn2C2CCCCO2)cc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(-c2cc(NC(=O)c3cc(NC(=O)c4cc(-c5ccc(C)cc5)n(C5CCCCO5)n4)n(C4CCCCO4)n3)nn2C2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 17.4 %

Procedure:
5-Amino-1-(tetrahydro-2H-pyran-2-yl)-N-(1-(tetrahydro-2H-pyran-2-yl)-5-p-tolyl-1H-pyrazol-3-yl)-1H-pyrazole-3-carboxamide (102 mg, 0.23 mmol) was added to a solution of 1-(tetrahydro-2H-pyran-2-yl)-5-p-tolyl-1H-pyrazole-3-carboxylic acid (59 mg, 0.20 mmol), 2-chloro-1-methylpyridinium iodide (79 mg, 0.31 mmol) and N,N′-diisopropylethylamine (105 μL, 0.62 mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 16 hrs. The reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with brine, dried with Na2SO4 and concentrated. The crude product was purified by silica gel column chromatography (PE-EtOAc, 7:3) and gave 1-(tetrahydro-2H-pyran-2-yl)-N-(1-(tetrahydro-2H-pyran-2-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-5-p-tolyl-1H-pyrazol-3-ylcarbamoyl)-1H-pyrazol-5-yl)-5-p-tolyl-1H-pyrazole-3-carboxamide (25 mg, 15%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1([O:12][CH3:13])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5].C([O-])([O-])=O.[K+].[K+].[CH2:20]([O:22][C:23]([N:25]1[CH2:31][CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)=[O:24])[CH3:21].C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-].O>[CH3:13][O:12][C:6]1([C:4]([O:3][CH3:2])=[O:5])[CH2:7][CH2:8][N:9]([CH:28]2[CH2:29][CH2:30][CH2:31][N:25]([C:23]([O:22][CH2:20][CH3:21])=[O:24])[CH2:26][CH2:27]2)[CH2:10][CH2:11]1
Reactant: CCOC(=O)N1CCCC(=O)CC1
Reactant: COC(=O)C1(OC)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Solvent: CO
Solvent: O
Product: CCOC(=O)N1CCCC(N2CCC(OC)(C(=O)OC)CC2)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 16.7 %

Procedure:
4-Methoxypiperidine-4-carboxylic acid methyl ester hydrochloride (0.50 g, 2.38 mmol) was dissolved in methanol (10 mL) and treated with K2CO3 (0.328 g, 2.38 mmol) in a minimum of water to de-salt. Reaction mixture was concentrated in vacuo and azeotroped to dryness with toluene. The residue and 4-oxoazepane-1-carboxylic acid ethyl ester (0.441 g, 2.38 mmol) were dissolved in methanol (20 mL) at rt and treated with zinc chloride (0.975 g, 7.15 mmol). The reaction mixture was stirred at 50° C. for 2 h. The solution was cooled to room temperature, sodium cyanoborohydride (0.299 g, 4.77 mmol) was added and the reaction mixture was stirred at 50° C. overnight under nitrogen. The solvents were removed in vacuo, and the residue was suspended between DCM and sat. NaHCO3 sol. The turbid mixture, was passed through a pad of celite which was washed with DCM. The organics layers were combined, washed with sat. NaCl sol. and dried by passing through a Biotage Phase Separator cartridge. The solvents were removed in vacuo and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-63 μm, 60 Å, 50 mL per min, gradient 1% to 6% MeOH in DCM]) to give ethyl 4-[4-methoxy-4-(methoxycarbonyl)piperidin-1-yl]azepane-1-carboxylate (0.136 g, 16.4%) as a colourless oil.
Reaction SMILES: C(OC([N:8]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22]Br)=[CH:18][N:17]=1)C(OC(C)(C)C)=O)=O)(C)(C)C.[P:24]([O:31]CC)([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27].Cl.C([O-])(O)=O.[Na+]>O1CCOCC1.C(Cl)Cl>[CH2:26]([O:25][P:24]([CH2:22][C:19]1[CH:18]=[N:17][C:16]([NH2:8])=[CH:21][CH:20]=1)(=[O:31])[O:28][CH2:29][CH3:30])[CH3:27]
Reactant: CCOP(OCC)OCC
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ccc(CBr)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOP(=O)(Cc1ccc(N)nc1)OCC
Temperature: 110 °C
Reaction time: 4 h
Yield: 31 %

Procedure:
A mixture of di-tert-butyl[5-(bromomethyl)pyridin-2-yl]imidodicarbonate (Compound 309B, 1.162 g, 3 mmol) and triethyl phosphite (0.598 g, 3.6 mmol) in dioxane (2 mL) was stirred at 110° C. for 4 h. The cooled reaction mixture (room temperature) was treated with 4 N HCl in dioxane (5 mL) and DCM (10 mL) and allowed to stir at room temperature for 6 h. Sat. NaHCO3 (aq, 15 mL) was added and the mixture was extracted with DCM (3×40 mL). The combined organic phases were dried over MgSO4, concentrated, and purified by silica gel chromatography (5% 7 N ammonia in MeOH in DCM) to afford 227 mg of the title compound (yield: 31%). 1H NMR (CDCl3, 400 MHz): δ=1.29 (t, J=6.8 Hz, 6H), 2.98 (d, J=20.8 Hz, 2 H), 4.02-4.09 (m, 4H), 5.65 (s, br, 2H), 6.58 (d, J=8.8 Hz, 1H), 7.51 (dt, J=2.4, 8.8 Hz, 1H), 7.82 (t, J=2.4 Hz, 1H). MS (ES+): m/z 245.09 [MH+]. HPLC: tR=0.70 min (UPLC TOF, polar—3 min).
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[CH2:1]([NH:5][S:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:21])=[O:20])[CH:2]([CH3:4])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)CN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CNS(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4.14 g of isobutylamine (56.6 mmol) and 2.86 g of triethylamine (28.3 mmol) in 40 mL of CH2Cl2 was slowly added 5.0 g of benzenesulfonyl chloride (28.3 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 30 min and then at rt for 1 hr. 150 mL of CH2Cl2 were added, and the organic layer was washed with saturated aqueous solution of NH4Cl and brine (30×2 mL), dried over MgSO4, filtered, and the filtrate was concentrated to give the title compound. 1H NMR (CDCl3) δ 0.87 (d, J=6.6 Hz, 6 H), 1.71 (tsept, J=6.7, 6.5 Hz, 1 H), 2.76 (dd, J=6.5, 6.7 Hz, 2 H), 4.61 (t, J=6.5 Hz, 1 H), 7.49-7.88 (m, 5 H). Mass Spectrum (CI+) m/e=214 (M+1).