Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH2:10].C(N(CC)CC)C.[C:18]([C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][N:10]1[C:18]([OH:25])([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:26]2[C:27](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:28]1=[O:29]
Reactant: O=C(Cl)c1ccccc1C(=O)c1ccccc1
Reactant: NCCc1ccccc1F
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(O)(c2ccccc2)N1CCc1ccccc1F

Procedure:
At room temperature, 0.31 g (2.2 mmol) of 2-(2-fluorophenyl)ethylamine and 0.22 g (2.2 mmol) of triethylamine in 10 ml of absolute toluene were admixed dropwise with a solution of 0.49 g (2.0 mmol) of 2-benzoylbenzoyl chloride in 10 ml of absolute toluene. The reaction mixture was heated under eflux for 3 h. After cooling, the turbid solution was admixed with 20 ml of water. The organic phase was separated off, diluted with 20 ml of toluene and washed three times with 1 M hydrochloric acid. To complete the extraction, the combined aqueous phases were extracted with diethyl ether. The combined organic phases were washed three times with 1 M aqueous sodium hydroxide solution and once with saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness using a rotary evaporator. The residue was recrystallized from toluene. The resulting colorless crystalline product was filtered off with suction and dried. Yield: 53 g. M.p.: 208° C.
Reaction SMILES: S1CCSC1.C(C(N[C@H](C(N[C@H:30]([C:38]([O:40][CH2:41][CH3:42])=[O:39])CC1C=CC=CC=1)=O)CC(C)C)=O)(C1C=CC=CC=1)C1C=CC=CC=1.NCCCN1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1>>[CH3:42][CH2:41][O:40][C:38]([CH3:30])=[O:39].[CH3:48][CH2:49][O:50][CH2:51][CH3:52]
Reactant: NCCCN1CCOCC1
Reactant: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(C)C)NC(=O)C(c1ccccc1)c1ccccc1
Solvent: C1CSCS1
Product: CCOC(C)=O
Product: CCOCC
Yield: 20 %

Procedure:
This compound was synthesized from 1,3-dithiolane derivative of Ph2CHCO-Leu-Phe-COOEt and N-aminopropylmorpholine, and purified by column chromatography using AcOEt followed by crystallization from AcOEt/ether (20% yield). Yellow solid, single spot on TLC, Rf =0.45 (AcOET/CH3OH 9:1), mp 158°-160° C. 1H NMR (CDCl3) ok, MS (FAB) m/e=627 (M+1). Anal: calcd. for C37H46N4O5, 626; C, 70.90; H, 7.40; N, 8.94. Found, C, 70.05; H, 7.43; N, 8.68.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:24][CH2:25][NH:26][C:27](=[O:31])[CH2:28][C:29]#[N:30])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.[CH2:32]1[CH:34]([CH:35](O)C#N)[CH2:33]1.N1CCCCC1.O>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:24][CH2:25][NH:26][C:27](=[O:31])[C:28]([C:29]#[N:30])=[CH:35][CH:34]3[CH2:32][CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12
Reactant: N#CCC(=O)NCCn1nc(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc21
Reactant: N#CC(O)C1CC1
Solvent: O
Solvent: CO
Solvent: C1CCNCC1
Product: N#CC(=CC1CC1)C(=O)NCCn1nc(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc21
Yield: 32.2 %

Procedure:
A solution of N-(2-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-2-cyanoacetamide (90 mg, 0.22 mole), cyclopropylcarboxaldehyde (18 mg, 0.26 mmole) and piperidine (22 mg, 0.26 mmole) in MeOH (5 mL) was stirred for 3 hr at room temperature. Then water was added and extracted with ethyl acetate. The organic layers were combined and washed with aq. NaHCO3 and brine, then dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography (3% MeOH/DCM) to provide 39 mg (38% yield) of the title compound as a white solid. LCMS m/z 466 (M+H)+.
Reaction SMILES: ClC1C=C(N=C=O)C=C(Cl)C=1.C([O:14][C:15](=[O:36])[C@:16]1([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=2)[CH2:20][CH2:19][CH2:18][N:17]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])C.[Li+].[OH-].C1COCC1>O.CO>[C:24]([O:23][C:21]([N:17]1[CH2:18][CH2:19][CH2:20][C@@:16]1([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=1)[C:15]([OH:36])=[O:14])=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CCOC(=O)[C@]1(Cc2ccc(Br)cc2)CCCN1C(=O)OC(C)(C)C
Agent: O=C=Nc1cc(Cl)cc(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@]1(Cc1ccc(Br)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 108 %

Procedure:
means resin polymer.) (1) A mixture of N-(tert-butoxycarbonyl)-2-(4-bromobenzyl)proline ethyl ester (3.00 g), LiOH (10 mmol), THF (25 mL), MeOH (10 mL) and H2O (5 mL) was stirred at room temperature overnight. The mixture was then heated at 74° C. overnight. The mixture was concentrated in vacuo, and water was added. The mixture was washed with Et2O and the aqueous layer was made acidic with the addition of 1N H2SO4. The aqueous layer was extracted with EtOAc. The EtOAc layer was washed with brine, dried over Na2SO4, and evaporated to give N-(tert-butoxycarbonyl)-2-(4-bromobenzyl)proline (3.02 g). MS (m/z) 284 (MH+-t-Boc); mp: 143.9° C. (2) To a solution of the compound obtained above (2.45 g) in DMF (100 mL) was added Merrifield Resin (4.70 g) and KF (1.1 g). The resulting mixture was stirred under N2 at 80° C. overnight. The resin was filtered, and washed thoroughly with MeOH, H2O and CH2Cl2, then dried in vacuo overnight to yield the resin-bound N-(tert-butoxycarbonyl)-2-(4-bromobenzyl)proline (6.66 g); FTIR (cm−1) 1740, 1697, 1397, 1131, 1011. (3) The compound obtained above was then deprotected using a 50% solution of TFA in CH2Cl2, followed by thorough washing, to give the resin-bound 2-(4-bromobenzyl)proline (6.09 g); FTIR (cm−1) 1722. (4) To the compound obtained above (200 mg) was added a DMF solution of 2,6-dichloro-4-pyridyl isocyanate (5 equiv.). This mixture was shaken at room temperature in a sealed receptacle overnight. The mixture was filtered, and the resin was washed with DMF, water and MeOH, and air-dried to give the resin-bound N-[(2,6-dichloro-4-pyridyl)carbamoyl]-2-(4-bromobenzyl)proline. (5) A solution of DIEA (350 μL) in DMF (5 mL) was added to the compound obtained above, and the resulting mixture was then shaken at 50° C. for 2 hours, then at room temperature overnight. The resin was filtered and washed with MeOH, and the filtrate was evaporated. The residue was purified by reverse phase HPLC (gradient of 0%-70% CH3CN in water) to yield 3-(2,6-dichloro-4-pyridyl)-5-(4-bromobenzyl)-1,3-diazabichclo[3.3.0]octane-2,4-dione (58.0 mg). MS (m/z): 456 (MH+); mp: 76.3° C.;
Reaction SMILES: Br[CH:2]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[NH:18]1[CH2:21][CH:20]([C:22]([C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[CH:29]=2)([OH:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:19]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH:2]([N:18]2[CH2:21][CH:20]([C:22]([C:28]3[CH:29]=[C:30]([F:35])[CH:31]=[C:32]([F:34])[CH:33]=3)([OH:27])[C:23]([CH3:24])([CH3:25])[CH3:26])[CH2:19]2)[C:3]2[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=2)[C:6]#[N:7])=[CH:12][CH:13]=1
Reactant: CC(C)(C)C(O)(c1cc(F)cc(F)c1)C1CNC1
Reactant: N#Cc1cccc(C(Br)c2ccc(Cl)cc2)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(O)(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2cccc(C#N)c2)C1

Procedure:
The reaction mixture of 135 mg (0.44 mmol) of 3-[bromo(4-chlorophenyl)methyl]benzonitrile, 105 mg (0.367 mmol) of 1-azetidin-3-yl-1-(3,5-difluorophenyl)-2,2-dimethylpropan-1-ol (3) and 230 uL (1.32 mmol) of N,N-diisopropylethylamine in 6 mL of acetonitrile was refluxed for 3 h. Then it was concentrated and the residue was dissolved in 5 mL of hexane/ether. 1 mL of 1N HCl in ether was added to above solution to make salt. It was filtered and washed with hexane/ether. The residue was neutralized with base and was purified by silica gel chromatography with hexanes/ethyl acetate to afford one racemic diastereomer of the title compound; Mass Spectrum: m/e=481 (M+1 35Cl) and 483 (M+1 37Cl). Further elution of the column afforded the other racemic diastereomer of the title compound; Mass Spectrum: m/e=481 (M+1 35Cl) and 483 (M+1 37Cl).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12](O)=[O:13])=[CH:11][C:6]=2[N:5]=[C:4]1[NH:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:19]=2[N:20]=1)[CH3:2].[CH3:29][O:30][C:31]([CH3:35])([CH3:34])[CH2:32][NH2:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:29][O:30][C:31]([CH3:35])([CH3:34])[CH2:32][NH:33][C:12]([C:10]1[CH:9]=[CH:8][C:7]2[N:3]([CH2:1][CH3:2])[C:4]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([C:25]([F:26])([F:28])[F:27])[CH:22]=[CH:21][C:19]=4[N:20]=3)=[N:5][C:6]=2[CH:11]=1)=[O:13]
Reactant: CCn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: COC(C)(C)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)NCC(C)(C)OC)ccc21
Yield: 43 %

Procedure:
1-Ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-methoxy-2-methyl-propyl)-amide (78.0 mg) was prepared by following General Procedure F starting from 1-ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (150.0 mg), 2-methoxy-2-methyl-propylamine (50.0 mg), HBTU (200.0 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 493; and 1H NMR (DMSO-d6, 400 MHz): δ 8.25 (1H, br. s), 8.20-8.17 (1H, m), 8.11 (1H, br. s), 7.81 (1H, m), 7.70 (1H, m), 7.57 (1H, m), 4.25 (2H, m), 3.37-3.35 (2H, d), 3.32 (2H, s), 3.18 (3H, s), 1.35-1.32 (3H, t), 1.14 (6H, s).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25]([OH:27])=O)[CH:4]=[N:3]1.[Cl-].[Li+].[CH3:30][O:31][CH2:32][CH2:33][NH:34][CH2:35][CH2:36][O:37][CH3:38].C(N(C(C)C)CC)(C)C.CCCP(=O)=O>O1CCCC1.C(OCC)(=O)C>[CH3:30][O:31][CH2:32][CH2:33][N:34]([CH2:35][CH2:36][O:37][CH3:38])[C:25]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[C:7]([NH:8][C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:17]=[C:11]2[CH:10]=1)=[O:24])=[O:27]
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Reactant: COCCNCCOC
Agent: CCCP(=O)=O
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCCN(CCOC)C(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 84.8 %

Procedure:
A suspension of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid with 1 eq. lithium chloride (80 mg, 0.198 mmol), bis(2-methoxyethyl)amine (87 ul, 0.59 mmole), diisopropylethylamine (104 ul, 0.59 mmol) and propylphosphonic anhydride (50% in ethyl acetate, 291 ul, 0.494 mmol) in tetrahydrofurane (4 ml) is stirred for 2.5 hours at 70° C. giving after 20 min a light yellow solution. The cooled solution is diluted with ethyl acetate, washed once with sat. aqueous sodium carbonate solution, once with 1N aqueous hydrochloric acid, once with brine, dried with magnesium sulfate and the solvent is evaporated to dryness affording N4,N4-bis(2-methoxyethyl)-1-methyl-N5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-4,5-dicarboxamide (80 mg, 84.8%) as a colorless waxy solid. MS: m/z=478.2 (M+H+).
Reaction SMILES: P(OCC)(OCC)(OCC)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH:26]([C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][C:29]=1[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])=O.[F:42][C:43]([F:55])([F:54])[C:44]1[CH:45]=[C:46]([NH:50][C:51]([NH2:53])=[O:52])[CH:47]=[CH:48][CH:49]=1.[C:56]([O:62][CH2:63][CH:64]=[CH2:65])(=[O:61])[CH2:57][C:58]([CH3:60])=O>CC(OC)(C)C>[C:32]([C:31]1[CH:34]=[CH:35][C:28]([CH:26]2[C:57]([C:56]([O:62][CH2:63][CH:64]=[CH2:65])=[O:61])=[C:58]([CH3:60])[N:50]([C:46]3[CH:47]=[CH:48][CH:49]=[C:44]([C:43]([F:54])([F:55])[F:42])[CH:45]=3)[C:51](=[O:52])[NH:53]2)=[C:29]([S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])[CH:30]=1)#[N:33]
Reactant: NC(=O)Nc1cccc(C(F)(F)F)c1
Reactant: CC(C)S(=O)(=O)c1cc(C#N)ccc1C=O
Reactant: C=CCOC(=O)CC(C)=O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: COC(C)(C)C
Solvent: CCOP(=O)(OCC)OCC
Product: C=CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1S(=O)(=O)C(C)C
Temperature: 90 °C

Procedure:
The reaction was carried out under argon. Triethyl phosphate (1.049 g, 5.76 mmol) and diphosphorus pentoxide (0.454 g) were stirred at 40° C. overnight. The mixture was then diluted with MTBE (25 ml), and 4-formyl-3-[(1-methylethyl)sulfonyl]benzonitrile (0.759 g, 3.2 mmol), 1-[3-(tri-fluoromethyl)phenyl]urea (0.653 g, 3.2 mmol) and allyl acetoacetate (0.682 g, 4.8 mmol; 1.5 eq.) were added. The mixture was stirred under reflux for 6 h. The reaction mixture was then concentrated by distillative removal of MTBE and subsequently heated at 90° C. for a further 2 h. For work-up, residual solvent was removed under reduced pressure and the residue was suspended in MTBE (20 ml) and then filtered off with suction. The solid was washed with MTBE (2×10 ml). This gave 1.25 g (48% of theory) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[CH2:9]2)=[CH:4][CH:3]=1.Cl[C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>>[O:1]=[C:2]1[CH2:11][C:10]2[CH:9]=[C:8]([O:12][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=3)[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: O=C1CCc2ccc(O)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CC(=O)CC3)nc1
Yield: 22.7 %

Procedure:
Using a method similar to Example A, using 7-hydroxy-2-tetralone (1.88 g, 11.6 mmol), 6-chloronicotinamide (1.81 g, 11.6 mmol) and K2CO3 (2.40 g, 17.4 mmol) gives the title compound (742 mg), after purification on silica gel (30% THF/DCM), as an amber foam. Mass spectrum (ion spray): m/z=283 (M+1); 1HNMR (DMSO-d6): 8.57 (s, 1H), 8.23 (d, 1H), 8.01 (s, 1H), 7.46 (s, 1H), 7.30 (d, 2H), 7.05 (d, 1H), 6.96 (m, 2H), 3.59 (s, 2H), 3.02 (t, 2H), 2.45 (t, 2H).
Reaction SMILES: C[N:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+]([O-])=O)[C:3]1=O.[S:15]1[CH2:20]CC(=O)[CH2:17][CH2:16]1.N>CO>[N+:8]([C:6]1[CH:7]=[N:2][C:3]2[CH2:17][CH2:16][S:15][CH2:20][C:4]=2[CH:5]=1)([O-:10])=[O:9]
Reactant: Cn1cc([N+](=O)[O-])cc([N+](=O)[O-])c1=O
Reactant: O=C1CCSCC1
Agent: N
Solvent: CO
Product: O=[N+]([O-])c1cnc2c(c1)CSCC2
Yield: 99.5 %

Procedure:
A mixture of 1-methyl-3,5-dinitro-2-pyridone (0.6 g, 3.0 mmol), tetrahydrothiopyran-4-one (0.35 g, 3.0 mmol) and ammonia solution in methanol (2.0 M, 30 mL) was refluxed for 6 h. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The soluble portion was flash chromatographed over silica gel (eluent: 90:10 v/v ethyl acetate-hexane)to give a yellow solid (0.586 g, 99% yield).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[NH:52]1[CH2:57][CH2:56][CH:55]([NH:58][C:59]2[CH:60]=[C:61]([CH:64]=[CH:65][CH:66]=2)[C:62]#[N:63])[CH2:54][CH2:53]1>CN(C=O)C.O>[C:62]([C:61]1[CH:60]=[C:59]([NH:58][CH:55]2[CH2:56][CH2:57][N:52]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:18]3[CH:17]=[C:16]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:20][N:19]=3)=[O:22])[CH2:53][CH2:54]2)[CH:66]=[CH:65][CH:64]=1)#[N:63]
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: N#Cc1cccc(NC2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccc(NC2CCN(C(=O)CNC(=O)c3cc(-c4ccccc4)[nH]n3)CC2)c1
Reaction time: 8 h
Yield: 42 %

Procedure:
DIPEA (135 mg, 1.0 mmol) was added to a stirred of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (150 mg, 0.7 mmol) in DMF (4 mL) followed by HOBt (108 mg, 0.8 mmol) and EDCI.HCl (160 mg, 0.8 mmol). After 2 minutes of stirring 3-(piperidin-4-ylamino)-benzonitrile dihydrochloride (prepared according to Step 2 and 5 of the General Scheme) was added and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with brine and concentrated. The residue was purified by column chromatography (using neutral alumina and 5% MeOH in CHCl3) to afford 91 mg (42% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(3-cyano-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 429.2, 92.9%, 1H NMR (300 MHz, DMSO-d6): δ 8.0 (m, 1H), 7.8 (m, 2H), 7.5 (m, 2H), 7.4 (m, 1H), 7.2 (m, 1H), 7.1 (b, 1H), 6.9 (m, 2H), 6.2 (m, 1H), 4.3 (m, 1H), 4.2 (m, 1H), 3.8 (m, 1H), 3.6 (m, 1H), 3.4 (m, 1H), 2.8 (m, 1H), 2.0 (m, 2H), 1.4 (m, 1H), 1.2 (m, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:13])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.[H][H].C(O)(=O)C.[C:20]([O:23][CH:24]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH3:25])(=[O:22])[CH3:21]>O>[CH3:3][N:4]([CH3:13])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH:21][C:20]([O:23][CH:24]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH3:25])=[O:22])=[CH:7][CH:6]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: [H][H]
Reactant: CCCCCCC(C)OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCC(C)OC(=O)C=Cc1ccc(N(C)C)cc1
Reaction time: 8 h
Yield: 48.1 %

Procedure:
Sodium hydride (1.9 g of an 80% dispersion in oil) was added portionwise with stirring over 0.5 hour to 4-dimethylaminobenzaldehyde (7.46 g) in 2-octyl acetate (153 g) at 25° C. The temperature was raised until a steady evolution of hydrogen began (100° C.) and held at this temperature for eight hours. The cooled mixture was treated with glacial acetic acid (4 ml) and then water (50 ml) added. The upper layer was separated, washed with 10% sodium carbonate solution, water, and dried (MgSO4). The excess of 2-octyl acetate was removed by distillation at 15 mm pressure, and the residue fractionated under high vacuum, yielding 7.3 g 2-octyl 4-dimethylaminocinnamate as a pale amber viscous oil, b.p. 194°-200° C./0.25 mm. After freezing it remelted at -11° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](Cl)=[O:9])[CH2:4][CH2:3]1.Cl.[O:12]1[C:18]2[CH:19]=[CH:20][C:21]([C:23]3[S:27][C:26]([NH:28][C:29](=[O:31])[CH3:30])=[N:25][CH:24]=3)=[CH:22][C:17]=2[CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].CO>CN(C)C=O>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:15]2[CH2:16][C:17]3[CH:22]=[C:21]([C:23]4[S:27][C:26]([NH:28][C:29](=[O:31])[CH3:30])=[N:25][CH:24]=4)[CH:20]=[CH:19][C:18]=3[O:12][CH2:13][CH2:14]2)=[O:9])[CH2:4][CH2:3]1
Reactant: CC1CCN(C(=O)Cl)CC1
Reactant: CC(=O)Nc1ncc(-c2ccc3c(c2)CNCCO3)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncc(-c2ccc3c(c2)CN(C(=O)N2CCC(C)CC2)CCO3)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64150.9 %

Procedure:
4-Methylpiperidine-1-carbonyl chloride (reagent preparation 37) (103 mg, 0.64 mmol) was added to a mixture of N-[5-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1,3-thiazol-2-yl]acetamide hydrochloride, (173 mg, 0.53 mmol) and potassium carbonate (374 mg, 2.7 mmol) in N,N-dimethylformamide (2 mL). The resulting mixture was stirred at room temperature for 18 hours, then methanol (2 mL) was added and concentrated. The residue was diluted with ethyl ether (40 mL), a solid was collected by filtration, and washed with ether and water to give N-(5-{4-[(4-methylpiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}-1,3-thiazol-2-yl)acetamide (140 mg, 0.34 mol, 63% yield), 1H NMR (400 MHz, DMSO-d6): 7.58 (s, 1H), 7.35 to 7.32 (m, 2H), 6.91 (d, 1H), 4.36 (s, 2H), 4.12 (br, 2H), 3.54 to 3.47 (m, 4H), 2.71 to 2.65 (m, 2H), 2.00 (s, 3H), 1.60 to 1.43 (m, 3H), 1.16 to 1.067 (m, 2H), 0.92 (d, 3H); MS (EI) for C21H26N4O3S: 415 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([I:16])=[CH:9][CH:10]=3)[C@:5]3([CH2:21][O:20][CH2:19][C:18](=S)[NH:17]3)[C:4]=2[CH:3]=1.N.[CH3:24][C:25]([O:28][C:29]([O:31]C(OC(C)(C)C)=O)=O)([CH3:27])[CH3:26].CC[N:41](CC)CC>O1CCOCC1.[Hg](Cl)Cl.C(Cl)Cl>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([I:16])=[CH:9][CH:10]=3)[C@@:5]3([N:17]=[C:18]([NH:41][C:29](=[O:31])[O:28][C:25]([CH3:27])([CH3:26])[CH3:24])[CH2:19][O:20][CH2:21]3)[C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CCN(CC)CC
Reactant: S=C1COC[C@]2(N1)c1cc(Br)ccc1Oc1ccc(I)cc12
Agent: Cl[Hg]Cl
Agent: N
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(COC1)c1cc(Br)ccc1Oc1ccc(I)cc12
Reaction time: 1.5 h

Procedure:
In a 350-mL resealable vessel, the (S)-2′-bromo-7′-iodospiro[morpholine-3,9′-xanthene]-5-thione (1.25 g, 2.56 mmol) was dissolved in a dioxane solution of ammonia (0.5 M, 61.5 mL, 30.7 mmol). After the solid had dissolved, mercury(II) chloride (1.043 g, 3.84 mmol) was added. The vessel was sealed and placed in a 55° C. oil bath overnight. The reaction was filtered through Celite, rinsing with DCM (50 mL). The mixture was concentrated to remove the DCM, and Boc2O (0.84 g, 3.84 mmol) and Et3N (0.535 mL, 3.84 mmol) were added. After 1.5 h, the mixture was concentrated, and the residue was purified by chromatography (15% EtOAc/hexanes) to afford impure (S)-tert-butyl 2′-bromo-7′-iodo-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthene]-5-ylcarbamate.
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[C:6]([CH3:12])[CH:7]=[CH:8][C:9]=2[OH:11])[CH2:4][CH2:3]1.[Br:13]Br>C(O)(=O)C>[BrH:13].[NH2:1][CH:2]1[C:10]2[C:5](=[C:6]([CH3:12])[CH:7]=[C:8]([Br:13])[C:9]=2[OH:11])[CH2:4][CH2:3]1
Reactant: Cc1ccc(O)c2c1CCC2N
Reactant: BrBr
Solvent: CC(=O)O
Product: Br
Product: Cc1cc(Br)c(O)c2c1CCC2N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5 Grams of 1-amino-7-hydroxy-4-methylindane was dissolved in 30 ml of acetic acid, then an acetic acid solution containing 1.73 ml of bromine was added and stirred at a room temperature for 1 hour. The crystals precipitated were collected by filtration, and were recrystallized from isopropanol to obtain 2 g of 1-amino-6-bromo-7-hydroxy-4-methylindane hydrobromide in the form of yellow needle-like crystals. Melting point: 178°-190° C. (decomp.) The structure was determined by means of NMR.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[F:16][CH:17]([F:29])[CH2:18][O:19][C:20]1[C:21]([CH3:28])=[CH:22][C:23]([CH2:26][NH2:27])=[N:24][CH:25]=1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:27]([CH2:26][C:23]3[CH:22]=[C:21]([CH3:28])[C:20]([O:19][CH2:18][CH:17]([F:29])[F:16])=[CH:25][N:24]=3)[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: Cc1cc(CN)ncc1OCC(F)F
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: Cc1cc(CN2Cc3c(ccnc3Cl)C2=O)ncc1OCC(F)F
Yield: 72 %

Procedure:
The title compound is prepared in 72% yield (360 mg, pale yellow solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (350 mg, 1.3 mmol, Step-1 of Intermediate-1) and (5-(2,2-difluoroethoxy)-4-methylpyridin-2-yl)methanamine hydrochloride (410 mg, 1.3 mmol, Amine-52) in a similar manner to Intermediate-2.