Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[C:6]([O:10][C:11]([NH:13][CH2:14][C:15]1[C+:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]1[CH2:24][CH:25]=[C:26]([CH3:28])[CH:27]=[C:19]1[C:18]2([CH3:30])[CH3:29])=[O:12])([CH3:9])([CH3:8])[CH3:7].CO[CH:33](OC)[N:34]([CH3:36])[CH3:35].N12CCCN=C1CCCCC2>CN(C)C=O>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[C:6]([O:10][C:11]([NH:13][CH2:14][C:15]1[C+:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]1[CH2:24][CH:25]=[C:26]([CH:28]=[CH:33][N:34]([CH3:36])[CH3:35])[CH:27]=[C:19]1[C:18]2([CH3:30])[CH3:29])=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: COC(OC)N(C)C
Reactant: CC1=CCN2C3=CC=C(CNC(=O)OC(C)(C)C)[C+]=C3C(C)(C)C2=C1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CN(C)C=CC1=CCN2C3=CC=C(CNC(=O)OC(C)(C)C)[C+]=C3C(C)(C)C2=C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(tert-Butoxycarbonylamino-methyl)-8,10,10-trimethyl-10H-pyrido[1,2-a]indolylium perchlorate (34 g, 0.077 mol; Sigma-Aldrich) was placed in 1-L round-bottom, one-necked flask equipped with magnetic stir bar and a reflux condenser. 75 mL of dimethylformamide and 38.5 mL of 1,1-Dimethoxy-N,N-dimethylmethanamine (38.5 mL, 0.290 mol; Aldrich) were added to the flask followed by 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.1 g, 0.0006 mol; Aldrich). The flask was immersed in oil bath with temperature set to 100° C. Stirring was started and continued for 30 min. The flask was cooled to room temperature, the solvent was evaporated in vacuum and the residue was recrystallized from methanol. The yield was 29 g (green crystals, 71% of theory).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:14][N:15]([CH3:17])[CH3:16])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].C(N(CC)CC)C.[CH3:25][N:26]1[C:30]([C:31]2[S:35][C:34]([S:36](Cl)(=[O:38])=[O:37])=[CH:33][CH:32]=2)=[CH:29][C:28]([C:40]([F:43])([F:42])[F:41])=[N:27]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:17][N:15]([CH3:16])[CH2:14][C@H:2]([NH:1][S:36]([C:34]1[S:35][C:31]([C:30]2[N:26]([CH3:25])[N:27]=[C:28]([C:40]([F:41])([F:42])[F:43])[CH:29]=2)=[CH:32][CH:33]=1)(=[O:37])=[O:38])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: Cn1nc(C(F)(F)F)cc1-c1ccc(S(=O)(=O)Cl)s1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nn2C)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To a solution of (R)-benzyl 3-amino-4-(dimethylamino)butanoate (27 mg, 0.086 mmol), triethylamine (50 μL, 0.36 mmol) and DMAP (1 mg, 0.008 mmol) in anhydrous CH2Cl2 (1 mL) was added 5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)thiophene-2-sulfonyl chloride (82 mg, 0.25 mmol). The solution was stirred overnight at room temperature. The solvents were removed in vacuo and the residue was purified by preparatory HPLC. The residue was dissolved into CH2Cl2 (50 mL) and washed with 0.1 N NaOH (5 mL), dried over MgSO4 and concentrated to give the title compound as a white solid (26 mg, 57%). MS ESI 531.2 [M+H]+, calcd for [C22H25F3N4O4S2+H]+ 531.13.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(Cl)Cl.C(O)(C(F)(F)F)=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]2)=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc(Br)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Brc1ccc(CC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of tert-butyl 4-(4-bromobenzyl)piperidine-1-carboxylate (780 mg, 2.2 mmol) in CH2Cl2 (15 mmol), was added TFA (0.5 mL) and the mixture was stirred at rt for 1 h. The solvent was removed in vacuo and the residue dissolved into CH2Cl2 (50 mL), washed with NaOH (0.1M, 10 mL), brine (10 mL), dried over MgSO4 and concentrated to dryness to give the title compound as a beige solid (520 mg, 93%).
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][C@H:16]1[NH:21][C@@H:20]([CH3:22])[CH2:19][N:18]([C:23]2[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=2)[CH2:17]1.C(O)(=O)C>CO>[CH3:22][C@H:20]1[N:21]([CH3:1])[C@@H:16]([CH3:15])[CH2:17][N:18]([C:23]2[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=2)[CH2:19]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCOC(=O)c1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)c1ccc(N2C[C@@H](C)N(C)[C@@H](C)C2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.9 %

Procedure:
Sodium triacetoxyborohydride (5.30 g, 25.00 mmol) was added to ethyl 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzoate (2.62 g, 10 mmol), and acetic acid (1.145 mL, 20.00 mmol) in methanol (15 mL) at 25° C. The resulting solution was stirred at ambient temperature for 18 h. The reaction mixture was quenched with saturated NaHCO3 (15 mL) to pH7 and the crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford an oil. The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford ethyl 4-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)benzoate (1.960 g, 70.9%) as a yellow oil. MS: m/z 277 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13](O)=[O:14])[N:10]=[C:9]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:8]=2)=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[C:36]([NH:39][NH2:40])(=[O:38])[CH3:37]>C1COCC1.CN(C=O)C.O>[C:36]([NH:39][NH:40][C:13](=[O:14])[CH2:12][N:11]1[C:7]([CH2:6][C:5]2[CH:22]=[CH:23][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:8][C:9]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[N:10]1)(=[O:38])[CH3:37]
Reactant: O=C(O)Cn1nc(-c2ccncc2)cc1Cc1ccc(F)cc1
Reactant: CC(=O)NN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)NNC(=O)Cn1nc(-c2ccncc2)cc1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of [5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetic acid (300 mg, 0.96 mmol) in THF (5 mL) and DMF (2 mL) was added CDI (345 mg, 2.12 mmol) and the suspension sonicated for 5 minutes to give a solution that was stirred for 2 hours at room temperature. To this was added acetic hydrazide (210 mg, 2.89 mmol) and the resulting suspension stirred for 18 hours at room temperature. The resulting suspension was diluted with water (50 mL) and the solid filtered off and washed with water (30 mL) and EtOAc (50 mL) to yield pure N′-acetyl-2-[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetohydrazide. This was suspended in THF (5 mL) then Burgess' reagent (279 mg, 1.17 mmol) was added and the mixture heated to reflux for 2 hours. The reaction was cooled to ambient temperature, the volatiles removed in vacuo, and the residue was taken into EtOAc (50 mL) and washed with water (2×50 mL), brine (50 mL), dried over MgSO4, filtered and stripped. The residue was purified by Biotage flash chromatography, eluting with 1-4% MeOH/DCM to afford the title compound as a white solid, 200 mg, 73%. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 8.50-8.68 (2 H, m), 7.52-7.70 (2 H, m), 7.16 (2 H, dd, J=8.59, 5.31 Hz), 6.93-7.08 (2 H, m), 6.44 (1 H, s), 5.40 (2 H, s), 4.08 (2 H, s), 2.47 (3 H, s); m/z (APCI+) for C19H16N5FO 350.1 (M+H)+.
Reaction SMILES: [C:1]([NH2:7])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[S:8](=O)(=[O:11])([OH:10])N>>[CH3:5][C:3]1[O:4][S:8](=[O:11])(=[O:10])[NH:7][C:1](=[O:6])[CH:2]=1
Reactant: CC(=O)CC(N)=O
Reactant: NS(=O)(=O)O
Product: CC1=CC(=O)NS(=O)(=O)O1

Procedure:
cyclizing the acetoacetamide derivative; the process comprises using, as the sulfamic acid derivative in stage (a), a salt of sulfamic acid which is at least partly soluble in the inert organic solvent employed, cyclizing the acetoacetamide-N-sulfonate formed in this stage or the free acetoacetamide-N-sulfonic acid in stage (b) by the action of an at least approximately equimolar amount of SO3, if appropriate in an inert inorganic or organic solvent, to give 6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxide, and then, if desired, also neutralizing with a base, in a stage (c), the product obtained here in the acid form.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:13][CH:12]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27]>C(O)CCC>[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH:27][C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:13][CH:12]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1cccc(Cl)c1
Reactant: Clc1ncnc2[nH]c(-c3ccc(-c4ccccc4)cc3)cc12
Solvent: CCCCO
Product: Clc1cccc(Nc2ncnc3[nH]c(-c4ccc(-c5ccccc5)cc4)cc23)c1
Reaction time: 8 h

Procedure:
A suspension of 220 mg (0.72 mmol) of 4-chloro-6-(biphen-4-yl)-7H-pyrrolo[2,3-d]-pyrimidine and 151 μl (1.44 mmol) of 3-chloro-aniline in 5 ml of butanol is heated at boiling overnight. Cooling, filtering and washing with a large amount of ethanol and, finally, hexane yield the title compound; 1H-NMR (200 MHz, DMSO-d6): 12.46 (sb, 1H), 9.6 (s, 1H), 8.40 (s, 1H), 8.28 (m, 1H), 7.98 (d, J=8, 2H), 7.8 (m, 5H), 7.52 and 7.38 (2t, J=8, each 2H), 7.30 (s, 1H), 7.08 (db, J=8, 1H); MS: (M)+ =397.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]#[N:11])[CH:8]=2)[CH:3]=[CH:2]1.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[CH2:14]>ClCCCl.C(Cl)Cl>[C:10]([C:7]1[CH:8]=[C:9]2[C:4]([C:3]([CH2:14][CH2:13][C:12]([O:16][CH2:17][CH3:18])=[O:15])=[CH:2][NH:1]2)=[CH:5][CH:6]=1)#[N:11]
Reactant: C=CC(=O)OCC
Reactant: N#Cc1ccc2cc[nH]c2c1
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOC(=O)CCc1c[nH]c2cc(C#N)ccc12
Temperature: 120 °C
Reaction time: 2 h

Procedure:
1H-indole-6-carbonitrile (D12) (3.2 g), ferric chloride (3.7 g) and ethyl acrylate (7.3 mL) in DCE (7 mL) was added to a sealed tube. The tube was sealed, and the reaction mixture was stirred at 120° C. for 2 hours. After cooling, the reaction mixture was diluted with DCM. The organic layer was washed with 0.5 M HCl, brine, dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was purified by column chromatography (20% EtOAc in hexane) to afford ethyl 3-(6-cyano-1H-indol-3-yl)propanoate (D106) (3.1 g) as a yellow solid. δH (CDCl3, 400 MHz): 1.24 (3H, t), 2.71 (2H, t), 3.11 (2H, t), 4.14 (2H, q), 7.24 (1H, dd), 7.36 (1H, dd), 7.67 (1H, d), 7.70 (1H, dd), 8.36 (1H, br s). MS (ES): C14H14N2O2 requires 242. found 243.1 (M+H+).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:15]([CH3:19])([CH3:18])[CH2:16][OH:17])[C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])C.[Li+].[OH-]>CO.O>[OH:17][CH2:16][C:15]([N:9]1[C:10]([C:11]([F:12])([F:13])[F:14])=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]1)([CH3:19])[CH3:18]
Reactant: CCOC(=O)c1cnn(C(C)(C)CO)c1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(CO)n1ncc(C(=O)O)c1C(F)(F)F
Yield: 94.9 %

Procedure:
To a solution of 1-(2-hydroxy-1,1-dimethyl-ethyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (328 mg, 1.17 mmol) in methanol (5 mL) and water (5 mL) was added LiOH (34 mg, 1.4 mmol). The reaction mixture was stirred at reflux overnight, and then the solution was concentrated under reduced pressure to remove the methanol. The residue was diluted with water and the solution was acidified to pH=2 with concentrated HCl. The resulting mixture was then extracted with ethyl acetate three times. The combined organic extracts were concentrated in vacuo to give 1-(2-hydroxy-1,1-dimethyl-ethyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (280 mg, 95%), which was used without further purification.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([C:11]2[O:15][N:14]=[C:13]([CH2:16]O)[CH:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O>C1(C)C=CC=CC=1>[Cl:3][CH2:16][C:13]1[CH:12]=[C:11]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[O:15][N:14]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(-c2ccccc2)on1
Solvent: Cc1ccccc1
Solvent: O
Product: ClCc1cc(-c2ccccc2)on1
Temperature: 80 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
Thionyl chloride (7.55 ml) was added to a solution of (5-phenyl-3-isoxazolyl)methanol (12.1 g) in toluene (50 ml) and stirred at 80° C. for 3 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to obtain 3-(chloromethyl)-5-phenylisoxazole (11.8 g, yield 88%) as pale-yellow crystals. m.p. 46-47° C.
Reaction SMILES: C1OC2C(=CC3C=C(CNC(C)CCCCO)C4C(C=3C=2)=CC(OCC2C=CC=CC=2)=CC=4)O1.[CH2:35]1[O:51][C:50]2[C:37](=[CH:38][C:39]3[CH:40]=[C:41]([C:60]([NH:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][C:68]([O:70]C)=[O:69])=O)[C:42]4[C:47]([C:48]=3[CH:49]=2)=[CH:46][C:45]([O:52][CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[CH:44][CH:43]=4)[O:36]1.N>>[CH2:35]1[O:51][C:50]2[C:37](=[CH:38][C:39]3[CH:40]=[C:41]([CH2:60][NH:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][C:68]([OH:70])=[O:69])[C:42]4[C:47]([C:48]=3[CH:49]=2)=[CH:46][C:45]([O:52][CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[CH:44][CH:43]=4)[O:36]1
Reactant: COC(=O)CCCCCNC(=O)c1cc2cc3c(cc2c2cc(OCc4ccccc4)ccc12)OCO3
Agent: CC(CCCCO)NCc1cc2cc3c(cc2c2cc(OCc4ccccc4)ccc12)OCO3
Agent: N
Product: O=C(O)CCCCCNCc1cc2cc3c(cc2c2cc(OCc4ccccc4)ccc12)OCO3

Procedure:
N-(2,3-Methylenedioxy-6-benzyloxy-phenanthr-9-ylmethyl)-5-aminohexanol (13) General procedure f from 10 (95%); white powder; mp 175-177° C.; 1H NMR (400.13 MHz) δ 7.90 (d, J=4 Hz, 1H), 7.86 (d, J=2 Hz, 1H), 7.76 (s, 1H), 7.45 (s, 1H), 7.44 (d, J=4 Hz, 2H), 7.32 (t, J=4 Hz, 2H), 7.26 (m, 1H), 7.24 (dd, J=4 Hz, 2 Hz, 1H), 7.14 (s, 1H), 6.03 (s, 2H), 5.22 (s, 2H), 4.24 (s, 2H), 3.53 (t, J=6 Hz, 2H), 2.72 (t, J=6 Hz, 2H), 1.58 (m, 2H), 1.47 (m, 2H), 1.29 (m, 4H); MS (DCI/NH3) m/e: 458 (M+H)+. Anal. (C29H31O4N) C, H, N.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH:5][NH2:6])=[S:4].[CH2:7]([O:9][CH2:10][CH2:11][C:12](O)=O)[CH3:8]>C(OCC)C>[NH2:1][N:2]1[C:12]([CH2:11][CH2:10][O:9][CH2:7][CH3:8])=[N:6][N:5]=[C:3]1[SH:4]
Reactant: NNC(=S)NN
Reactant: CCOCCC(=O)O
Solvent: CCOCC
Product: CCOCCc1nnc(S)n1N
Reaction time: 1 h

Procedure:
63.6 g (0.6 mole) of thiocarbohydrazide and 100.0 g (0.85 mole) of 3-ethoxypropionic acid are stirred and heated at reflux until solution is achieved. The resultant solution is cooled to room temperature, diluted with 700 ml of diethyl ether and refrigerated for 1 hour. The crude white solid (94.6 g) when filtered and recrystallized from 1200 ml of water, gives 54.6 g of lustrous white plates of 4-amino-5-(2-ethoxyethyl)-4H-1,2,4-triazole-3-thiol. m.p. 123°-124° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10][O:11][CH2:12][C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:40][N:41]([C@@H:58]([C:66](=[O:74])[NH:67][CH2:68][CH:69]1[CH2:73][CH2:72][CH2:71][O:70]1)[CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:42](=[O:57])[C@H:43]([NH:55][CH3:56])[CH2:44][C:45]1[CH:54]=[CH:53][C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:46]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10][O:11][CH2:12][C:13](=[O:15])[N:55]([CH3:56])[C@@H:43]([C:42](=[O:57])[N:41]([CH3:40])[C@@H:58]([C:66](=[O:74])[NH:67][CH2:68][CH:69]1[CH2:73][CH2:72][CH2:71][O:70]1)[CH2:59][C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1)[CH2:44][C:45]1[CH:54]=[CH:53][C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:46]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)NCC1CCCO1
Reactant: CC(C)(COCC(=O)O)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C(=O)COCC(C)(C)NC(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)NCC1CCCO1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.9 %

Procedure:
(2-tert Butoxycarbonylamino-2-methylpropoxy)acetic acid (0.5 g; 2.06 mmol) was dissolved in methylene chloride (10 mL). 1-Hydroxy-7-azabenzotriazole (0.2 g; 1.51 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.30 g; 1.58 mmol) were added. The reaction mixture was stirred for 15 min at room temperature. (2R)-N-Methyl-2-methylamino-3-(2-naphthyl)-N-((1R)-2-phenyl-1-(((tetrahydrofuran-2-yl)methyl)carbamoyl)ethyl)propionamide (0.65 g; 1.37 mmol) and diisopropylethylamine (0.26 mL; 1.51 mmol) were added and the reaction mixture was stirred for 12 hours at room temperature. Methylene chloride (100 mL) was added. The reaction mixture was washed with an aqueous solution of sodium hydrogen sulfate (10%; 50 mL), an aqueous solution of sodium hydrogen carbonate (sat; 50 mL) and dried (magnesium sulfate). The solvent was removed in vacuo and the residue was filtered through silica to afford 0.76 g of (1,1-dimethyl-2-((N-methyl-N-((1R)-1-(N-methyl-N-((1R)-2-phenyl-1-((tetrahydrofuran-2-ylmethyl)carbamoyl)ethyl)-carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)methoxy)ethyl)carbamic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.ClC(OCC)=O.[NH2:20][CH2:21][CH:22]1[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)[CH2:23]1>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:20][CH2:21][CH:22]2[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH:29]3[CH2:30][CH2:31][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH2:34]3)[CH2:23]2)=[O:8])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCOC(CN)C2)CC1
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CN(CC2CCN(C(=O)OC(C)(C)C)CC2)CCO1
Yield: 47.6 %

Procedure:
To a suspension of 4-amino-5-chloro-2-methoxybenzoic acid (27.6 g) in chloroform (200 ml) was added dropwise TEA (16.6 g) at room temperature with stirring. The internal temperature of the reaction solution was ice-cooled, and then thereto was slowly added dropwise ethyl chloroformate (16.3 g) so that the internal temperature did not rise over 5° C. After completion of addition, the mixture was stirred at internal temperature of 0 to 5° C. for 1 hour. To the reaction solution was slowly added dropwise a solution of 2-aminomethyl-4-[1-(tert-butoxycarbonyl)-4-piperidinylmethyl]morpholine (Reference Example 12) (42.9 g) in chloroform (50 ml) so that the internal temperature did not rise over 5° C., and after completion of addition, the mixture was stirred overnight without an ice bath. The reaction solution was sequentially washed with water, 5% aqueous potassium hydroxide solution, water, 5% aqueous solution of citric acid, water and brine. The solution was dried over anhydrous magnesium sulfate, and then the solvent was removed in vacuo. The residue was purified by silica gel column chromatography (eluent: ethyl acetate) to give the titled compound (32.4 g) as an amorphous solid.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[CH2:40])[CH2:4][O:5][C:6]1[CH:39]=[CH:38][C:9]([CH2:10][NH:11][C:12]2[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]3[CH:37]=[CH:36][C:28]([C:29]([O:31]C(C)(C)C)=[O:30])=[CH:27][CH:26]=3)[N:13]=2)=[CH:8][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][CH2:2][C:3](=[CH2:40])[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][NH:11][C:12]2[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:36][CH:37]=3)[N:13]=2)=[CH:38][CH:39]=1
Reactant: C=C(CCl)COc1ccc(CNc2nc(Nc3ccc(C(=O)OC(C)(C)C)cc3)nc(OCC(F)(F)F)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C(CCl)COc1ccc(CNc2nc(Nc3ccc(C(=O)O)cc3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.7 %

Procedure:
To a solution of tert-butyl 4-((4-((4-((2-(chloromethyl)allyl)oxy)benzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzoate (1.3 g) in DCM (8 mL) was added TFA (3 ml). The mixture was stirred at room temperature for 3 hours. All the solvents were removed under vacuum to give 4-(4-(4-(2-(chloromethyl)allyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (1.1 g).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([Cl:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1>>[Cl:23][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: COc1ccc(Br)cc1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3cccnc3Cl)c2)cn1
Product: COc1ccc(C(=O)c2cn(-c3cccc(-c4cccnc4Cl)c3)cn2)cc1

Procedure:
This compound is prepared by method C using compound 12l and 4-bromoanisole
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)(=[O:14])=[O:13].CI.[C:26]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]([CH3:26])[S:12]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)(=[O:14])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)Cc1ccccc1NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)Cc1ccccc1N(C)S(=O)(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 8 h

Procedure:
2-(2-(3,4-Dichlorophenylsulfonamido)phenyl)acetic acid methyl ester (14.3 g, 38.21 mmol) and methyl iodide (8.2 ml, 132.25 mmol) were dissolved in acetone (300 ml); K2CO3 (7.3 g, 52.90 mmol) was added thereto, and stirring was carried out overnight at 40° C. in a closed flask. The suspension was cooled and then filtered, concentrated, filtered over silica gel (eluant DCM) and concentrated.
Reaction SMILES: [N:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([OH:18])=O)=[CH:13][CH:14]=3)[N:9]([C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.[CH3:25][C:26]1[N:30]=[C:29]([C@H:31]([NH2:33])[CH3:32])[O:28][N:27]=1.CN1CCOCC1.ON1C2N=CC=CC=2N=N1>CN(C)C=O>[CH3:25][C:26]1[N:30]=[C:29]([C@H:31]([NH:33][C:16]([C:12]2[CH:11]=[C:10]3[C:15]([C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[N:8][N:9]3[C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)=[CH:14][CH:13]=2)=[O:18])[CH3:32])[O:28][N:27]=1
Reactant: O=C(O)c1ccc2c(N3CCOCC3)nn(-c3ccsc3)c2c1
Reactant: Cc1noc([C@@H](C)N)n1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1noc([C@@H](C)NC(=O)c2ccc3c(N4CCOCC4)nn(-c4ccsc4)c3c2)n1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(morpholin-4-yl)-1-(thiophen-3-yl)-1H-indazole-6-carboxylic acid (20.0 mg, 45.0 μmol), (1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethanamine hydrochloride (18.1 mg, 90 μmol, and N-methylmorpholine (24.8 μL, 226 μmol) in N,N-dimethylformamide (226 μL) were added N-[2-(dimethylamino)ethyl]-N-ethylcarbodiimide hydrochloride (15.1 mg, 79.0 μmol), 1-hydroxy-7-azabenzotriazole (3.1 mg, 23 pawl). The mixture was stirred at 50° C. for 1 h. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.05% ammonium hydroxide) gave the title compound (19 mg). HRMS [M+1] found=439.1545. 1H NMR (400 MHz, DMSO-d6) δ: 9.37 (1H, d, J=7.33 Hz), 8.20 (1H, s), 8.05 (1H, d, 8.57 Hz), 7.77-7.74 (2H, m), 7.64 (1H, dd, J=8.56, 1.33 Hz), 7.56 (1H, 4.58, 2.12 Hz), 5.43-5.37 (1H, m), 3.83 (4H, t, J=4.39 Hz), 3.43 (4H, t, J=4.39 Hz), 2.33 (3H, s), 1.64 (3H, d, J=7.15 Hz).