Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH2:26][CH3:27])[C:3](=[O:25])[C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][NH:8][N:7]1[C:12](=[O:24])[CH2:13][CH2:14][CH2:15][C:16]#[C:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)=[O:5]>CO.O=[Pt]=O>[CH3:1][C:2]([CH3:28])([CH2:26][CH3:27])[C:3](=[O:25])[C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][NH:8][N:7]1[C:12](=[O:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)=[O:5]
Reactant: CCC(C)(C)C(=O)C(=O)C1CCCNN1C(=O)CCCC#Cc1cccnc1
Agent: O=[Pt]=O
Solvent: CO
Product: CCC(C)(C)C(=O)C(=O)C1CCCNN1C(=O)CCCCCc1cccnc1

Procedure:
0.1 g PtO2 was added to a solution of 3,3-dimethyl-1-[2-(6-(3-pyridyl)hex-5 ynoyl)perhydropyridazinyl]pentane-1,2-dione (0.3 g, 0.8 mmol) in 20 ml dry MeOH. The mixture was under hydrogenation at room pressure (1 atm) overnight. The product was obtained as clear oil after filtering the catalyst, concentration and purifying on a silica gel (0.125 g, 41%). Rf=0.18 (EtOAc). 1H NMR (CDCl3, 400 MHz): δ 0.89 (t, 3H, J=7.4); 1.24 (s, 6H); 1.38 (m, 2H); 1.66 (m, 10H); 2.14 (m, 2H); 2.63 (m, 2H); 2.82 (m, 2H); 4.60 (m, 2H); 7.23 (m, 4H). Anal. Calcd. for C22H33N3O3: C, 68.19; H, 8.58; N, 10.84. Found: C, 68.40; H, 8.52; N, 10.62.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1([NH2:10])[CH2:9][O:8][CH2:7]1)C.[CH3:12][NH2:13]>>[NH2:10][C:6]1([CH2:5][C:4]([NH:13][CH3:12])=[O:3])[CH2:9][O:8][CH2:7]1
Reactant: CCOC(=O)CC1(N)COC1
Reactant: CN
Product: CNC(=O)CC1(N)COC1
Yield: 102 %

Procedure:
A solution of (3-Amino-oxetan-3-yl)-acetic acid ethyl ester (CAN 1207175-54-9, 0.3 g, 1.88 mmol) in methanamine 41% aqueous solution (1.86 g, 2.09 ml, 24.5 mmol) was stirred overnight at 60° C. The reaction was evaporated down to dryness and to yield the title compound (278 mg, 102%) as a crude solid which was used without any purification. MS (ESI, m/z): 145.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([OH:24])[CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18](Cl)[N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:26][S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])=[O:28].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([OH:24])[CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18]([N:33]3[CH2:34][CH2:35][N:30]([S:27]([CH3:26])(=[O:29])=[O:28])[CH2:31][CH2:32]3)[N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)Cc2nc(Cl)ncc2Cl)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(O)Cc2nc(N3CCN(S(C)(=O)=O)CC3)ncc2Cl)CC1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A mixture of 4-[2-(2,5-dichloro-pyrimidin-4-yl)-1-hydroxy-ethyl]-piperidine-1-carboxylic acid tert-butyl ester (100 mg), 1-methanesulfonyl-piperazine hydrochloride (70 mg), potassium carbonate (100 mg), and N,N-dimethylformamide (1 mL) is stirred for 4 h at 60° C. After cooling to room temperature ethyl acetate is added. The organic phase is separated, washed with water and brine, dried over MgSO4, and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 50:50→0:100) to give the title compound. LC (method 7): tR=1.46 min; Mass spectrum (ESI+): m/z=504 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:23][C:24]1[CH:40]=[CH:39][C:27]([O:28][C:29]([CH3:38])([CH3:37])[C:30]([O:32]C(C)(C)C)=[O:31])=[CH:26][CH:25]=1)[CH2:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][C:11]=1[C:19]([F:22])([F:21])[F:20])=[O:8].FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:28][C:29]([CH3:38])([CH3:37])[C:30]([OH:32])=[O:31])=[CH:39][CH:40]=1)[CH2:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][C:11]=1[C:19]([F:22])([F:21])[F:20])=[O:8]
Reactant: COCCN(CC(=O)Nc1ccc(C(C)C)cc1C(F)(F)F)Cc1ccc(OC(C)(C)C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCN(CC(=O)Nc1ccc(C(C)C)cc1C(F)(F)F)Cc1ccc(OC(C)(C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.842 g (1.49 mmol) of the compound from Example 3-7 is initially charged in 10 ml of dichloromethane. At room temperature, 10 ml of trifluoroacetic acid are added. The reaction mixture is stirred at room temperature for 2 hours. The mixture is then concentrated under reduced pressure using a rotary evaporator. The residue is taken up in ethyl acetate and washed with water, 20% strength sodium acetate solution, water and saturated sodium chloride solution. The organic phase is dried over magnesium sulphate and freed from the solvent under reduced pressure. The product is purified chromatographically on silica gel (dichloromethane/methanol 30:1) and then dried under reduced pressure. This gives 0.648 g (85% of theory) of the title compound.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]O)(=[O:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:47]I>C(Cl)Cl.C1C=CC=CC=1>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][I:47])(=[O:3])[CH3:2]
Reactant: II
Reactant: CC(=O)OCCCCCCCCCCCCCCCCCO
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: ClCCl
Product: CC(=O)OCCCCCCCCCCCCCCCCCI
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
17-Acetoxy-heptadecanol (4.4 g, 13.99 mmol), Ph3P (4.4 g, 16.78 mmol) and imidazole (1.57 g, 23.08 mmol) were dissolved in the mixture of CH2Cl2 (40 ml) and benzene (20 ml). The mixture was cooled to 0° C. and solid I2 (4.26 g, 16.78 mmol) was added in one portion. The mixture was stirred at 0° C. for 15 min and at room temperature for 30 min. The reaction was quenched by the addition of EtOH (1.5 ml), stirred for 10 min at room temperature, diluted with hexane-EtOAc (1:1) mixture and washed with aqueous NaHCO3—Na2S2O3 solution. The organic extract was dried Na2SO4 and evaporated. Residue was stirred with hexane (300 ml) for 20 min and the suspension was filtered to remove Ph3PO. The filtrate was evaporated and the residue was chromatographed on silica gel in hexane-EtOAc (98:2) to give 17-acetoxy-heptadecyl iodide (5.89 g, 99%).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[OH:12][CH2:13][C:14]1[N:15]([CH3:31])[C:16](=[O:30])[C:17]2[C:22]([C:23]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2>ClCCl.C(OCC)C>[CH3:31][N:15]1[C:14]([CH:13]=[O:12])=[C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:30]
Reactant: Cn1c(CO)c(-c2ccccc2)c2ccccc2c1=O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: Cn1c(C=O)c(-c2ccccc2)c2ccccc2c1=O
Reaction time: 1.75 h
Yield: 69.7 %

Procedure:
A stirred suspension of pyridinium chlorochromate (23.36 g) in dichloromethane (250 ml) was treated with a suspension of 3-hydroxymethyl-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline (19.1 g) in dichloromethane (1000 ml), and stirred for 1.75 hours. Then the reaction mixture was diluted with diethyl ether (3000 ml), stirred for 20 minutes, and filtered through diatomaceous earth. The filter pad was washed with diethyl ether (1000 ml) and the combined filtrate and washings were filtered through a 3 inch thick pad of silica gel. The filtrate was evaporated and the resulting residue was crystallised from ethyl acetate, to give 2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-carbaldehyde (13.22 g) in the form of white crystals, m.p.181°-182° C. [Elemental analysis: C,77.4; H,4.94; N,5.29%; calculated: C,77.6; H,4.98; N,5.32%].
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:16])[NH:10][O:11][CH2:12][C:13]([OH:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C@@H:18]([CH2:41][C:42]([NH:44][C:45]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43])[C:19]([N:21]([CH2:31][C:32]1[C:33]2[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=2[S:35][CH:36]=1)[C@@H:22]([CH3:30])[CH:23]([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])=[O:20]>>[S:35]1[CH:36]=[C:32]([CH2:31][N:21]([C@@H:22]([CH3:30])[CH:23]([O:24][CH2:25][CH3:26])[O:27][CH2:28][CH3:29])[C:19](=[O:20])[C@@H:18]([NH:17][C:13](=[O:15])[CH2:12][O:11][NH:10][C:9]([NH:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:16])[CH2:41][C:42](=[O:43])[NH:44][C:45]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[C:33]2[CH:40]=[CH:39][CH:38]=[CH:37][C:34]1=2
Reactant: O=C(O)CONC(=O)NCc1ccccc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)CONC(=O)NCc1ccccc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-benzylureidooxy)acetic acid (Compound VI-1) 52 mg (0.23 mmol) was coupled with (S)-2-amino-N1-(benzo[b]thiophen-3-ylmethyl)-N1—((S)-1,1-diethoxypropan-2-yl)-N4-tritylsuccinamide (Compound IV-21) 100 mg (0.15 mmol) to obtain the title compound.
Reaction SMILES: Cl.[CH:2]1([NH:9][C:10](=[O:39])[NH:11][C:12]2[C:13]([F:38])=[CH:14][C:15]([CH3:37])=[C:16]([C:18]3[C:19]([CH3:36])=[N:20][C:21]4[C:26]([CH:27]=3)=[CH:25][N:24]=[C:23]([NH:28]C(=O)OC(C)(C)C)[CH:22]=4)[CH:17]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>CO>[NH2:28][C:23]1[CH:22]=[C:21]2[C:26]([CH:27]=[C:18]([C:16]3[C:15]([CH3:37])=[CH:14][C:13]([F:38])=[C:12]([NH:11][C:10]([NH:9][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]4)=[O:39])[CH:17]=3)[C:19]([CH3:36])=[N:20]2)=[CH:25][N:24]=1
Reactant: Cc1cc(F)c(NC(=O)NC2CCCCCC2)cc1-c1cc2cnc(NC(=O)OC(C)(C)C)cc2nc1C
Agent: Cl
Solvent: CO
Product: Cc1cc(F)c(NC(=O)NC2CCCCCC2)cc1-c1cc2cnc(N)cc2nc1C
Temperature: 50 °C
Yield: 75.5 %

Procedure:
Add HCl (6.0 M, 1.058 mL, 6.35 mmol) to a solution of tert-butyl (3-(5-(3-cycloheptylureido)-4-fluoro-2-methylphenyl)-2-methyl-1,6-naphthyridin-7-yl)carbamate (0.331 g, 0.635 mmol) in MeOH (10 mL) and heat at 50° C. for 1 h. Cool to RT, concentrate to dryness, add DCM and TEA and concentrate to dryness again. Add water to the residue, extract with DCM (4×), dry the combined organics over Na2SO4, concentrate to dryness and purify via silica gel chromatography (MeOH/DCM) to afford the title compound (202 mg, 76%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 8.82 (s, 1H), 8.21 (s, 1H), 7.95 (m, 2H), 7.16 (d, J=12.3 Hz, 1H), 6.65-6.62 (m, 2H), 6.39 (s, 2H), 3.62 (s, 1H), 2.28 (s, 3H), 1.95 (s, 3H), 1.76 (m, 2H), 1.44-1.41 (m, 10H); MS (ESI) m/z: 422.2 (M+H+).
Reaction SMILES: [C:1]1([C:7]2([NH:10][C:11]3[C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=[C:13]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([N:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)[CH:22]=4)[CH:12]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:33][C:34](OC(C)=O)=[O:35].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:34]([N:30]1[CH2:31][CH2:32][N:27]([C:23]2[CH:22]=[C:21]([NH:20][C:13]3[CH:12]=[C:11]([NH:10][C:7]4([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[CH2:9][CH2:8]4)[C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:26]=[CH:25][CH:24]=2)[CH2:28][CH2:29]1)(=[O:35])[CH3:33]
Reactant: NC(=O)c1cnc(Nc2cccc(N3CCNCC3)c2)cc1NC1(c2ccccc2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(c2cccc(Nc3cc(NC4(c5ccccc5)CC4)c(C(N)=O)cn3)c2)CC1

Procedure:
To a solution of 4-(1-phenylcyclopropylamino)-6-(3-(piperazin-1-yl)phenylamino)nicotinamide (30 mg, 0.07 mmol) in DCM was added Ac2O (0.0066 mL, 0.07 mmol) and DIPEA (0.024 mL, 0.14 mmol), the mixture was concentrated and purified by preparative HPLC to give 6-(3-(4-acetylpiperazin-1-yl)phenylamino)-4-(1-phenylcyclopropylamino)nicotinamide. MS found for C27H30N6O2 as (M+H)+ 471.4. UV: λ=251.8 nm. 1H NMR: (CD3OD) δ 8.14 (s, 1H), 7.27 (m, 4H), 7.12 (dd, J=8.8, 1.2 Hz, 2H), 6.93 (dd, J=8.4, 2.4 Hz, 1H), 6.72 (s, 1H), 6.56 (dd, J=7.6, 1.2 Hz, 1H), 6.11 (s, 1H), 3.68 (m, 4H), 3.17 (m, 2H), 3.09 (m, 2H), 2.15 (s, 3H), 1.38 (m, 4H) ppm.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([C:14]1[C:15]2[CH:16]=[CH:17][NH:18][C:19]=2[CH:20]=[CH:21][CH:22]=1)=[O:13].O.[OH-].[Na+].C(=O)([O-])[O-].[K+].[K+].[C:32]([NH2:36])([CH3:35])([CH3:34])[CH3:33]>C(O)C.C(OCC)(=O)C>[CH3:33][C:32]([NH:36][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([C:14]1[C:15]2[CH:16]=[CH:17][NH:18][C:19]=2[CH:20]=[CH:21][CH:22]=1)=[O:13])([CH3:35])[CH3:34]
Reactant: O=C(Nc1ccccc1OCCCl)c1cccc2[nH]ccc12
Reactant: CC(C)(C)N
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)NCCOc1ccccc1NC(=O)c1cccc2[nH]ccc12

Procedure:
With stirring at a pressure of 2 bars, a solution of 2.3 g of the product from Step A in 40 ml of ethanol and 37.5 ml of tert-butyl-amine was heated at 120° C. for 24 hours. After dilution with 400 ml of water and 400 ml of ethyl acetate, the solution was alkalized with sodium hydroxide and saturated with potassium carbonate. The mixture was extracted with ethyl acetate and the crystals obtained were triturated with ether to obtain 2.3 g of N-[2-[2-[(1,1-dimethylethyl)amino]ethoxy]phenyl]-1H-indol-4-carboxamide melting at ≃148° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11](=[O:13])[CH3:12])=[N:9][NH:8][C:5]2=[CH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].O>CC#N>[C:25]([O:24][C:22](=[O:23])[CH2:21][N:8]1[C:5]2=[CH:6][N:7]=[C:2]([CH3:1])[CH:3]=[C:4]2[C:10]([C:11](=[O:13])[CH3:12])=[N:9]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(=O)c1n[nH]c2cnc(C)cc12
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(=O)c1nn(CC(=O)OC(C)(C)C)c2cnc(C)cc12

Procedure:
To a solution of 1-(5-methyl-1H-pyrazolo[3,4-c]pyridin-3-yl)-ethanone (1 g, 5.71 mmol) in CH3CN (30 mL) were added potassium carbonate (1.81 g, 13.13 mmol) and tert-butyl bromoacetate (0.927 mL, 6.28 mmol). The reaction mixture was stirred at reflux for 1 h, then poured into water and extracted with EtOAc (×3). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 1:0 to 3:2). TLC, Rf (c-hexane/EtOAC 1:1)=0.25; MS (UPLC/MS): 290 [M+H]+; tR (HPLC conditions f): 1.50 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].N1C=CC=CC=1.[F:22][C:23]([F:29])([F:28])[S:24](O)(=[O:26])=[O:25]>C1(C)C=CC=CC=1>[F:22][C:23]([F:29])([F:28])[S:24]([O:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=1)[C:12]([O:14][CH3:15])=[O:13])(=[O:26])=[O:25]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(OS(=O)(=O)C(F)(F)F)cc(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Into a 5 liter four-necked flask equipped with a thermometer, a Dimroth condenser, a calcium chloride tube and a stirrer, 190.0 g (0.904 moles) of dimethyl 5-hydroxyisophthalate, 3 liters of dehydrated toluene and 214.7 g (2.718 moles) of dehydrated pyridine were placed and the resultant mixture was cooled at −30° C. under stirring. To the cooled mixture, 510.2 g (1.808 moles) of anhydrous trifluoromethanesulfonic acid was slowly added dropwise with sufficient care so that the temperature did not exceed −25° C. It took 1 hour to complete the addition. After the addition was completed, the temperature of the reaction was elevated at 0° C. and the reaction was allowed to proceed for 1 hour. Then, the temperature was elevated to the room temperature and the reaction was allowed to proceed for 5 hours. The obtained reaction mixture was poured into 4 liters of ice water and separated into an aqueous layer and an organic layer. The aqueous layer was treated twice by extraction with 500 ml of toluene and the extract was combined with the organic layer. The obtained organic layer was washed twice with 3 liters of water and dried with 100 g of anhydrous magnesium sulfate. From the resultant mixture, anhydrous magnesium sulfate was removed by filtration and toluene was removed by distillation using a rotary evaporator. After drying under a reduced pressure, 294.0 g of dimethyl 5-trifluoromethanesulfonyloxyisophthalate was obtained as a light yellow solid substance (the yield: 95%). The crude product obtained above was recrystallized from hexane and white needle crystals were obtained. The obtained crystals were used for the next reaction.
Reaction SMILES: [CH3:1][NH2:2].[C:3]([CH:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[S:9][CH2:8][CH2:7]1)(=O)[CH3:4]>C1C=CC=CC=1.CO>[CH3:1][N:2]=[C:3]([CH:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[S:9][CH2:8][CH2:7]1)[CH3:4]
Reactant: CN
Reactant: CC(=O)C1CCSc2[nH]c3ccccc3c21
Solvent: c1ccccc1
Solvent: CO
Product: CN=C(C)C1CCSc2[nH]c3ccccc3c21
Temperature: 100 °C

Procedure:
To a solution of the product (1.70 g) in the above (2) in benzene (36 ml) is added a 30% solution of methylamine in methanol (36 ml). The mixture is heated at 100° C. in a sealed tube for 18 hours and then evaporated to give 4-(1-methyliminoethyl)-2,3,4,9-tetrahydrothiopyrano[2,3-b]indole. The product is dissolved in a mixture of tetrahydrofuran (50 ml) and methanol (50 ml) and sodium borohydride (562 mg) is added thereto with stirring on an ice bath. The mixture is stirred at room temperature for 40 minutes and evaporated. The residue is extracted with ether after addition of some pieces of ice and a 10% aqueous solution of sodium hydroxide. The extract is washed with water, dried and evaporated to give the title compound (1.77 g). Recrystallization from acetone gives colorless prisms melting at 179°-187° C. Yield: 64%.
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH3:4][O:5][C:6]1[CH:17]=[CH:16][CH2:15][C:14]2[C:7]=1[CH:8]=[C:9]1[C:13]=2[C:12](=[O:18])[NH:11][N:10]1[CH2:19][CH:20]([OH:22])[CH3:21]>C(OCC)C.CO>[CH3:3][O:18][C:12]1[C:13]2[C:9](=[CH:8][C:7]3[C:14]=2[CH2:15][CH:16]=[CH:17][C:6]=3[O:5][CH3:4])[N:10]([CH2:19][CH:20]([OH:22])[CH3:21])[N:11]=1
Reactant: COC1=C2C=c3c(c(=O)[nH]n3CC(C)O)=C2CC=C1
Reactant: C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: COC1=C2C=c3c(c(OC)nn3CC(C)O)=C2CC=C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.9 %

Procedure:
A solution of 0.79 g (18.8 mmol) of diazomethane in 56 ml of anhydrous diethyl ether was added while stirring to a solution of 2.44 g (9.37 mmol) of (RS)-1-(7-methoxy-1,4-dihydro-indeno[2,1-c]pyrazol-3-on-1-yl)-propan-2-ol in 80 ml of anhydrous diethyl ether and 50 ml of anhydrous methanol. The mixture was stirred at room temperature for a further 15 hours and subsequently concentrated in a vacuum. 2.08 g (81%) of (RS)-1-(3,7-dimethoxy-1,4-dihydro-indeno[2,1-c]pyrazol-1-yl)-propan-2-ol were obtained as a brown solid which was used directly in the next reaction.
Reaction SMILES: C([Mg]Br)C.[CH3:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1.[CH2:14](Br)[CH:15]=[CH2:16].[Cl-].[NH4+]>CCOCC>[CH3:5][N:6]([CH2:16][CH:15]=[CH2:14])[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1
Reactant: C=CCBr
Reactant: CNc1ccc(Br)cc1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: C=CCN(C)c1ccc(Br)cc1
Reaction time: 0.5 h

Procedure:
280 ml of a solution of ethyl magnesium bromide in ether were added dropwise at less than 20° C. under an inert atmosphere to 50.05 g of N-methyl-4-bromo-aniline and after stirring for 30 minutes, 28 ml of allyl bromide were added thereto over 15 minutes. The mixture was refluxed for 40 minutes and was allowed to cool. 25 ml of a solution N of ethyl magnesium bromide in ether were added thereto dropwise and the mixture was stirred for 25 minutes and poured into iced ammonium chloride solution. The decanted aqueous phase was extracted with methylene chloride and the organic phase was dried and evaporated to dryness to obtain 61.35 g of N-methyl-N-allyl-4-bromo-aniline.
Reaction SMILES: [O:1]=[C:2]1[C@H:8]([CH2:9][C:10]([OH:12])=O)[CH2:7][C:6]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][C:20]3[N:21]=[C:22]4[N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25][CH2:24][N:23]4[CH:35]=3)=[CH:16][C:5]=2[CH2:4][N:3]1[CH2:36][C:37]([F:40])([F:39])[F:38].[CH2:41]([OH:48])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47].[ClH:49].O1CCOCC1>>[ClH:49].[O:1]=[C:2]1[C@H:8]([CH2:9][C:10]([O:48][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:12])[CH2:7][C:6]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][C:20]3[N:21]=[C:22]4[NH:27][CH2:26][CH2:25][CH2:24][N:23]4[CH:35]=3)=[CH:16][C:5]=2[CH2:4][N:3]1[CH2:36][C:37]([F:38])([F:39])[F:40]
Reactant: CCCCCCCO
Reactant: CC(C)(C)OC(=O)N1CCCn2cc(CCOc3ccc4c(c3)CN(CC(F)(F)F)C(=O)[C@H](CC(=O)O)C4)nc21
Agent: Cl
Solvent: C1COCCO1
Product: CCCCCCCOC(=O)C[C@@H]1Cc2ccc(OCCc3cn4c(n3)NCCC4)cc2CN(CC(F)(F)F)C1=O
Temperature: 50 °C
Reaction time: 4 h

Procedure:
70.0 mg (0.124 mmol) of (4S)-3-oxo-8-[2-(8-tert-butoxycarbonyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrimidin-2-yl)ethoxy]-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-4-acetic acid obtained in Example 5-(a) and 88 μL (0.62 mmol) of heptyl alcohol were mixed, 1.55 mL (6.20 mmol) of 4N hydrogen chloride/1,4-dioxane solution was added to the mixture, and the resulting mixture was stirred under nitrogen gas atmosphere at 50° C. for 4 hours.
Reaction SMILES: [CH:1]1([N:7]2[CH2:33][CH2:32][C:9]3([N:13]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([C:21]5[CH:22]=[CH:23][C:24]([C:27]([NH:29][CH3:30])=[O:28])=[N:25][CH:26]=5)=[CH:17][CH:16]=4)[CH2:12][C@H:11](O)[CH2:10]3)[C:8]2=[O:34])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(S(F)(F)[F:41])CC)C>>[CH:1]1([N:7]2[CH2:33][CH2:32][C:9]3([N:13]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([C:21]5[CH:22]=[CH:23][C:24]([C:27]([NH:29][CH3:30])=[O:28])=[N:25][CH:26]=5)=[CH:17][CH:16]=4)[CH2:12][C@@H:11]([F:41])[CH2:10]3)[C:8]2=[O:34])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CNC(=O)c1ccc(-c2ccc(CN3C[C@H](O)CC34CCN(C3CCCCC3)C4=O)cc2)cn1
Reactant: CCN(CC)S(F)(F)F
Product: CNC(=O)c1ccc(-c2ccc(CN3C[C@@H](F)CC34CCN(C3CCCCC3)C4=O)cc2)cn1

Procedure:
5-(4-{[(3R)-7-Cyclohexyl-3-hydroxy-6-oxo-1,7-diazaspiro[4.4]non-1-yl]methyl}phenyl)-N-methylpyridine-2-carboxamide (prepared according to a procedure analogous to that described for the synthesis of Example 42) was treated with diethylaminosulfur trifluoride as outlined in the synthesis of Example 81 to afford the desired product. LC/MS: 465.2 (M+1H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:12]=[CH:11][C:10]=1[C:18]1([OH:29])[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:32]I>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:12]=[CH:11][C:10]=1[C:18]1([O:29][CH3:32])[C:19](=[O:28])[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:26]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc(C2(O)C(=O)c3ccccc3C2=O)c(OCc2ccccc2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(c2ccc(C(C)C)cc2OCc2ccccc2)C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 13 h
Yield: 12 %

Procedure:
2-(2-benzyloxy-4-isopropyl-phenyl)-2-hydroxy-indan-1,3-dione (0.10 g, 0.25 mmol) was completely dissolved in anhydrous DMF (2 ml). This solution was added with sodium hydride (0.007 g, 0.31 mmol) and methyl iodide (0.04 g, 0.28 mmol), and stirred at room temperature for 13 hrs. The reaction mixture was extracted with dichloromethane, and the concentrated organic layer was purified using column chromatography (ethylacetate:hexane=1:4) to afford the title compound (12 mg, 12%).