Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([O:21]C)=O)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C@H:23]2[C@H:27]([OH:28])[C@H:26]([OH:29])[C@@H:25]([C:30]([NH:32][CH2:33][CH3:34])=[O:31])[O:24]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:41]([NH2:44])[CH2:42][NH2:43]>ClCCl>[NH2:43][CH2:42][CH2:41][NH:44][C:19]([C:17]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[C@H:23]2[C@H:27]([OH:28])[C@H:26]([OH:29])[C@@H:25]([C:30]([NH:32][CH2:33][CH3:34])=[O:31])[O:24]2)=[C:10]([NH:9][CH2:8][CH:7]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:18]=1)=[O:21]
Reactant: NCCN
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)OC)nc32)[C@H](O)[C@@H]1O
Solvent: ClCCl
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCN)nc32)[C@H](O)[C@@H]1O
Temperature: 105 °C
Yield: 86.1 %

Procedure:
A mixture of methyl 6-[(2,2-diphenylethyl)amino]-9-{(2R,3R,4S,5S)-5-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-9H-purine-2-carboxylate (Preparation 9) (1.1 g, 2 mmol) and 1,2-ethylenediamine (1.1 g, 18.3 mmol) was heated at 105° C. for 2.5 hours. The mixture was dissolved in a little dichloromethane and purified by column chromatography on silica gel eluting with dichloromethane:methanol:concentrated aqueous ammonia (85:15:1.5, by volume). After evaporation of appropriate fractions the residue was triturated with diethyl ether, filtered and dried to yield the target compound as a white solid, (0.99 g, 86%).
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:14]2[N:19]3[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:22]=[C:18]3[N:17]=[C:16]([NH:29][NH2:30])[CH:15]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[OH:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH:35]=O>C(O)C>[OH:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH:35]=[N:30][NH:29][C:16]1[CH:15]=[C:14]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:19]2[N:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:22]=[C:18]2[N:17]=1
Reactant: O=Cc1cccc(O)c1
Reactant: NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: Oc1cccc(C=NNc2cc(N3CCOCC3)n3nc(-c4ccccc4)cc3n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
There was dissolved, in ethanol (2 mL), trifluoroacetic acid salt of (7-morpholin-4-yl-2-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-hydrazine (25.0 mg, 0.0464 mM), then 3-hydroxy-benzaldehyde (6.2 mg, 0.051 mM) was added to the solution and the mixture was stirred at room temperature for one hour. This reaction liquid was filtered and the resulting solid was purified by the NH-silica gel column chromatography (methanol/methylene chloride=1/20) to thus give the title compound (19.2 mg, yield: quantitative).
Reaction SMILES: [OH-].[Na+].C([O:6][C:7]1[CH:8]=[C:9]([C:21]#[C:22][C:23]2([CH3:37])[CH2:28][CH2:27][C:26]3[C:29]([CH3:36])=[C:30]([OH:35])[C:31]([CH3:34])=[C:32]([CH3:33])[C:25]=3[O:24]2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=O)C.C(O)(=O)C>CO>[OH:6][C:7]1[CH:8]=[C:9]([C:21]#[C:22][C:23]2([CH3:37])[CH2:28][CH2:27][C:26]3[C:29]([CH3:36])=[C:30]([OH:35])[C:31]([CH3:34])=[C:32]([CH3:33])[C:25]=3[O:24]2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(=O)Oc1cc(C#CC2(C)CCc3c(C)c(O)c(C)c(C)c3O2)ccc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1ccc(OCc3ccccc3)c(O)c1)O2
Reaction time: 1.5 h

Procedure:
Sodium hydroxide, 0.12 g (3 mmol), was added to a solution of 0.47 g (1 mmol) of rac-2-{[3-acetyloxy-4-(phenylmethoxy)phenyl]ethynyl}-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol in 10 ml of methanol. The mixture was stirred under argon for 1.5 hours and was then acidified with glacial acetic acid and partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution. The methylene chloride layer was separated, dried and passed over a pad of silica gel. The filtrate was evaporated and the residue was crystallized from ether/hexane to give colorless crystals with m.p. 103°-106°.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:24][C:25]#[CH:26])[C:13]([NH:15][CH:16]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]([OH:19])=O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl-].[N:49]([CH2:52][CH2:53][CH2:54][NH:55][C:56](=[O:65])[CH2:57][CH2:58][CH:59]([NH3+:64])[C:60]([O:62][CH3:63])=[O:61])=[N+:50]=[N-:51].CCN(C(C)C)C(C)C>CN(C=O)C>[N:49]([CH2:52][CH2:53][CH2:54][NH:55][C:56](=[O:65])[CH2:57][CH2:58][CH:59]([C:60]([O:62][CH3:63])=[O:61])[NH:64][C:17](=[O:19])[CH:16]([CH2:20][CH:21]([CH3:23])[CH3:22])[NH:15][C:13](=[O:14])[CH:12]([CH2:24][C:25]#[CH:26])[NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[N+:50]=[N-:51]
Reactant: COC(=O)C([NH3+])CCC(=O)NCCCN=[N+]=[N-]
Reactant: C#CCC(NC(=O)OCc1ccccc1)C(=O)NC(CC(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C#CCC(NC(=O)OCc1ccccc1)C(=O)NC(CC(C)C)C(=O)NC(CCC(=O)NCCCN=[N+]=[N-])C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
To a solution of compound 4 (11.7 g; 31 mmol) in dry DMF (100 mL) was added EDCI (7.25 g; 37.82 mmol), HOBt (5.79 g; 37.82 mmol), and the reaction mixture was stirred at room temperature for 30 min (solution A). In the meantime, to a solution of compound 9 (8.67 g: 31 mmol) in dry DMF (100 mL) kept at 0° C. was added DIEA (10.01 g; 77.7 mmol) and stirred for 30 min (solution B). Solution B was mixed with solution A and the reaction mixture was stirred overnight at room temperature. The solvent was removed on the rotary evaporator and the residue was taken up in ethyl acetate (300 mL) and washed sequentially with saturated sodium bicarbonate (2×75 mL), 5% HCl (2×75 mL) and brine (75 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated, yielding a crude product which was purified using recrystallization to yield 9 as an off white solid (8.3 g; 46% yield). NMR (CDCl3) δ 8.1 (s, 1H), 7.9 (s, 1H), 7.8 (s, 1H), 7.5 (s, 1H) 7.3 (m, 5H), 5.0 (s, 2H), 4.3 (m, 1H), 4.1 (m, 1H), 3.3 (t, 1H), 2.8 (s, 1H), 2.4 (d, 2H), 2.2 (d, 2H), 2.1 (m, 2H), 1.9 (m, 2H), 1.8 (m, 2H), 1.6 (m, 2H), 1.4 (m, 1H), 0.8 (d, 6H)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[N:11]=[N:12][N:13]([C:15]3[CH:29]=[CH:28][C:18]([CH2:19][NH:20]C(=O)OC(C)(C)C)=[CH:17][CH:16]=3)[CH:14]=2)=[N:2]1.C(Cl)[Cl:31].CO>Cl.O1CCOCC1>[ClH:31].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[N:11]=[N:12][N:13]([C:15]3[CH:29]=[CH:28][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=3)[CH:14]=2)=[N:2]1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-n2cc(-c3n[nH]c4ccccc34)nn2)cc1
Reactant: ClCCl
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NCc1ccc(-n2cc(-c3n[nH]c4ccccc34)nn2)cc1
Reaction time: 48 h
Yield: 98 %

Procedure:
A solution of tert-butyl {4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzyl}carbamate (1.17 g; 3.00 mmol; 1.0 eq.) in HCl solution in 1,4-dioxane (7.5 mL, 4N) was stirred at RT. After 48 h, the reaction mixture was concentrated to dryness affording a sticky solid, which was sonicated in a 1:1 mixture of DCM/MeOH. The suspension obtained was concentrated to dryness to afford the title compound as a beige solid (967 mg, 98%). HPLC (Condition A): Rt 2.08 min (purity 95.3%). MS (ESI+): 291.1, MS (ESI−): 289.2. Purification by preparative HPLC of 50 mg of this crude by afforded a pure sample (35 mg): 1H NMR (300 Mz, DMSO-d6) δ: 13.40 (brs, 1H), 9.33 (s, 1H), 8.36 (dt, J=8.2 Hz, J=1.0 Hz, 1H), 8.07 (d, J=8.5 Hz, 2H), 7.68 (d, J=8.5 Hz, 2H), 7.62 (dt, J=8.2 Hz, 1.0 Hz, 1H), 7.47-7.42 (m, 1H), 7.29-7.24 (m, 1H), 4.02 (s, 2H). HPLC (Condition A): Rt 2.06 min (purity 97.5%). MS (ESI+): 291.1, MS (ESI−): 289.1.
Reaction SMILES: [F:1][CH2:2][C:3]([NH:5][C:6]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:7]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[CH3:18])=[O:9])=O.B(F)(F)F.CCOCC>C(O)(=O)C>[F:1][CH2:2][C:3]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[CH3:18])[C:8](=[O:9])[C:7]2[C:6](=[CH:22][CH:21]=[C:20]([N+:23]([O-:25])=[O:24])[CH:19]=2)[N:5]=1
Reactant: Cc1cc(Cl)ccc1NC(=O)c1cc([N+](=O)[O-])ccc1NC(=O)CF
Agent: FB(F)F
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cc1cc(Cl)ccc1-n1c(CF)nc2ccc([N+](=O)[O-])cc2c1=O
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
22.0 g of N-(2-fluoroacetamido-5-nitrobenzoyl)-2-methyl-4-chloroaniline are dissolved in 170 ml of acetic acid, and 20 g of boron trifluoride etherate are added thereto. The mixture is stirred at 95° to 100° C. for 30 minutes. The mixture is cooled and concentrated under reduced pressure to remove acetic acid. Water is added to the residue and the mixture is neutralized with sodium bicarbonate. The mixture is extracted with chloroform, and the extract is washed with water, dried and then concentrated to dryness under reduced pressure. Isopropanol is added to the crystalline residue and the crystals are collected therefrom. The thus-obtained crystals are recrystallized from a mixture of dimethylformamide and ethanol (1:2). 18.5 g of 2-fluoromethyl-3-(2-methyl-4-chlorophenyl)-6-nitro-4(3H)-quinazolinone are obtained as colorless prisms.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=[O:18])[N:10]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:19][C:20]1[C:28]2[NH:27][N:26]=[CH:25][C:24]=2[C:23]2[CH2:29][N:30]([CH2:55][C:56]([CH3:59])([CH3:58])[CH3:57])[C:31](=[O:54])[C@H:32]([CH2:34][C:35](=[O:53])N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)[CH2:33][C:22]=2[CH:21]=1>>[Cl:19][C:20]1[C:28]2[NH:27][N:26]=[CH:25][C:24]=2[C:23]2[CH2:29][N:30]([CH2:55][C:56]([CH3:59])([CH3:58])[CH3:57])[C:31](=[O:54])[C@H:32]([CH2:34][C:35](=[O:53])[N:15]3[CH2:14][CH2:13][CH:12]([N:10]4[CH:11]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[NH:8][C:9]4=[O:18])[CH2:17][CH2:16]3)[CH2:33][C:22]=2[CH:21]=1
Reactant: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Reactant: O=c1[nH]c(-c2ccccc2)cn1C1CCNCC1
Product: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(n3cc(-c4ccccc4)[nH]c3=O)CC2)C1=O
Yield: 46 %

Procedure:
Title compound was prepared from 4-phenyl-1-(piperidin-4-yl)-1H-imidazol-2(3H)-one in a manner analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Material was obtained as white solid in 46% yield. MS m/e (M+H)+=589.2. 1H NMR (500 MHz, DMSO-D6): δ=13.55 (s, 1H), 10.68 (s, 1H), 8.37 (s, 1H), 7.50 (d, J=7.63, 2H), 7.32 (t, J=7.02, 2H), 7.24 (s, 1H), 7.16 (m, 2H), 5.37 (d, J=14.34, 1H), 4.63 (d, J=16.79, 1H), 4.51 (t, J=10.83, 1H), 4.13 (m, 2H), 3.89 (m, 1H), 3.57 (m, 1H), 3.18 (m, 1H), 3.03 (m, 3H), 2.89 (t, J=115.11, 1H), 2.66 (m, 1H), 2.34 (d, J=16.17 1H), 1.84 (m, 3H), 1.60 (m, 1H), 0.73 (d, J=13.73, 9H).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][N:5]=[N:4]1.Br[CH2:9][CH2:10][CH2:11][Cl:12].CO>CN(C=O)C>[Cl:12][CH2:11][CH2:10][CH2:9][N:3]1[CH:7]=[N:6][N:5]=[N:4]1
Reactant: ClCCCBr
Reactant: c1nnn[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: ClCCCn1cnnn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To anhydrous DMF (25 mL) was added NaH (0.70 g, 17.50 mmol, 60%) in one portion in an ice bath, and the mixture was warmed to rt and stirred at rt for 30 min. Then a solution of 1H-tetrazole (1.00 g, 14.28 mmol) in anhydrous DMF (6 mL) was added dropwise to the mixture cooled in an ice bath. The reaction mixture was then warmed to rt and stirred for 1.5 h followed by dropwise addition of 1-bromo-3-chloropropane (2.35 g, 14.93 mmol) to the mixture. The reaction mixture was stirred further at rt overnight. MeOH (1 mL) was added in one portion, and the mixture was filtered. The filtrate was concentrated in vacuo to give the crude product, which was used for next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2].[CH3:16][Si:17]([CH3:27])([CH3:26])[C:18]#[C:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[C:9]2[C:8](=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[NH:11][C:18]([Si:17]([CH3:27])([CH3:16])[CH3:26])=[C:19]2[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:15])[CH3:2]
Reactant: CCOC(=O)c1ccc(N)c([N+](=O)[O-])c1
Reactant: C[Si](C)(C)C#Cc1ccccc1
Product: CCOC(=O)c1cc([N+](=O)[O-])c2[nH]c([Si](C)(C)C)c(-c3ccccc3)c2c1

Procedure:
4-Amino-3-nitro-benzoic acid ethyl ester and trimethyl-phenylethynyl-silane were reacted according to the same procedures as Preparation 19 to give 7-nitro-3-phenyl-2-trimethylsilanyl-1H-indole-5-carboxylic acid ethyl ester.
Reaction SMILES: [NH3:1].[C:2]([C:6]1[N:10]2[CH:11]=[CH:12][N:13]=[C:14](Cl)[C:9]2=[C:8]([C:16]2[CH:25]=[C:24]3[C:19]([CH:20]=[CH:21][C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[N:23]3)=[CH:18][CH:17]=2)[N:7]=1)([CH3:5])([CH3:4])[CH3:3]>N.CC(O)C>[C:2]([C:6]1[N:10]2[CH:11]=[CH:12][N:13]=[C:14]([NH2:1])[C:9]2=[C:8]([C:16]2[CH:25]=[C:24]3[C:19]([CH:20]=[CH:21][C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[N:23]3)=[CH:18][CH:17]=2)[N:7]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: N
Reactant: CC(C)(C)c1nc(-c2ccc3ccc(-c4ccccc4)nc3c2)c2c(Cl)nccn12
Solvent: CC(C)O
Product: CC(C)(C)c1nc(-c2ccc3ccc(-c4ccccc4)nc3c2)c2c(N)nccn12
Temperature: 110 °C

Procedure:
Gaseous NH3 was condensed into a cooled (−78° C.) solution of 7-(3-tert-butyl-8-chloroimidazo[1,5-a]pyrazin-1-yl)-2-phenylquinoline (92.5 mg, 0.224 mmol) in NH3/i-PrOH (2M, 5 mL) in a pressure tube until the volume had doubled. The tube was sealed and heated to 110° C. for 21 h. After excess NH3 and i-PrOH were removed in vacuo, the residue was suspended between CH2Cl2 and water, the layers were separated, and the aqueous layer was extracted with CH2Cl2 (3×15 mL). The combined organic layers were washed with brine (3×25 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by chromatography on silica gel [Jones Flashmaster, 5 g/25 mL cartridge, eluting with MeOH (7N NH3):CH2Cl2 1%→2%], affording the title compound, as a fine yellow solid. 1H NMR (CDCl3, 400 MHz) δ 1.25 (s, 9H), 5.18 (s, —NH2), 7.08 (d, J=4.8 Hz, 1H), 7.45-7.51 (m, 1H), 7.51-7.57 (m, 3H), 7.90-7.97 (m, 3H), 8.17-8.22 (m, 2H), 8.27 (d, J=8.4 Hz, 1H), 8.42-8.44 (m, 1H); MS (ES+): m/z 394.1 (25) [MH+]; HPLC: tR=2.5 min (OpenLynx, polar—5 min).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]([C:15]([OH:17])=O)=[C:13]([CH3:18])[NH:12][C:11](=[O:19])[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[F:20][C:21]1[CH:22]=[C:23]([NH:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([NH2:37])[CH:35]=3)[NH:30][N:29]=2)[CH:24]=[CH:25][CH:26]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:20][C:21]1[CH:22]=[C:23]([NH:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([NH:37][C:15]([C:14]4[CH:9]([C:4]5[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=5)[NH:10][C:11](=[O:19])[NH:12][C:13]=4[CH3:18])=[O:17])[CH:35]=3)[NH:30][N:29]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: Nc1ccc2[nH]nc(Nc3cccc(F)c3)c2c1
Reactant: CC1=C(C(=O)O)C(c2ccc(F)c(F)c2)NC(=O)N1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Nc4cccc(F)c4)c3c2)C(c2ccc(F)c(F)c2)NC(=O)N1

Procedure:
The titled compound was prepared following the procedure of Example 175 using 4-(3,4-Difluoro-phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid, N3-(3-fluoro-phenyl)-1H-indazole-3,5-diamine, PyBroP and diisopropylethylamine in methylene chloride. MS (ESI) m/z=493 [M+H]+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([O:10][CH2:11][C:12]#[CH:13])=[CH:8][C:7]([N:14]2[C:19](=[O:20])[N:18]([CH3:21])[C:17](=[O:22])[CH:16]=[N:15]2)=[C:6]([F:23])[CH:5]=1.[Br:24]Br.O>O1CCCC1>[Cl:3][C:4]1[C:9]([O:10][CH2:11][C:12]#[C:13][Br:24])=[CH:8][C:7]([N:14]2[C:19](=[O:20])[N:18]([CH3:21])[C:17](=[O:22])[CH:16]=[N:15]2)=[C:6]([F:23])[CH:5]=1
Reactant: C#CCOc1cc(-n2ncc(=O)n(C)c2=O)c(F)cc1Cl
Reactant: BrBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(=O)cnn(-c2cc(OCC#CBr)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
To a stirred mixture of 0.05 g (0.002 mole) of sodium hydride in 5 mL of tetrahydrofuran was added a solution of 0.55 g (0.0018 mole) of 2-[4-chloro-2-fluoro-5-(2-propynyloxy)phenyl]-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione (Compound 21, see Example III, Step J) in 5 mL of tetrahydrofuran. To this mixture was added a solution of 0.28 g (0.0018 mole) of bromine in 5 mL of tetrahydrofuran. After complete addition, the reaction mixture was stirred at room temperature for one hour. Water, 5 mL, was added to the mixture, and the total stirred at room temperature for two days. The mixture was partitioned between water and ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to yield 0.45 g of 2-[4-chloro-2-fluoro-5-(3-bromo-2-propynyloxy)phenyl]-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione as a solid (mp 127°-129° C.), Compound 48 in the tables.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[N-:12]=[N+:13]=[N-:14].[Na+].O>CO>[N:12]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)CCCCCBr
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)CCCCCN=[N+]=[N-]
Yield: 103.5 %

Procedure:
A solution of ethyl 6-bromohexanoate (10.0 g, 44.8 mmol), NaN3 (5.83 g, 89.6 mmol) and 25 ml of water in 75 ml of MeOH was refluxed for 3.5 hrs. The MeOH was removed in vacuo and the residue was partitioned between CHCl3 (200 ml) and water (50 ml). The organic layer was separated and washed with water. After drying (Na2SO4) and evaporation of solvent, ethyl 6-azidohexanoate (8.59 g, 100%) was obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[NH:31][C:32]([O:34]C1C=CC=CC=1)=O)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[O:14])[CH:7]=1.[NH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.CN(C)C=O>O>[NH:41]([C:32]([NH:31][C:30]1[CH:29]=[CH:28][C:4]([O:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]([CH:15]3[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])[CH2:19][CH2:20]3)=[O:14])[CH:7]=2)=[CH:3][C:2]=1[Cl:1])=[O:34])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cc(Oc3ccc(NC(=O)Oc4ccccc4)c(Cl)c3)ccn2)CC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cc(Oc3ccc(NC(=O)Nc4ccccc4)c(Cl)c3)ccn2)CC1
Yield: 48.1 %

Procedure:
t-Butyl 4-{[(4-{3-chloro-4-[(phenoxycarbonyl)amino]phenoxy}-2-pyridyl)amino]carbonyl}-1-piperidine carboxylate (250 mg), aniline (84 mg) and dimethylformamide (3 ml) were stirred at 130° C. for 70 minutes. The mixture was returned to room temperature, water was added and extraction was performed with ethyl acetate. Silica gel was added to the extract, the solvent was distilled off under reduced pressure, and the reaction product was adsorbed onto the silica gel. The silica gel was charged into a dry column packed with silica gel, and column purification was performed (hexane:ethyl acetate=1:1, followed by ethyl acetate). The solvent was distilled off under reduced pressure to obtain 120 mg of a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:24][N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:4][N:5]([S:14]([C:17]2[O:18][C:19]([CH:22]=[O:23])=[CH:20][CH:21]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.[CH3:34][Mg]Br.Cl>O1CCCC1>[F:1][C:2]1[C:3]([CH2:24][N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[CH:4][N:5]([S:14]([C:17]2[O:18][C:19]([CH:22]([OH:23])[CH3:34])=[CH:20][CH:21]=2)(=[O:15])=[O:16])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: C[Mg]Br
Reactant: CN(Cc1cn(S(=O)(=O)c2ccc(C=O)o2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC(O)c1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)o1
Reaction time: 2 h
Yield: 86 %

Procedure:
To a solution of tert-butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(5-formyl-2-furyl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (464 mg) in tetrahydrofuran (5 mL) was added a 1.0 mol/L solution (1.3 mL) of methylmagnesium bromide in tetrahydrofuran under ice-cooling and the mixture was stirred for 2 hr. 1 mol/L Hydrochloric acid was added to the reaction mixture and the mixture was further stirred for 1 hr and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→3:2) to give the title compound as a pale-yellow oil (yield 410 mg, 86%).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([CH:24]=[O:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:40])([F:39])[C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:22])[CH3:23])[C:12]([C@H:24]([C:28]3[CH:29]=[CH:30][C:31]([C:34]([F:39])([F:40])[C:35]([F:37])([F:38])[F:36])=[CH:32][CH:33]=3)[OH:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: FC(F)(F)C(F)(F)c1ccc(Br)cc1
Reactant: CC(C)c1nc2c(c(I)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Product: CC(C)c1nc2c(c(I)c1[C@@H](O)c1ccc(C(F)(F)C(F)(F)F)cc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 1-bromo-4-(perfluoroethyl)benzene.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:18]([NH:20][CH:21]3[C:30]4[C:25](=[C:26]([O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:27]=[CH:28][CH:29]=4)[CH2:24][CH2:23][CH2:22]3)[CH3:19])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.IC.[C:40]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:40][N:20]([CH:21]1[C:30]2[C:25](=[C:26]([O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][CH2:22]1)[CH:18]([C:9]1[O:10][C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1)[CH3:19]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)COc1cccc2c1CCCC2NC(C)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc2c1CCCC2N(C)C(C)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Yield: 48.6 %

Procedure:
A solution of 1-[1-(4,5-diphenyloxazol-2-yl)ethylamino]-1,2,3,4-tetrahydro-5-ethoxycarbonylmethoxynaphthalene (0.24 g), iodomethane (77 mg) and K2CO3 (82 mg) in DMF (5 ml) was stirred for 5 hours at room temperature. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine. The dried solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel to give 1-[N-methyl-N-[1-(4,5-diphenyloxazol-2-yl)ethyl]amino]-1,2,3,4-tetrahydro-5-ethoxycarbonylmethoxynaphthalene (0.12 g). MS (m/z): 511 (M+ +1) IR (Film): 1730 cm-1NMR (CDCl3, δ): 1.29 (3H, t, J=7.1 Hz), 1.63 (3H, d, J=7.1 Hz), 1.58-1.88 (3H, m), 1.95-2.18 (1H, m), 2.26 (3H, m), 2.46-2.68 (1H, m), 2.80-3.00 (1H, m), 4.12 (2H, q, J=7.1 Hz), 4.26 (3H, q, J=7.1 Hz), 4.60 (2H, s), 6.56 (1H, d, J=7.9 Hz), 7.11 (1H, dd, J=7.9, 7.9 Hz), 7.26-7.50 (7H, m), 7.59-7.68 (4H, m)