Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([CH3:12])[N:3]=1.[OH-].[K+].Cl>CC(O)(C)C.CO>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:12])[N:3]=1
Reactant: COC(=O)c1ccc(Cl)nc1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)(C)O
Product: Cc1nc(Cl)ccc1C(=O)O
Temperature: 60 °C

Procedure:
Methyl 6-chloro-2-methylnicotinate (Example 423, Step 2) (900 mg, 4.85 mmol) was taken up in 2-methylpropan-2-ol (48.5 ml) and methanol (48.5 ml) and aqueous 1 molar potassium hydroxide (24.2 ml, 24.2 mmol) was added. The resulting slurry was heated at 60° C. for 4 hours, cooled to room temperature, and hydrochloric acid (1 M in water, 24.2 mL, 24.2 mmol) was added dropwise. The solution was then concentrated under reduced pressure until to afford a white solid, which was taken up in methanol and concentrated under reduced pressure. Water and ethyl acetate were added and the layers were separated. The aqueous layer was extracted with ethyl acetate three times. The combined organic layers were concentrated under reduced pressure to afford the title compound.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[CH3:18][C:19](=[N:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38](=[N:43][O:44][CH3:45])[C:39](OC)=[O:40])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1.ClCCl>CO>[CH3:18][C:19](=[N:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38](=[N:43][O:44][CH3:45])[CH:39]=[O:40])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[CH:21]=1
Reactant: CON=C(C(=O)OC)c1ccccc1ON=C(C)c1cccc(C(F)(F)F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CO
Product: CON=C(C=O)c1ccccc1ON=C(C)c1cccc(C(F)(F)F)c1
Reaction time: 3 h
Yield: 49.1 %

Procedure:
1M diisobutylaluminum hydride/toluene solution (11 ml, 16.5 mmol) was added dropwise to a mixture of methyl 2-[(α-methyl-3-trifluoromethylbenzylidene)aminooxy]-α-methoxyiminophenylacetate (4.83 g, 11.8 mmol) and dichloromethane (47 ml) at −65° C. or lower over 4 minutes, and the mixture was stirred at −78° C. to room temperature for 3 hours. Methanol (7 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The precipitated insoluble materials were removed, and the remaining mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-[(α-methyl-3-trifluoromethylbenzylidene)aminooxy]-α-methoxyiminophenylacetaldehyde (2.11 g, 47.3%) as a colorless
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH:3]=[CH2:4].Cl[CH2:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([OH:13])=[O:12].[H-].[Na+].CC(=C)COCC1C=C(C=CC=1)C(O)=O>>[CH2:1]([O:5][CH2:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([OH:13])=[O:12])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCO
Reactant: O=C(O)c1cccc(CCl)c1
Agent: C=C(C)COCc1cccc(C(=O)O)c1
Agent: [H-]
Agent: [Na+]
Product: C=CCCOCc1cccc(C(=O)O)c1

Procedure:
The reaction of But-3-en-1-ol and 3-chloromethyl-benzoic acid in the presence of sodium hydride was performed as described for Compound 37 to give 3-But-3-enyloxymethyl-benzoic acid as colorless oil. 1H-NMR (400 MHz, d6-DMSO): 7.89 (m, 1 arom.H); 7.84 (m, 1 arom.H); 7.54 (m, 1 arom.H); 7.47 (m, 1 arom.H); 5.80 (m, —CH═CH2); 5.06 (2 d-like, —CH═CH2); 4.61 (s, —OCH2—C6H4); 3.49 (m, CH2—CH—CH2CH2O); 2.31 (m, CH2═CH—CH2CH2O). 13C-NMR (100 MHz, d6-DMSO): 167.14 (—C═O); 139.11; 135.52; 131.72; 130.76; 128.54; 128.27; 128.10; 126.44; 71.17; 69.06; 33.70.
Reaction SMILES: [C:1]([N:3]1[C:11]2[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[C:5]2[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][C:4]1=2)#[CH:2].Br[C:19]1[CH:20]=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O>[CH3:17][N:14]1[CH2:15][CH2:16][C:4]2[N:3]([C:1]#[C:2][C:19]3[CH:20]=[N:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:11]3[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=3[C:5]=2[CH2:13]1
Reactant: C#Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Reactant: Brc1cnc2ccccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2C#Cc2cnc3ccccc3c2)CCN(C)C1

Procedure:
A mixture of 5-ethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (260 mg, 1.160 mmol), 3-bromoquinoline (200 mg, 0.961 mmol), TBAF.3H2O (1.1 g, 3.492 mmol) and dichloro bis(triphenylphosphine) palladium (II) (41 mg, 0.058 mmol) was stirred at 85° C. for 10 min. The reaction mixture was diluted with water and extracted with EtOAc (4×30 mL). The combined organic layer was washed with water (4×30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude product, which was purified by column chromatography using neutral alumina and 0.5% MeOH-DCM to yield 2,8-dimethyl-5-quinolin-3-ylethynyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CDCl3, freebase) δ (ppm): 9.0 (s, 1H), 8.25 (s, 1H), 8.1 (d, 1H), 7.8 (d, 1H), 7.7 (t, 1H), 7.6 (t, 1H), 7.5 (d, 1H), 7.2 (s, 1H), 7.1 (d, 1H), 3.62 (s, 2H), 3.0 (t, 2H), 2.7 (t, 2H), 2.6 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: FC1C=CC([CH2:6][N:7]2CCN3C=C(C(OCC)=O)C(O)=C3C2=O)=CC=1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:46]=[CH:47][C:48]=1[Cl:49])[CH2:29][N:30]1[CH2:35][CH2:34][N:33]2[CH:36]=[C:37]([C:40]([O:42]CC)=O)[C:38]([OH:39])=[C:32]2[C:31]1=[O:45]>>[Cl:25][C:26]1[CH:27]=[C:28]([CH:46]=[CH:47][C:48]=1[Cl:49])[CH2:29][N:30]1[CH2:35][CH2:34][N:33]2[CH:36]=[C:37]([C:40]([NH:7][CH3:6])=[O:42])[C:38]([OH:39])=[C:32]2[C:31]1=[O:45]
Reactant: CCOC(=O)c1cn2c(c1O)C(=O)N(Cc1ccc(Cl)c(Cl)c1)CC2
Reactant: CCOC(=O)c1cn2c(c1O)C(=O)N(Cc1ccc(F)cc1)CC2
Product: CNC(=O)c1cn2c(c1O)C(=O)N(Cc1ccc(Cl)c(Cl)c1)CC2

Procedure:
The title compound was prepared using a procedure similar to that described in Example 5, except that ethyl 2-(4-fluorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-α]pyrazine-7-carboxylate was substituted with ethyl 2-(3,4-dichlorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-α]pyrazine-7-carboxylate (Example 15).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH2:3][CH2:4][S:5]([CH2:8][C:9]#[N:10])(=[O:7])=[O:6].N1[CH2:20][CH2:19][CH2:18][CH:14]1[C:15](O)=O.C1(=O)CCCC1.[BH4-].[Na+].Cl>C(OCC)(=O)C.O.O1CCCC1>[CH:15]1([CH:8]([S:5]([CH2:4][CH2:3][C:2]([F:1])([F:11])[F:12])(=[O:6])=[O:7])[C:9]#[N:10])[CH2:20][CH2:19][CH2:18][CH2:14]1
Reactant: O=C(O)C1CCCN1
Reactant: N#CCS(=O)(=O)CCC(F)(F)F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C1CCCC1
Solvent: O
Solvent: C1CCOC1
Product: N#CC(C1CCCC1)S(=O)(=O)CCC(F)(F)F
Temperature: 0 °C
Reaction time: 6 h
Yield: 359.8 %

Procedure:
A mixture of 1.00 g of (3,3,3-trifluoropropylsulfonyl)acetonitrile, 30 ml of tetrahydrofuran, 0.12 g of DL-proline and 1.01 g of cyclopentanone was heated and stirred for 6 hours under the reflux condition. The reaction mixture was cooled to 0° C., and 0.42 g of sodium borohydride was added thereto. The mixture was stirred at room temperature for 6 hours. After the reaction mixture was cooled to 0° C., 10 ml of water and 30 ml of ethyl acetate were added. While the mixture was stirred, 50 ml of 1N hydrochloric acid was added dropwise thereto, followed by extraction with 30 ml of ethyl acetate twice. Organic layers were combined, washed successively with 30 ml of an aqueous saturated sodium hydrogen carbonate solution and 30 ml of an aqueous saturated sodium chloride solution, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.01 g of 2-cyclopentyl-2-(3,3,3-trifluoropropylsulfonyl)acetonitrile (referred to as the present compound (46)) represented by the following formula (46).
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][N:16]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[C:6]([CH3:21])[CH:5]=[CH:4][C:3]=1[NH2:22].[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29].C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1[C:7]([O:8][C:9]2[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][N:16]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[C:6]([CH3:21])[CH:5]=[CH:4][C:3]=1[NH:22][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][CH:33]=[C:25]([C:24]([F:23])([F:34])[F:35])[CH:26]=1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(N)c(C)c1Oc1ncccc1-c1ccncn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)c(C)c1Oc1ncccc1-c1ccncn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Dissolved 2,4-dimethyl-3-(3-(pyrimidin-4-yl)pyridin-2-yloxy)benzenamine (100 mg, 0.342 mmol) in dichloromethane (1.0 mL), added 3-(trifluoromethyl)benzoyl chloride (107 mg, 0.513 mmol) and triethylamine (0.12 mL). Stirred at ambient temp for 4 hours and then concentrated and purified by reverse-phase HPLC (Gilson, acidic mobile phase) to yield the title compound. MS m/z=465 (M+H)+. Calc'd for C25H19F3N4O2: 464.45.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[CH:4][C:3]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=O)=[CH:9][CH:8]=1.Cl.[Br:18][C:19]1[CH:20]=[CH:21][C:22]([C@H:25]([NH2:27])[CH3:26])=[N:23][CH:24]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([C@H:25]([NH:27][C:14](=[O:16])[CH2:13][C:10]2[CH:9]=[CH:8][C:7]([C:3]3[CH:4]=[N:5][O:6][C:2]=3[CH3:1])=[CH:12][CH:11]=2)[CH3:26])=[N:23][CH:24]=1
Reactant: C[C@@H](N)c1ccc(Br)cn1
Reactant: Cc1oncc1-c1ccc(CC(=O)O)cc1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1oncc1-c1ccc(CC(=O)N[C@H](C)c2ccc(Br)cn2)cc1
Reaction time: 1.5 h

Procedure:
To a solution of 0.20 g (0.921 mmol) [4-(5-methylisoxazol-4-yl)phenyl]acetic acid in 2.00 ml DMF was added 0.22 g (0.92 mmol) (1R)-1-(5-bromopyridin-2-yl)ethanamine hydrochloride salt, 0.16 g (1.20 mmol) HOAT, 0.23 g (1.20 mmol) EDC, and 0.48 mL (2.76 mmol) DIEA. After 1.5 h at room temperature, the reaction mixture was diluted with CH2Cl2, washed three times with water, and washed with brine. The organic layer was dried over NaSO4, filtered and concentrated in vacuo. Purification by flash chromatography (1×14 cm silica gel, linear gradient 38-85% EtOAc:hexane) afforded N-[(1R)-1-(5-bromopyridin-2-yl)ethyl]-2-[4-(5-methylisoxazol-4-yl)phenyl]acetamide. 1H NMR (CDCl3, 400 MHz) 8.53 (d, 1H, J=2.11 Hz); 8.35 (s, 1H); 7.76 (dd, 1H, J=2.38 Hz, 8.33 Hz); 7.35 (s, 4H); 7.13 (d, 1H, J=8.24 Hz); 6.73 (br d, 1H, J=6.32 Hz); 5.11 (m, 1H); 3.61 (s, 2H); 2.58 (s, 3H); 1.42 (d, 3H, J=6.87). Electrospray mass spec M+H=402.0.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13](=[O:20])[N:14]([CH3:19])[CH:15]=[C:16](Br)[CH:17]=2)=[CH:7][CH:6]=1)[CH3:2].[C:22]([C:26]1[CH:50]=[CH:49][C:29]([C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35](B3OC(C)(C)C(C)(C)O3)[C:34]=2[CH3:48])=[O:31])=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13](=[O:20])[N:14]([CH3:19])[CH:15]=[C:16]([C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([NH:32][C:30](=[O:31])[C:29]4[CH:28]=[CH:27][C:26]([C:22]([CH3:23])([CH3:24])[CH3:25])=[CH:50][CH:49]=4)[C:34]=3[CH3:48])[CH:17]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: CCOC(=O)c1ccc(Nc2cc(Br)cn(C)c2=O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1ccc(Nc2cc(-c3cccc(NC(=O)c4ccc(C(C)(C)C)cc4)c3C)cn(C)c2=O)cc1
Temperature: 100 °C
Yield: 77.8 %

Procedure:
A mixture of 4-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)-benzoic acid ethyl ester (2) (380 mg; 1.1 mmol), 4-tert-butyl-N-[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzamide (5) (510 mg; 1.3 mmol), tetrakis(triphenylphosphine)palladium (130 mg; 0.1 mmol), 1N sodium carbonate (1.6 mL; 3.2 mmol), and 1,2-dimethoxyethane (8 mL) was heated at 100° C. in a sealed pressure vessel for 16 h. The mixture was cooled to room temperature, treated with water (70 mL) and extracted with ethyl acetate (3×60 mL). The combined organic extracts were washed with water (1×40 mL) and brine (1×40 mL), dried over sodium sulfate and concentrated in vacuo. The crude residue was purified by flash chromatography (3:1-1:3, hexane/EtOAc, gradient) to give 4-{5-[3-(4-tert-butyl-benzoylamino)-2-methylphenyl]-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino}-benzoic acid ethyl ester (6) as a brown solid (460 mg).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[C:19]([C:21]3[C:32](=[O:33])[N:31]([CH3:34])[C:24]4[N:25]=[C:26](SC)[N:27]=[CH:28][C:23]=4[CH:22]=3)[CH:18]=[CH:17][C:16]=2[F:35])=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][N:37]([CH3:41])[CH2:38][CH2:39][NH2:40]>>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[C:19]([C:21]3[C:32](=[O:33])[N:31]([CH3:34])[C:24]4[N:25]=[C:26]([NH:40][CH2:39][CH2:38][N:37]([CH3:41])[CH3:36])[N:27]=[CH:28][C:23]=4[CH:22]=3)[CH:18]=[CH:17][C:16]=2[F:35])=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cccc(C(C)(C)C)c4)c3)c(=O)n(C)c2n1
Reactant: CN(C)CCN
Product: CN(C)CCNc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cccc(C(C)(C)C)c4)c3)c(=O)n(C)c2n1
Yield: 69.3 %

Procedure:
Using a procedure analogous to Example A1, 1-(3-tert-butylphenyl)-3-(2-fluoro-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (0.200 g, 0.407 mmol) and N,N-dimethylethylenediamine (0.181 mL, 1.65 mmol) were combined to afford 1-(3-tert-butylphenyl)-3-(5-(2-(2-(dimethylamino)ethylamino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)urea (0.150 g, 86% yield) as a light yellow solid. It was converted to corresponding HCl salt by reacting with HCl (4.0 M HCl in dioxane, 1.0 eq.). 1H NMR (400 MHz, DMSO-d6): δ 9.28 (s, 1H), 8.73 (s, 1H), 8.64 (d, J=1.6 Hz, 1H), 8.39 (d, J=7.6 Hz, 1H), 8.04 (s, 1H), 7.93 (s, 1H), 7.43 (s, 1H), 7.28-7.24 (m, 3H), 7.18 (t, J=8.0 Hz, 1H), 6.99 (tt, J=7.6, 0.8 Hz, 1H), 3.74 (broad, 2H), 3.63 (s, 3H), 3.30 (broad, 2H), 2.81 (d, J=4.8 Hz, 6H), 1.25 (s, 9H); MS (ESI) m/z: 532.3 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:3]([Br:18])=[CH:4][C:5]2[NH:11][C:10]3[N:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](=[O:16])[NH:7][C:6]=2[CH:17]=1.[Cl:19][CH2:20][C:21](Cl)=[O:22].C(N(CC)CC)C>O>[Cl:19][CH2:20][C:21]([N:11]1[C:5]2[CH:4]=[C:3]([Br:18])[C:2]([Br:1])=[CH:17][C:6]=2[NH:7][C:8](=[O:16])[C:9]2[CH:15]=[CH:14][CH:13]=[N:12][C:10]1=2)=[O:22]
Reactant: O=C(Cl)CCl
Reactant: O=C1Nc2cc(Br)c(Br)cc2Nc2ncccc21
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1Nc2cc(Br)c(Br)cc2N(C(=O)CCl)c2ncccc21

Procedure:
6,11-Dihydro-8,9-dibromo-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one (0.1 mol) in 300 ml. of water-free dioxane is dissolved by heating to reflux. To the boiling solution is added, dropwise over 30 minutes, a solution of 15. g. (0.14 mol) of chloroacetyl chloride, dissolved in 40 ml. of water-free dioxane, and simultaneously 14.4 (0.14 mol) of triethylamine, dissolved in 30 ml. of water-free dioxane. The mixture is refluxed for 8 hours and then filtered while hot. The filtrate is evaporated in vacuo, and the resulting residue is recrystallized from acetonitrile to give 11-chloroacetyl-8,9-dibromo-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one.
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH:40]=[C:39]([C:41](Cl)=[O:42])[C:38]([CH2:44][CH2:45][CH3:46])=[N:37]2)=[CH:32][CH:31]=1>>[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([N:36]2[CH:40]=[C:39]([C:41]([NH:1][C@H:2]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:3][CH2:4][N:5]3[CH2:10][CH2:9][CH:8]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:12]=4)[CH2:7][CH2:6]3)=[O:42])[C:38]([CH2:44][CH2:45][CH3:46])=[N:37]2)=[CH:34][CH:35]=1
Reactant: CCCc1nn(-c2ccc(Cl)cc2)cc1C(=O)Cl
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Product: CCCc1nn(-c2ccc(Cl)cc2)cc1C(=O)N[C@@H](CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-(4-chlorophenyl)-3-propyl-1H-pyrazole-4-carbonyl chloride: ESMS m/e: 626.3 (M+H)+.
Reaction SMILES: OCCCCCCCCN[C:11]([C:13]1[CH:14]=[C:15]([S:19]([C:22]2[CH:23]=[C:24]3[C:29](=[C:30]([CH3:32])[CH:31]=2)[N:28]=[CH:27][C:26]([C:33]([NH2:35])=[O:34])=[C:25]3[NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=2)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)=[O:12].[NH2:45][C:46]1[CH:97]=[CH:96][C:49]([CH2:50][CH2:51][O:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][N:59]([CH2:67][C@@H:68]([C:77]2[CH:86]=[CH:85][C:84]([O:87][C:88]([O:90][C:91]([CH3:94])([CH3:93])[CH3:92])=[O:89])=[C:83]3[C:78]=2[CH:79]=[CH:80][C:81](=[O:95])[NH:82]3)[O:69][Si:70]([C:73]([CH3:76])([CH3:75])[CH3:74])([CH3:72])[CH3:71])[C:60](=[O:66])[O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[CH:48][CH:47]=1>>[C:91]([O:90][C:88]([O:87][C:84]1[CH:85]=[CH:86][C:77]([C@@H:68]([O:69][Si:70]([C:73]([CH3:76])([CH3:75])[CH3:74])([CH3:72])[CH3:71])[CH2:67][N:59]([CH2:58][CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][O:52][CH2:51][CH2:50][C:49]2[CH:48]=[CH:47][C:46]([NH:45][C:11](=[O:12])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([C:22]4[CH:23]=[C:24]5[C:29](=[C:30]([CH3:32])[CH:31]=4)[N:28]=[CH:27][C:26]([C:33](=[O:34])[NH2:35])=[C:25]5[NH:36][C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=4)(=[O:20])=[O:21])[CH:14]=3)=[CH:97][CH:96]=2)[C:60](=[O:66])[O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[C:78]2[C:83]=1[NH:82][C:81](=[O:95])[CH:80]=[CH:79]2)=[O:89])([CH3:94])([CH3:93])[CH3:92]
Reactant: CC(C)(C)OC(=O)Oc1ccc([C@H](CN(CCCCCCOCCc2ccc(N)cc2)C(=O)OC(C)(C)C)O[Si](C)(C)C(C)(C)C)c2ccc(=O)[nH]c12
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCCO)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(CCOCCCCCCN(C[C@H](O[Si](C)(C)C(C)(C)C)c6ccc(OC(=O)OC(C)(C)C)c7[nH]c(=O)ccc67)C(=O)OC(C)(C)C)cc5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 70, using Intermediate 111 in place of 8-aminooctanol. ES/MS calcd. for C61H75N6O11SSi+ 1127.5. Found m/z=1127.7 (M+H)+.
Reaction SMILES: [C:1]1([CH3:38])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22]([C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:13][CH:12]([NH:29]C(OC(C)(C)C)=O)[C:11]2=[O:37])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1>Cl.O1CCOCC1>[C:1]1([CH3:38])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22]([C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:13][CH:12]([NH2:29])[C:11]2=[O:37])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)c1ccco1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(N)CN2C(=O)c1ccco1
Temperature: 50 °C
Reaction time: 1 h
Yield: 108.5 %

Procedure:
1-(2-Toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-(furan-2-ylcarbonyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (1.00 g) was dissolved in 4N HCl-dioxane (10 ml), the solution was stirred for one hour at 50° C. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water, the solution was washed with diethyl ether, alkalified with saturated aqueous sodium bicarbonate, and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, to thereby obtain 875 mg of the titled compound (Yield: 100%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH3:11])[CH3:10])[N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.CN(C)C=O.[F:24][C:25]1[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=1[NH2:27].Cl.O1CCOCC1.C(O)C(N)(CO)CO.C(=O)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O.C(Cl)(Cl)Cl>[F:24][C:25]1[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=1[NH:27][C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH3:11])[CH3:10])[N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1
Reactant: CC(C)Nc1nc(Cl)nc(Nc2ccccc2)n1
Reactant: Nc1ccccc1F
Agent: Cl
Agent: NC(CO)(CO)CO
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Solvent: ClC(Cl)Cl
Product: CC(C)Nc1nc(Nc2ccccc2)nc(Nc2ccccc2F)n1
Temperature: 80 °C
Reaction time: 7 h

Procedure:
A 14 mg portion of 6-chloro-N-isopropyl-N′-phenyl-1,3,5-triazine-2,4-diamine was dissolved in 800 μl of N-methyl-2-pyrrolidone, and 200 μl of 0.5 mM 2-fluoroaniline N,N-dimethylformamide solution and 50 μl of 4 M hydrochloric acid/dioxane were added thereto and stirred at 80° C. for 7 hours. After cooling down the reaction solution to 60° C., 50 mg (4.27 mmol/g) of PS-trisamine and 50 mg (1.53 mmol/g) of PS-benzaldehyde both manufactured by Algonote were added to the reaction solution and further stirred at 60° C. for 16 hours. The reaction solution was cooled down to room temperature and then mixed with saturated sodium bicarbonate aqueous solution and chloroform and stirred. After filtration of the solution, the organic layer was dried using anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure to obtain 13 mg of N-(2-fluorophenyl)-N′-isopropyl-N″-phenyl-1,3,5-triazine-2,4,6-triamine as a brown resinous substance.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH2:13]([NH:15][C:16]1[CH:24]=[C:23]([I:25])[CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19])[CH3:14]>O1CCOCC1>[CH2:13]([N:15]1[C:16]2[CH:24]=[C:23]([I:25])[CH:22]=[CH:21][C:17]=2[C:18](=[O:20])[O:19][C:2]1=[O:4])[CH3:14]
Reactant: CCNc1cc(I)ccc1C(=O)O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: CCn1c(=O)oc(=O)c2ccc(I)cc21
Temperature: 110 °C
Reaction time: 2 h
Yield: 283 %

Procedure:
0.785 g (2.65 mmol) of triphosgene were added at room temperature to 2.2 g (7.55 mmol) of 2-ethylamino-4-iodo-benzoic acid in 30 ml of dioxane. The reaction mixture was then heated and stirred at 110° C. during 2 hours. The solution was evaporated to dryness and reevaporated twice after 2 additions of 20 ml of toluene to give 2.39 g (7.5 mmol) of a solid.
Reaction SMILES: [CH:1]1([NH:7][S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-])=O)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[Pd]>[NH2:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[S:8]([NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NC1CCCCC1
Agent: [Pd]
Solvent: CO
Product: Nc1ccccc1S(=O)(=O)NC1CCCCC1
Reaction time: 12 h
Yield: 95.6 %

Procedure:
To a solution of N-cyclohexyl-2-nitrobenzenesulfonamide (25.7 g, 90.5 mmol) in methanol (500 mL) was added palladium on carbon (10%). The mixture was stirred under an atmosphere of hydrogen for 12 hours. The catalyst was removed by filtration and the filtrate was evaporated to afford the product 2-amino-N-cyclohexylbenzenesulfonamide (22 g, yield 95.7%). 1H NMR (400 MHz, CDCl3) δ ppm 7.72-7.74 (dd, 1H, J=1.2 Hz, 8.0 Hz), 7.27-7.33 (m, 1H), 6.75-6.82 (m, 2H), 4.84 (s, 3H), 3.05-3.07 (m, 1H), 1.59-1.70 (m, 4H), 1.46-1.50 (m, 1H), 1.08-1.22 (m, 5H).