Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].CO.Cl.[NH2:5][C:6]([NH2:8])=[NH:7].Cl.[Cl:10][C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH3:22])[CH:20]=2)[N:15]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][N:24]=2)[CH:14]=1)=[O:12]>COCCOC>[ClH:10].[NH:7]([C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH3:22])[CH:20]=2)[N:15]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][N:24]=2)[CH:14]=1)=[O:12])[C:6]([NH2:8])=[NH:5]
Reactant: Cc1ccc2c(c1)c(C(=O)Cl)cn2-c1nccc2ccccc12
Reactant: N=C(N)N
Agent: Cl
Agent: [Na]
Solvent: COCCOC
Solvent: CO
Product: Cc1ccc2c(c1)c(C(=O)NC(=N)N)cn2-c1nccc2ccccc12
Temperature: 20 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
0.457 g (19.8 mmol) of sodium is added at 20° C. under an argon atmosphere to 60 cm3 of methanol. After complete dissolution, 1.79 g (18.75 mmol) of guanidine hydrochloride are added. After stirring at 20° C. for 2 hours, the reaction mixture is filtered under an argon atmosphere. The filtrate is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is dissolved in 20 cm3 of 1,2-dimethoxyethane. 1.2 g of 3-chlorocarbonyl-1-(isoquinol-1-yl)-5-methyl-1H-indole hydrochloride, suspended in 40 cm3 of 1,2-dimethoxyethane, are subsequently added at 20° C. under an argon atmosphere. After stirring at 20° C. for 17.5 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is triturated in 20 cm3 of water. After stirring at 22° C. for 1 hour, the suspension is filtered and then dried to give a beige-coloured solid which is purified by flash chromatography [eluent: cyclohexane/ethyl acetate (7/3 by volume) and then dichloromethane/methanol/20% aqueous ammonia (18/3/0.5 by volume)]. After concentrating the fractions under reduced pressure, 1.2 g of a beige-coloured solid are obtained, which solid is triturated in 12 cm3 of N hydrochloric acid for 1 hour. After filtering off, the residue is recrystallised under hot conditions from 80 cm3 of methanol to give 0.885 g of 3-guanidinocarbonyl-1-(isoquinol-1-yl)-5-methyl-1H-indole hydrochloride in the form of beige-coloured crystals melting at 268° C. IR spectrum (KBr): 3350, 3092, 1693, 1625, 1524, 1462, 1406, 1216 and 832 cm−1.
Reaction SMILES: FC1C=CC([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][NH:17][C@H:16]([CH3:20])[CH2:15]3)=[CH:10][CH:9]=2)=CC=1.BrC1C=CC([Cl:28])=CC=1>>[Cl:28][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][NH:17][C@H:16]([CH3:20])[CH2:15]2)=[CH:10][CH:9]=1
Reactant: Clc1ccc(Br)cc1
Reactant: C[C@@H]1CN(c2ccc(-c3ccc(F)cc3)cc2)CCN1
Product: C[C@@H]1CN(c2ccc(Cl)cc2)CCN1

Procedure:
The title compound was prepared following the procedure of Intermediate 22 but starting from 1-bromo-4-chlorobenzene. Purification by flash chromatography (CHCl3/MeOH) gave the title compound as a beige solid. M+(ESI): 211.2. HPLC purity: >96%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:3]1.[Cl:14][C:15]1[C:20]([C:21]2[C:25]([C:26](Cl)=[O:27])=[C:24]([CH3:29])[O:23][N:22]=2)=[C:19]([F:30])[CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[CH3:13][O:12][C:10](=[O:11])[CH2:9][CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH:2]([NH:1][C:26]([C:25]2[C:21]([C:20]3[C:19]([F:30])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:14])=[N:22][O:23][C:24]=2[CH3:29])=[O:27])[CH2:3]1
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)Cl
Reactant: COC(=O)CC1CCCCC(N)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CC1CCCCC(NC(=O)c2c(-c3c(F)cccc3Cl)noc2C)C1
Yield: 873.9 %

Procedure:
A solution of 4.4 g (24 mmol) of methyl 2-(3-aminocycloheptyl)acetate, 0.03 g (0.46 mmol) of 3-(6-chloro-2-fluorophenyl)-5-methylisoxazole4-carbonyl chloride, and 0.07 ml (0.5 mmol) of triethylamine in dichloromethane (10 ml) was stirred for 12 hours. The solvent was removed in vacuo and replaced with ethyl acetate. The organic layer was washed with 1N HCl, then aq. NaHCO3, followed by brine and dried. The solvent was removed in vacuo then chromatographed on silica gel with hexane/EtOAc 3/1 to yield 1.7 g of the title compound. MS(ES+)m/z=423.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[C:18](B(O)O)=[CH:19][C:20]([F:23])=[N:21][CH:22]=1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:16][C:17]1[C:18]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([NH:8][CH2:9][CH:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:7]=2)=[CH:19][C:20]([F:23])=[N:21][CH:22]=1
Reactant: Brc1cccc(NCC2CCOCC2)n1
Reactant: OB(O)c1cc(F)ncc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Fc1cc(-c2cccc(NCC3CCOCC3)n2)c(Cl)cn1
Temperature: 25 °C
Yield: 80.8 %

Procedure:
A mixture of 6-bromo-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (C, 271 mg, 1 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (351 mg, 2.000 mmol), PdCl2(dppf).CH2Cl2 adduct (82 mg, 0.100 mmol) in DME (4.5 mL) and 2M Na2CO3 (318 mg, 3.00 mmol) was heated in a sealed tube at about 103° C. for about 2 hr. The mixture then was cooled to ambient temperature, diluted with EtOAc (˜25 mL) and MeOH (˜5 mL), filtered, and concentrated in vacuo to yield a resulting residue. The resulting residue was purified by column chromatography [SiO2, 12 g, EtOAc/heptane=10/90 to 50/50]. Fractions were combined and concentrated in vacuo providing 5′-chloro-2′-fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridin-6-amine (260 mg) as a yellow thick oil. LCMS (m/z): 322.1/323.9 [M+H]+; Retention time=0.60 min.
Reaction SMILES: Br[CH2:2][CH:3]1[N:9]2[C:10](=[O:13])[O:11][N:12]=[C:8]2[CH2:7][CH2:6][CH2:5][CH2:4]1.[O-:14][CH2:15][CH3:16].[Na+]>C(O)C>[CH2:15]([O:14][CH2:2][CH:3]1[N:9]2[C:10](=[O:13])[O:11][N:12]=[C:8]2[CH2:7][CH2:6][CH2:5][CH2:4]1)[CH3:16]
Reactant: CC[O-]
Reactant: O=c1onc2n1C(CBr)CCCC2
Agent: [Na+]
Solvent: CCO
Product: CCOCC1CCCCc2noc(=O)n21

Procedure:
Ex-37) To the product of Example 37a or the product of Example 15 in ethanol is added an ethanolic solution of sodium ethoxide. After thin layer chromatography indicates the reaction is complete, it is concentrated and the residue partitioned between water and an extraction solvent. The dried organic layer is stripped of all solvent and the residue chromatographed to produce the title material.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([N:33]([CH3:42])[CH2:34][C:35]([O:37]C(C)(C)C)=[O:36])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:28])=[C:18]([C:29]([F:32])([F:31])[F:30])[CH:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1.Cl>O1CCOCC1>[CH3:1][O:2][CH2:3][CH:4]([N:33]([CH3:42])[CH2:34][C:35]([OH:37])=[O:36])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:28])=[C:18]([C:29]([F:32])([F:31])[F:30])[CH:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1
Reactant: COCC(c1ccc(-c2noc(-c3ccc(-c4ccccc4C)c(C(F)(F)F)c3)n2)cc1)N(C)CC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COCC(c1ccc(-c2noc(-c3ccc(-c4ccccc4C)c(C(F)(F)F)c3)n2)cc1)N(C)CC(=O)O
Temperature: 80 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
To tert-butyl N-[2-methoxy-1-(4-{5-[2′-methyl-2-(trifluoromethyl)biphenyl-4-yl]-1,2,4-oxadiazol-3-yl}phenyl)ethyl]-N-methylglycinate (0.078 g; 0.13 mmol) was added HCl solution in dioxane (4 M; 4 mL) and the reaction mixture stirred at ambient temperature for 18 hours and at 80° C. for 2 hour. The reaction mixture was allowed to cool and the solvent evaporated in vacuo. The residue was triturated with ether and dried under vacuum. The solid was dissolved in DMSO-d6 and evaporated to afford the title compound as a colourless gum (0.055 g, 75%). 1H NMR: (DMSO-d6/D2O, 400 MHz) δ 8.57 (1H, s), 8.54-8.52 (1H, d, J=8 Hz), 8.24 (2H, d, J=8 Hz), 7.79 (2H, d, J=8 Hz), 7.69 (1H, d, J=8 Hz), 7.40-7.37 (2H, m), 7.33-7.31 (1H, m), 7.19 (1H, d, J=7.2 Hz), 4.78 (1H, m), 4.13-4.10 (1H, m), 3.97 (1H, m), 3.87-3.83 (2H, m), 3.36 (3H, s), 2.75 (3H, s), 2.03 (3H, s). LC/MS (Method B): 526 (M+H)+. HPLC (Method C) Rt 9.13 min (Purity: 98.2%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5](=[O:12])[N:6]([CH3:11])[C:7](=[O:10])[NH:8][N:9]=1.[F:13][C:14]([F:20])([F:19])[CH2:15][CH2:16][CH2:17]I>CN(C=O)C>[Br:3][C:4]1[C:5](=[O:12])[N:6]([CH3:11])[C:7](=[O:10])[N:8]([CH2:17][CH2:16][CH2:15][C:14]([F:20])([F:19])[F:13])[N:9]=1
Reactant: FC(F)(F)CCCI
Reactant: Cn1c(=O)[nH]nc(Br)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c(Br)nn(CCCC(F)(F)F)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
0.85 g (21.3 mmol) of NaH (at 60% in paraffin) are placed in 10 mL of DMF under nitrogen. A solution of 4 g (19.4 mmol) of intermediate 2a in 40 mL of DMF is poured dropwise. The reaction medium is stirred for 1 h at room temperature and then 5 g (21.3 mmol) of 1,1,1-trifluoro-4-iodo-butane are added dropwise, and stirring is then continued for 3 h at room temperature. After dry concentration, the obtained residue is taken up with H2O and extracted with ethyl acetate. After drying on MgSO4, the organic phases are evaporated and the obtained oil is purified by flash chromatography on silica (petroleum ether-AcOEt: 80-20). 5.3 g of crystals corresponding to the compound 4a (yield=87%) are isolated.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([Cl:23])([Cl:22])[CH2:5][N:6]([C:12]1[C:17]([N+:18]([O-])=O)=[CH:16][N:15]=[C:14]([Cl:21])[N:13]=1)[CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1>C(O)(=O)C.[Fe]>[Cl:21][C:14]1[N:15]=[CH:16][C:17]2[NH:18][C:3](=[O:2])[C:4]([Cl:23])([Cl:22])[CH2:5][N:6]([CH:7]3[CH2:11][CH2:10][CH2:9][CH2:8]3)[C:12]=2[N:13]=1
Reactant: COC(=O)C(Cl)(Cl)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Agent: [Fe]
Solvent: CC(=O)O
Product: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC1(Cl)Cl
Reaction time: 0.17 h
Yield: 35.1 %

Procedure:
To a solution of 2.2 g (0.0056 mole) of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-2,2-dichloro-propanoic acid methyl ester (IV-298) in 40 mL of acetic acid was added 2.2 g (0.039 g-atom) of iron powder. The mixture was heated to 80 degrees for 2 hours and then filtered while hot. Water and ethyl acetate were added to the filtrate and the mixture was stirred for 10 minutes and then filtered. The layers were separated. The organic layer was washed successively with ammonium hydroxide and water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with hexane-ethyl acetate (gradient, 95:5-50:50) gave 0.66 g of 2-chloro-9-cyclopentyl-7,7-dichloro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-298).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:26])[CH2:9][NH:10][C@H:11]([CH3:25])[CH2:12][C:13]2[C:21]3[C:16](=[C:17]([C:22](O)=[O:23])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:27][C@H:28]([C:33]([O:35][CH3:36])=[O:34])[CH2:29][CH:30]([CH3:32])[CH3:31].Cl.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:26])[CH2:9][NH:10][C@H:11]([CH3:25])[CH2:12][C:13]2[C:21]3[C:16](=[C:17]([C:22]([NH:27][C@@H:28]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:33]([O:35][CH3:36])=[O:34])=[O:23])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: C[C@H](Cc1c[nH]c2c(C(=O)O)cccc12)NC[C@H](O)c1cccc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CC(C)C)NC(=O)c1cccc2c(C[C@@H](C)NC[C@H](O)c3cccc(Cl)c3)c[nH]c12

Procedure:
A solution of 3-{(2R)-2-[2-(3-chlorophenyl)-(2R)-2-hydroxyethyl-amino]propyl}-1H-indole-7-carboxylic acid (22 mg, 0.059 mmol), L-Leu-OMe.HCl (107 mg, 0.59 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (113 mg, 0.59 mmol), 1-hydroxybenztriazole (80 mg, 0.59 mmol), triethylamine (164 μL, 1.18 mmol) in dimethylformamide (2 mL) is stirred at room temperature for 18 hours. The mixture is diluted with ethyl acetate, washed with a saturated aqueous sodium hydrogen carbonate solution, water, and a saturated brine, dried over sodium sulfate, and concentrated. The residue is purified by silica gel column chromatography (a saturated ammonia solution in chloroform) and preparative reversed phase HPLC (octadecylsilyl, trifluoroacetic acid/acetonitrile/water) to give the desired methyl (2S)-2-[(3-{(2R)-2-[2-(3-chlorophenyl)-(2R)-2-hydroxyethylamino]propyl}-1H-indole-7-carbonyl)amino]-4-methylpentanoate.trifluoroacetate (23 mg, yield: 63%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][NH:11][C:10]([CH3:15])([CH3:14])[CH2:9]1)=O)(C)(C)C.[CH:16]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH2:17]>CO>[CH3:21][S:18]([CH2:16][CH2:17][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C:10]1([CH3:14])[CH3:15])(=[O:20])=[O:19]
Reactant: C=CS(C)(=O)=O
Reactant: CC1(C)CN(C(=O)OC(C)(C)C)CCN1
Solvent: CO
Product: CC1(C)CNCCN1CCS(C)(=O)=O
Temperature: 65 °C
Reaction time: 96 h

Procedure:
A mixture of 3,3-dimethylpiperazine-1-carboxylic acid tert-butyl ester (500 mg, 2.33 mmol) and methyl vinyl sulfone (510 μL, 619 mg, 5.83 mmol) in MeOH (15 mL) was heated to 65° C. for 5.5 h then stirred at room temperature for 96 h. The reaction mixture was concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-3%) affording 1-(2-(Methanesulfonyl)ethyl)-2,2-dimethylpiperazine as a white waxy solid (550 mg, 74%). 1H NMR (CDCl3, 300 MHz): δ 3.47-3.40 (m, 2 H); 3.15 (s, 2 H); 3.09 (t, J=6.4 Hz, 2 H); 3.03 (s, 3 H); 2.89 (t, J=6.4 Hz, 2 H); 2.58-2.50 (m, 2 H); 1.45 (s, 9 H); 1.04 (s, 6 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][O:11][CH3:12])[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[O:15][CH2:16][O:17][CH3:18].CN(C)CCN(C)C.C([Li])CCC.B(F)(F)F.C[CH2:37][O:38]CC>O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C.C(OCC)C.C1C=CC=CC=1.CN(C)C=O>[CH3:1][O:2][C:3]1[C:4]([O:15][CH2:16][O:17][CH3:18])=[CH:5][C:6]([O:13][CH3:14])=[C:7]([O:9][CH2:10][O:11][CH3:12])[C:8]=1[CH:37]=[O:38]
Reactant: COCOc1cc(OC)c(OCOC)cc1OC
Reactant: CCOCC
Agent: CN(C)CCN(C)C
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: COCOc1cc(OC)c(OCOC)c(C=O)c1OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
10 Grams of 1,4-dimethoxy-2,5-bis(methoxymethoxy)benzene was dissolved in 500 ml of anhydrous tetrahydrofuran and 50 ml of hexamethylphosphoric triamide. Next 7 ml of N,N,N',N'-tetramethylethylenediamine (TMEDA) was added thereto, and under argon gas stream, the reaction mixture was cooled to -78° C. Then 30 ml of n-butyllithium (1.6M solution) was added dropwise to the reaction mixture and stirred for 30 minutes. Next, 10 ml of anhydrous N,N-dimethylformamide (DMF) was added, further 0.5 ml of boron trifluoride-diethyl ether (BF3 ·Et2O) (47% ether solution) was added as the reaction accelerator to the reaction mixture, and the mixture was stirred at -78° C. for 2 hours. The temperature of the reaction mixture was elevated to room temperature, then the solvent was removed by evaporation under reduced pressure, to the residue thus obtained was added 300 ml of benzene and 300 ml of diethyl ether, then the organic layer was washed 4 times with 200 ml of water, and further washed three times with 100 ml of a saturated sodium chloride aqueous solution. After concentrated the organic layer under reduced pressure, the resultant residue was treated on a silica gel column chromatography, and eluted with 20% ethyl acetate-n-hexane solution to yield 6 g of 2,5-dimethoxy-3,6-bis(methoxymethoxy)benzaldehyde. Light yellow powdery substance.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])[C:21]([Cl:37])=[CH:20][N:19]=1>>[Cl:37][C:21]1[C:22]([NH:24][C:25]2[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: CNC(=O)c1cccc(OC)c1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: CNC(=O)c1cccc(OC)c1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl

Procedure:
2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-3-methoxy-N-methyl-benzamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-methoxy-N-methyl-benzamide in an analogous manner to Example 313c. Product isolated as a yellow foam (64 mg, 37%). LCMS (m/e) 511 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.05 (s, 1H), 7.71 (s, 1H), 7.33-7.27 (m, 1H), 7.19 (d 1H, J=7.7 Hz), 7.13 (s, 1H), 7.10-7.04 (m, 2H), 6.89 (d, 1H, J=8.1 Hz), 6.85 (s, 1H), 6.04-5.96 (m, 1H), 3.84 (s, 3H), 3.55 (t, 2H, J=5.7 Hz), 3.39 (s, 3H), 2.90-2.84 (m, 2H), 2.79-2.63 (m, 8H), 2.75 (d, 3H, J=4.1 Hz).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[CH:22]=[N:23][C:24](S(C)(=O)=O)=[N:25][CH:26]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.CN1CCCC1=O.[F:38][C:39]1[CH:44]=[CH:43][C:42]([C@@H:45]([NH2:47])[CH3:46])=[CH:41][CH:40]=1.[OH-].[K+]>C(O)(=O)C>[Cl:19][C:17]1[CH:18]=[C:13]2[C:12]([CH2:20][C:21]3[CH:26]=[N:25][C:24]([NH:47][C@H:45]([C:42]4[CH:43]=[CH:44][C:39]([F:38])=[CH:40][CH:41]=4)[CH3:46])=[N:23][CH:22]=3)=[CH:11][NH:10][C:14]2=[N:15][CH:16]=1
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: CS(=O)(=O)c1ncc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: C[C@H](Nc1ncc(Cc2c[nH]c3ncc(Cl)cc23)cn1)c1ccc(F)cc1

Procedure:
In a microwave vial, 1-benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine (132, 12 mg, 0.026 mmol) was mixed with 600 μL of N-methylpyrrolidinone and (S)-1-(4-fluoro-phenyl)-ethylamine (133, 25.2 mg, 0.18 mmol). The reaction was irradiated at 200° C. for 40 minutes in microwave, then potassium hydroxide (500 μL, 4.00 M in water) was added and the reaction irradiated at 90° C. for 10 minutes in microwave. The reaction was neutralized with the addition of 120 μL of acetic acid, solvents were removed under vacuum, and the resulting material was dissolved in 400 μL of dimethyl sulfoxide for purification by HPLC. The desired compound was purified on Phenomenex C18 column (50 mm×10 mm ID) with mobile phase A of 0.1% trifluoroacetic acid in water, mobile phase B of 0.1% trifluoroacetic acid in acetonitrile, 20-100% B over 16 minutes at a flow rate of 6 mL/min. Appropriate fractions were collected and solvents removed under vacuum to provide the desired compound. MS (ESI) [M+H′]′=381.9.
Reaction SMILES: N#N.[OH:3][CH2:4][C:5]1[O:6][CH:7]=[C:8]([C:10](=[O:12])[CH3:11])[N:9]=1.CCN(CC)CC.[S:20](Cl)([CH3:23])(=[O:22])=[O:21]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:10]([C:8]1[N:9]=[C:5]([CH2:4][O:3][S:20]([CH3:23])(=[O:22])=[O:21])[O:6][CH:7]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)c1coc(CO)n1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1coc(COS(C)(=O)=O)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-(2-hydroxymethyl-oxazol-4-yl)-ethanone (45 mg, 0.32 mmol) in dry CH2Cl2 (5.0 mL) was treated at 0° C. with Et3N (0.06 mL, 0.41 mmol) followed by DMAP (3.9 mg, 0.03 mmol) and Ms-Cl (0.03 mL, 0.40 mmol). After stirring at 0° C. for 30 min, the reaction mixture was quenched with water (10 mL), extracted with CH2Cl2 (10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow oil. TLC: rf (EA)=0.63. LC-MS-conditions 02: tR=0.64 min; [M+H]+=220.22.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([OH:17])(=[O:16])[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.O1COCO[CH2:19]1.C([O-])(O)=O.[Na+]>O.C(O)(=O)C>[C:11]([C:10]1[CH:14]=[C:15]2[C:7](=[CH:8][CH:9]=1)[C:6](=[O:17])[O:16][CH2:19]2)([OH:13])=[O:12]
Reactant: C1OCOCO1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccc2c(c1)COC2=O
Temperature: 131.5 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To 892 g of fuming sulfuric acid, containing 25-27% of SO3, 100 g (0.6 m) of terephthalic acid are added at 20-23° C., under stirring, then 46 g (0.5 m) of 1,3,5-trioxane are added portionwise thereto at about 15° C. At the end of the addition, the mixture is heated 2 hours at 130-133° C. whereby a dark, clear solution is obtained. When the reaction is complete, as shown by a HPLC control, the mixture is cooled to 20-22° C. and 210 g of glacial acetic acid are slowly added thereto, without exceeding the temperature of 23-25° C. The mass is cooled to −5-0° C. and 1800 ml of cold deionized water are added thereto. During this operation the temperature rises to 43-45° C. At the end of the addition, the mixture is kept 1 hour under stirring at 23-25° C., then it is filtered, the solid is washed with deionized water abundantly and suspended, still wet, in 1200 ml of deionized water at room temperature. To the suspension thus obtained, about 1550 g of a 7% solution of NaHCO3 are added to a constant pH of 7,6-7,8. The mixture is filtered on Celite®, washing with deionized water. The pH of the filtrate is brought to about 1 by slow addition of about 120 ml of 35% hydrochloric acid at 22-25° C. The suspension is kept 1 hour under stirring at 22-25° C., then it is filtered and washed with deionized water abundantly. The product is dried in vacuo at about 50° C. to give 81 g of 5-carboxyphthalide with a titer (HPLC)>94% and purity (HPLC)>95%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:22][CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[C:6]2[O:29][CH2:30][O:31][C:5]2=[CH:4][CH:3]=1.Cl[CH2:33][C:34]#[N:35]>>[Cl:1][C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:22][CH:23]4[CH2:24][CH2:25][N:26]([CH2:33][C:34]#[N:35])[CH2:27][CH2:28]4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[C:6]2[O:29][CH2:30][O:31][C:5]2=[CH:4][CH:3]=1
Reactant: N#CCCl
Reactant: COc1cc2c(Nc3c(Cl)ccc4c3OCO4)ncnc2cc1OCC1CCNCC1
Product: COc1cc2c(Nc3c(Cl)ccc4c3OCO4)ncnc2cc1OCC1CCN(CC#N)CC1

Procedure:
Using an analogous procedure to that described in Example 12, 4-(6-chloro-2,3-methylenedioxyanilino)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline was reacted with 2-chloroacetonitrile to give the title compound as a solid; NMR Spectrum: (DMSOd6) 1.65 (m, 2H), 2.1 (m, 2H), 2.2 (m, 1H), 3.15 (m, 2H), 3.6 (m, 2H), 4.05 (s, 3H), 4.15 (m, 2H), 4.55 (s, 2H), 6.15 (s, 2H), 7.05 (d, 1H), 7.15 (d, 1H), 7.4 (s, 1H), 8.15 (s, 1H), 8.9 (s, 1H); Mass Spectrum: M−H− 480 and 482.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([N:11]2[CH2:18][CH:17]3[CH:13]([CH2:14][NH:15][CH2:16]3)[CH2:12]2)[N:4]=1.[F:19][C:20]1[CH:21]=[CH:22][C:23]([N:29]2[N:33]=[CH:32][CH:31]=[N:30]2)=[C:24]([CH:28]=1)[C:25](O)=[O:26]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([N:11]2[CH2:18][CH:17]3[CH:13]([CH2:14][N:15]([C:25]([C:24]4[CH:28]=[C:20]([F:19])[CH:21]=[CH:22][C:23]=4[N:29]4[N:33]=[CH:32][CH:31]=[N:30]4)=[O:26])[CH2:16]3)[CH2:12]2)[N:4]=1
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Reactant: COc1cc(OC)nc(N2CC3CNCC3C2)n1
Product: COc1cc(OC)nc(N2CC3CN(C(=O)c4cc(F)ccc4-n4nccn4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 39 and Intermediate 1. MS (ESI) mass calcd. for C22H22FN7O3, 439.18; m/z found, 440.1 [M+H]+. 1H NMR (CDCl3): 7.89 (dd, J=8.9, 4.7 Hz, 1H), 7.66 (s, 1H), 7.25-7.01 (m, 2H), 5.32 (s, 1H), 3.77 (m, 8H), 3.67-3.54 (m, 2H), 3.52-3.26 (m, 3H), 3.01-2.78 (m, 3H).