Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([OH:5])(=O)=[O:3].[Br:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[CH3:16][NH:17][CH3:18].Cl>O>[Br:6][C:7]1[CH:15]=[CH:14][C:13]([S:2]([N:17]([CH3:18])[CH3:16])(=[O:5])=[O:3])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: O=C(O)c1ccccc1Br
Reactant: CNC
Reactant: O=S(=O)(O)Cl
Agent: Cl
Solvent: O
Product: CN(C)S(=O)(=O)c1ccc(Br)c(C(=O)O)c1
Temperature: 25 °C

Procedure:
To 160 ml. of chlorosulfonic acid stirring at 0°-5° C. was gradually added 100.5 g. (0.33 mole) of 2-bromobenzoic acid. Stirring was continued as the temperature was allowed to increase to 25° C. The mixture was stirred and refluxed for three hours, then it was cooled and poured into ice-water. The solid was filtered and then washed with cold water until the filtrate was no longer acidic. The solid, thus isolated, was added, in portions, to 200 ml. of a 40% aqueous solution of dimethylamine. After being diluted with 500 ml. of water, the solution was made acidic with 2.5 N hydrochloric acid. Recrystallization of the precipitated solid from aqueous ethanol gave crystals of 2-bromo-5-dimethylaminosulfonylbenzoic acid, m.p. 170°-172° C.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[S:20]1[CH:24]=[CH:23][C:22]2[C:25]([NH2:29])=[CH:26][CH:27]=[CH:28][C:21]1=2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[S:20]1[C:21]2[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:16](=[O:18])[CH2:15][C:3]3[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([N:9]4[CH2:10][CH2:11][O:12][CH2:13][CH2:14]4)[N:4]=3)[C:22]=2[CH:23]=[CH:24]1
Reactant: Nc1cccc2sccc12
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cn1c(CC(=O)Nc2cccc3sccc23)nc(N2CCOCC2)cc1=O
Yield: 14.3 %

Procedure:
The product is prepared according to the procedure described in example 86, using 551 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 328 mg of benzo[b]thiophen-4-ylamine and 498 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 324 μl of pyridine and 8.0 ml of N,N-dimethylformamide. 110 mg of N-(1-benzothiophen-4-yl)-2-[1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:12]([OH:14])=O)[C:6]2[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1)#[N:2].C(Cl)(=O)C(Cl)=O.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C@H:28]([CH2:32][CH:33]=[CH2:34])[CH2:29][NH:30][CH3:31])=[CH:24][CH:23]=1.C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([C:12]([N:30]([CH2:29][C@H:28]([C:25]2[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=2)[CH2:32][CH:33]=[CH2:34])[CH3:31])=[O:14])[C:6]2[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1)#[N:2]
Reactant: N#Cc1cc2c(c(C(=O)O)c1)CCC2
Reactant: C=CC[C@H](CNC)c1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CC[C@H](CN(C)C(=O)c1cc(C#N)cc2c1CCC2)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 62.1 %

Procedure:
6-Cyanoindane-4-carboxylic acid (150 mg, 0.8 mmol) and oxalyl chloride (130 mg, 1.0 mmol) were mixed with CH2Cl2 (20 mL) whereupon DMF (100 mg) was added. After 1 h at room temperature [(2S)-2-(4-fluorophenyl)pent-4-en-1-yl]methylamine (Bioorg. Med. Chem. Lett; 2001; 265-270; 200 mg, 1.0 mmol) and triethylamine (200 mg, 2.0 mmol) were added to the mixture in the given order. The mixture was stirred at room temperature for 20 min and then the solvent was evaporated. The product was purified by chromatography on silica gel using hexane and ethyl acetate (1:1). There was obtained 180 mg (62%) of 6-cyano-N-[(2S)-2-(4-fluorophenyl)pent-4-en-1-yl]-N-methylindane-4-carboxamide as an oil. 1H NMR (300 MHz, CDCl3): 2.0-2.1 (m, 2H), 2.2 (t, 1H), 2.4 (m, 2H), 2.6 (s, 4H), 2.8-3.4 (m, 4H), 3.7 (dd, 1H), 3.8-3.9 (dd, 1H), 4.9-5.1 (m, 2H), 5.4-5.8 (m, 1H), 6.8-7.1 (m, 4H), 7.2 (m, 1H), 7.5 (s, 1H).
Reaction SMILES: C(N(CC)CC)C.[OH:8][C@@H:9]1[CH2:13][O:12][CH2:11][C@H:10]1[NH:14][S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16].[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:21][S:22]([O:8][C@H:9]1[C@H:10]([NH:14][S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[CH2:11][O:12][CH2:13]1)(=[O:24])=[O:23]
Reactant: CC(C)S(=O)(=O)N[C@@H]1COC[C@H]1O
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N[C@@H]1COC[C@H]1OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
Triethylamine (1.99 mL, 14.3 mmol) was added to a cooled (0° C.) solution of trans-N-(4-hydroxytetrahydrofuran-3-yl)propane-2-sulfonamide (1.99 g, 9.52 mmol) in dichloromethane (20 mL). Methanesulfonyl chloride (0.885 mL, 11.4 mmol) was then added and the reaction was stirred at 0° C. for 50 minutes. Saturated aqueous sodium bicarbonate solution (10 mL) was added, and the aqueous layer was extracted with methylene chloride. The combined organic layers were dried over sodium sulfate, filtered, concentrated in vacuo and purified by silica gel chromatography (Gradient: 10% to 50% ethyl acetate in heptane) to provide trans-4-[(isopropylsulfonyl)amino]tetrahydrofuran-3-yl methanesulfonate. Yield: 2.27 g, 7.90 mmol, 83%. 1H NMR (400 MHz, CDCl3) δ 1.40 (d, J=6.8 Hz, 3H), 1.41 (d, J=6.8 Hz, 3H), 3.14 (s, 3H), 3.25 (septet, J=6.8 Hz, 1H), 3.77 (dd, J=9.5, 2.4 Hz, 1H), 3.96 (dd, J=11.3, 2.2 Hz, 1H), 4.08-4.16 (m, 2H), 4.21 (dd, J=11.3, 5.1 Hz, 1H), 4.77 (d, J=8.0 Hz, 1H), 5.15 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 16.48, 16.54, 38.28, 54.28, 59.49, 71.83, 71.87, 83.97.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[OH-].[NH4+:10].Cl[S:12]([OH:15])(=O)=[O:13]>>[NH2:1][C:2]1[C:7]([S:12]([NH2:10])(=[O:15])=[O:13])=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1
Reactant: Nc1ccc(Br)cn1
Reactant: O=S(=O)(O)Cl
Reactant: [NH4+]
Agent: [OH-]
Product: Nc1ncc(Br)cc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
To a solution of chlorosulfonic acid (20 mL) at 0° C. was added 2-amino-5-bromopyridine (5.0 g, 0.029 mmol) portion wise. Upon completion of addition, the reaction mixture was heated to reflux where it stirred for 16 h. After this time, the reaction mixture was allowed to cool to RT. Once at the prescribed temperature, the reaction mixture was poured drop wise in to an aqueous ammonium hydroxide solution. The resulting mixture was extracted with ethyl acetate. The combined organic portions were washed with a brine solution, dried over Na2SO4 and concentrated under reduced pressure to yield 2-amino-5-bromopyridine-3-sulfonamide (4.7 g, 65%), which was used without further purification. LCMS Method Y: retention time 0.5 min, [M−1]=250.8.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:14][C:15]2[CH:16]=[N:17][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:19][CH:20]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11](=[S:13])[NH2:12])=[CH:7]2.[C:25]([O:30][CH2:31][CH3:32])(=[O:29])[C:26]#[C:27][CH3:28].O1CCCC1.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH2:31]([O:30][C:25](=[O:29])[CH2:26][CH:27]1[S:13][C:11]([C:8]2[NH:9][C:10]3[C:6]([CH:7]=2)=[CH:5][C:4]([O:14][C:15]2[CH:16]=[N:17][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:19][CH:20]=2)=[CH:3][C:2]=3[CH3:1])=[N:12][CH2:28]1)[CH3:32]
Reactant: Cc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(N)=S)[nH]c12
Reactant: CC#CC(=O)OCC
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(C)c3[nH]2)S1
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 76 %

Procedure:
To a mixed solution of 7-methyl-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carbothioamide (2.6 g), ethyl 2-butynoate (1.7 mL), tetrahydrofuran (40 mL), and toluene (60 mL) was added tri-n-butylphosphine (2.2 mL) under an argon atmosphere at room temperature, and the mixture was stirred at 40° C. for 2.5 hr. The reaction solution was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=40:60 to 65:35, volume ratio) to give the title compound (2.59 g, yield 76%) as a pale-yellow amorphous solid.
Reaction SMILES: [ClH:1].[NH:2]1[CH:6]=[C:5]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[CH2:15][CH2:14][CH2:13]3)[N:4]=[CH:3]1.[CH:21]1[C:26]([CH:27]=O)=[CH:25][CH:24]=[C:23]([C:29]([NH2:31])=[O:30])[CH:22]=1>[OH-].[K+].CCO>[ClH:1].[NH:2]1[CH:6]=[C:5]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[C:15](=[CH:27][C:26]2[CH:25]=[CH:24][C:23]([C:29]([NH2:31])=[O:30])=[CH:22][CH:21]=2)[CH2:14][CH2:13]3)[N:4]=[CH:3]1
Reactant: NC(=O)c1ccc(C=O)cc1
Reactant: O=C1CCCc2cc(OCCc3c[nH]cn3)ccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1ccc(C=C2CCc3cc(OCCc4c[nH]cn4)ccc3C2=O)cc1

Procedure:
According to the method of Example 34, 6-[2-(1H-imidazole-4-yl)-ethoxy]-3,4-dihydro-2H-naphthalen-1-one, monohydrochloride (0.313 g, 1.07 mmol) was reacted with benzamide-4-carboxaldehyde (0.178 g, 1.13 mmol) in 5 mL of 4% KOH in EtOH overnight to afford 0.197 (42%) of the title compound as an off-white powder, mp dec. >230° C.: CI-MS m/e 388 (M++1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]([CH2:12][C:13]([CH3:15])=[CH2:14])[S:8]([CH3:11])(=[O:10])=[O:9].ClC1C=CC=C(C(OO)=[O:24])C=1>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]([CH2:12][C:13]1([CH3:15])[CH2:14][O:24]1)[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)CN(Cc1ccco1)S(C)(=O)=O
Solvent: ClCCl
Product: CC1(CN(Cc2ccco2)S(C)(=O)=O)CO1
Temperature: 40 °C
Reaction time: 18 h
Yield: 26.4 %

Procedure:
To a stirring solution of N-(furan-2-ylmethyl)-N-(2-methylallyl)methanesulfonamide (1.0 g, 4.3 mmol) in anhydrous methylene chloride (20 mL) was added 3-chloroperbenzoic acid (70%, 2.1 g, 8.6 mmol). The mixture was stirred at ambient temperature for 2 hours and at 40° C. for 18 hours. The mixture was diluted with methylene chloride and successively washed with saturated aqueous sodium sulfite, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride solutions. The organic layer was dried (anhydrous sodium sulfate), filtered, and concentrated. The crude residue was purified by silica gel column chromatography (10-60% ethyl acetate in hexanes) to give a clear oil (0.278 g, 26%). 1H NMR (CDCl3, 300 MHz) δ 7.40-7.35 (dd, 1H, J=0.9, 1.8 Hz), 6.33-6.30 (m, 2H), 4.52-4.51 (m, 2H), 3.48-3.43 (d, 1H, J=15 Hz), 3.13-3.09 (d, 1H, J=15 Hz), 2.73-2.72 (d, 1H, J=4.5 Hz), 2.70 (s, 3H), 2.62-2.61 (d, 1H, J=4.5 Hz), 1.35 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]([NH2:26])=[N:11][C:12](=[O:25])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[NH:16][CH:15]=2)[CH:5]=[C:4]([Cl:27])[C:3]=1[NH:28][C:29](=[O:31])[CH3:30].[CH3:32]OC1C=C2C(=CC=1)NC=C2CC(O)=O.NC1C(C)=CC(CN)=CC=1Cl>>[Cl:27][C:4]1[CH:5]=[C:6]([CH2:8][NH:9][C:10]([NH2:26])=[N:11][C:12](=[O:25])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[NH:16][CH:15]=2)[CH:7]=[C:2]([CH3:32])[C:3]=1[NH:28][C:29](=[O:31])[CH3:30]
Reactant: COc1ccc2[nH]cc(CC(=O)N=C(N)NCc3cc(Cl)c(NC(C)=O)c(Cl)c3)c2c1
Reactant: COc1ccc2[nH]cc(CC(=O)O)c2c1
Agent: Cc1cc(CN)cc(Cl)c1N
Product: COc1ccc2[nH]cc(CC(=O)N=C(N)NCc3cc(C)c(NC(C)=O)c(Cl)c3)c2c1

Procedure:
In a manner similar to that used in the preparation of the compound of example 2, but using 2-(5-methoxy-1H-indol-3-yl)acetic acid in step 9 (A) and 4-amino-3-chloro-5-methylbenzylamine (preparation G) in step 9 (B), the title compound was prepared. MS (ESI) (M+H)+=442.04 1H-NMR (500 MHz, CD3OD) δ 7.20-7.39 (m, 3 H), 7.16 (s, 1 H), 7.05 (d, J=2.14 Hz, 1 H), 6.82 (dd, J=8.55, 2.44 Hz, 1 H), 4.46 (s, 2 H), 3.93 (s, 2 H), 3.82 (s, 3 H), 2.24 (s, 3 H), 2.18 (s, 3 H).
Reaction SMILES: [CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][C:4](=[O:13])[N:3]3[C:2]1=[O:14].Cl.[CH2:16]([OH:18])[CH3:17]>>[CH2:16]([O:18][C:2](=[O:14])[CH2:1][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[NH:3][C:4](=[O:13])[CH2:5][CH2:6]2)[CH3:17]
Reactant: O=C1CCc2cccc3c2N1C(=O)C3
Reactant: CCO
Agent: Cl
Product: CCOC(=O)Cc1cccc2c1NC(=O)CC2

Procedure:
A solution of 5,6-dihydro-4H-pyrrolo [3,2,1-ij]-quinoline-2,4(1H)-dione (1.87 g, 0.01 mole) in ethanol (10 ml) is treated with a drop of concentrated hydrochloric acid. The mixture is refluxed 24 hours (or until the dione starting material can no longer be detected by thin layer chromatography). The solution is cooled and concentrated at reduced pressure. The product is purified by flash chromatography to yield 1,2,3,4-tetrahydro-2-oxo-8-quinoline acetic acid ethyl ester.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:26])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:25])([C:14]([NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:6][CH2:5]2.[O:27]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[OH:27][C:7]([CH3:25])([CH2:6][CH2:5][C:4]1[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:26])[C:14]([NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCc1ccccc1)O2
Agent: [Ce+4]
Agent: [NH4+]
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(=O)NCCc2ccccc2)=C(C)C1=O
Yield: 90.3 %

Procedure:
Oxidation as described in protocol B, using 102 mg (0.287 mmol) of 6-hydroxy-2,5,7,8-tetramethyl-N-phenethylchroman-2-carboxamide and 355 mg CAN (0.647 mmol) yielded 95.8 mg of 2-hydroxy-2-methyl-N-phenethyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[N:11]=[C:10]2[S:12][CH:13]=[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]2=[C:8]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[CH:7]=1)[CH3:2].[C:30](=O)([O:34]CC)[O:31][CH2:32][CH3:33].[H-].[Na+]>C1COCC1.O>[CH2:1]([O:3][C:4](=[O:29])[CH:5]([C:6]1[N:11]=[C:10]2[S:12][CH:13]=[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]2=[C:8]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[CH:7]=1)[C:30]([O:31][CH2:32][CH3:33])=[O:34])[CH3:2]
Reactant: CCOC(=O)Cc1cc(NCc2ccccn2)c2c(-c3ccccc3)csc2n1
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C(=O)OCC)c1cc(NCc2ccccn2)c2c(-c3ccccc3)csc2n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
{3-Phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3-b]pyridin-6-yl}-acetic acid ethyl ester (180 mg, 0.45 mmol) was dissolved in dry THF (10 ml) under nitrogen. Diethyl Carbonate (0.27ml, 2.23 mmol) was added and the mixture cooled to 0° C. Sodium Hydride (36 mg, 0.89 mmol) was added and the mixture stirred at 0° C. for a further 10 min, then at room temperature for 20 min, then brought to reflux for 45 min. On cooling, the reaction was diluted with water (100 ml) and extracted with DCM (3×50 ml), the extracts combined, dried over magnesium sulphate and concentrated. The residue was purified on silica, eluting (Ethyl Acetate/DCM), 0-20%) to give 2-{3-Phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3-b]pyridin-6-yl}-malonic acid diethyl ester as a yellow solid. Yield=96 mg (45%).
Reaction SMILES: [C:1](O)(=O)[CH3:2].[NH2:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([NH2:13])=[O:12])=[O:8].[CH3:14]O>CC(C)=O>[CH3:14][C:1]1([CH3:2])[NH:5][CH2:6][C:7](=[O:8])[N:9]1[CH2:10][C:11]([NH2:13])=[O:12]
Reactant: CO
Reactant: CC(=O)O
Reactant: NCC(=O)NCC(N)=O
Solvent: CC(C)=O
Product: CC1(C)NCC(=O)N1CC(N)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of glycylglycinamide acetate (10 g) in methanol (250 ml) and acetone (125 ml), was added Amberlite IRA-68 resin (20 g) (available from Rohm & Haas, Philadelphia, USA). Amberlite is a registered trade mark and IRA-68 is a weakly basic resin. The suspension was stirred at room temperature for 1 hour, then resin was filtered off and the solution was evaporated under reduced pressure. The residue was suspended in refluxing acetone (250 ml) and methanol was added to obtain a clear solution, which was refluxed for 2 hours. Evaporation and trituration of the residue with acetone gave 6.85 g of the title compound.
Reaction SMILES: [CH3:1][N:2]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:3]([CH3:7])[C:4]([OH:6])=O.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:30][C:31]1[N:36]=[C:35]([C:37]#[C:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:34]([NH:45][C:46]([CH:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)=[O:47])=[CH:33][CH:32]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:11]([O:10][C:8](=[O:9])[N:2]([CH3:1])[CH:3]([CH3:7])[C:4]([NH:30][C:31]1[CH:32]=[CH:33][C:34]([NH:45][C:46]([CH:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)=[O:47])=[C:35]([C:37]#[C:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[N:36]=1)=[O:6])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: Nc1ccc(NC(=O)C2CCOCC2)c(C#Cc2ccccc2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C(=O)Nc1ccc(NC(=O)C2CCOCC2)c(C#Cc2ccccc2)n1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoic acid (34 mg, 0.17 mmol) and N,N′-dicyclohexylcarbodiimide (17 mg, 0.08 mmol) in DCM (1 ml) is stirred at RT for 20 minutes. This mixture is added to N-[6-amino-2-(2-phenylethynyl)pyridin-3-yl]oxane-4-carboxamide D5b (28 mg, 0.09 mmol) and DIPEA (17 μl; 0.10 mmol) in DCM (1 ml). After stirring for 6 days at 40° C. the reaction mixture is diluted with DCM and extracted with water. The combined organic layers are dried over MgSO4 to and concentrated in vacuo. The crude product (70 mg) is used in the next step without further purification.
Reaction SMILES: Br[C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@H:25]([CH2:28][OH:29])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[C:12]([F:21])[CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][CH:41]=[C:42]([CH:45]=2)[C:43]#[N:44])O1>>[C:43]([C:42]1[CH:45]=[C:38]([C:2]2[C:3]([N:23]3[CH2:27][CH2:26][C@H:25]([CH2:28][OH:29])[CH2:24]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:18])([F:19])[F:20])=[C:12]([F:21])[CH:11]=3)=[O:8])[CH:22]=2)[CH:39]=[N:40][CH:41]=1)#[N:44]
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)F)c(F)c1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Product: N#Cc1cncc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)c(F)c3)cnc2N2CC[C@H](CO)C2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 151 using (S)-5-bromo-N-(3-fluoro-4-(trifluoromethoxy)phenyl)-6-(3-(hydroxymethyl)pyrrolidin-1-yl)nicotinamide (Stage 201.1) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile to afford a white powder. UPLC-MS (Condition 3) tR=1.06 min, m/z=502.4 [M+H]+, m/z=500.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.51-1.66 (m, 1H) 1.79-1.92 (m, 1H) 2.16-2.30 (m, 1H) 2.96 (dd, J=11.00, 6.85 Hz, 1H) 3.10-3.28 (m, 4H) 3.32-3.41 (m, 1H) 4.60 (t, J=5.26 Hz, 1H) 7.50-7.65 (m, 2H) 7.98 (dd, J=13.08, 2.32 Hz, 1H) 8.07 (d, J=2.45 Hz, 1H) 8.40 (t, J=2.20 Hz, 1H) 8.79 (d, J=2.45 Hz, 1H) 8.90 (d, J=1.96 Hz, 1H) 9.02 (d, J=1.96 Hz, 1H) 10.30 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:11]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]2)[CH:7]=[CH:8][C:9]=1[Cl:10])([OH:3])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[C:38]12([CH2:48][CH2:49][NH2:50])[CH2:47][CH:42]3[CH2:43][CH:44]([CH2:46][CH:40]([CH2:41]3)[CH2:39]1)[CH2:45]2.C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[Cl:10][C:9]1[CH:8]=[CH:7][C:6]([N:11]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:13][CH2:12]2)=[CH:5][C:4]=1[C:1]([NH:50][CH2:49][CH2:48][C:38]12[CH2:47][CH:42]3[CH2:43][CH:44]([CH2:46][CH:40]([CH2:41]3)[CH2:39]1)[CH2:45]2)=[O:3]
Reactant: NCCC12CC3CC(CC(C3)C1)C2
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(Cl)c(C(=O)O)c2)CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc(Cl)c(C(=O)NCCC34CC5CC(CC(C5)C3)C4)c2)CC1
Reaction time: 14 h
Yield: 49.2 %

Procedure:
A solution of 4-(3-carboxy-4-chlorophenyl)hexahydro-1H-1,4-diazepine-1-carboxylic acid, 1,1-dimethylethyl ester (0.075 g, Example 5b) and 1,140 -carbonyldiimidazole (0.034 g) in dimethylformamide (3 ml) was stirred at room temperature of 2.5 h. Tricyclo[3.3.1.13,7]decane-1-ethanamine, hydrochloride salt (0.045 g) and N,N-diisopropylethylamine (0.037 ml) were then added and stirring continued for 14 h. The reaction mixture was poured into water and extracted with ethyl acetate three times. The ethyl acetate layers were combined and washed with 2M hydrochloric acid, 10% aqueous sodium hydroxide and brine, then dried over magnesium sulfate and concentrated under reduced pressure. Purification by chromatography on silica gel eluting with 20% ethyl acetate in iso-hexane gave the subtitle compound as a yellow oil (0.053 g).
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.Cl[N:17]([C:25]1[C:34]2[C:29](=[CH:30][C:31](O)=[C:32]([O:35][CH3:36])[CH:33]=2)[N:28]=[CH:27][N:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[F:24].N1C=CC=CC=1.C(Cl)[Cl:45]>>[Cl:45][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)=[C:19]([F:24])[CH:20]=1
Reactant: COc1cc2c(N(Cl)c3ccccc3F)ncnc2cc1O
Reactant: ClCCl
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
Trifluoromethanesulphonic anhydride (0.55 ml, 3.3 mmol) was added to a stirred suspension of 4-(chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (959 mg, 3 mmol), (prepared as described for the starting material in Example 2), in methylene chloride (2.2 ml) and pyridine (2.2 ml) under argon at 0° C. The reaction mixture was stirred for 1 hour at 0° C., allowed to warm to ambient temperature and stirred for a further 1.5 hours. The volatiles were removed by evaporation, the residue was dissolved in ethyl acetate, washed with dilute hydrochloric acid and brine, dried (MgSO4) and the solvent removed by evaporation. The residue was triturated with ether/petroleum ether to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(trifluoromethylsulphonyloxy)quinazoline (270 mg, 60%) as a beige solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[C:15](=[O:18])[NH:16][N:17]=[C:13]3[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:11]([CH3:29])=[C:10]2[C:30]([OH:32])=[O:31])=[CH:5][CH:4]=1)#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:57][N:58]([CH2:60][CH2:61][CH2:62]O)[CH3:59]>CN(C=O)C>[CH3:57][N:58]([CH3:59])[CH2:60][CH2:61][CH2:62][O:31][C:30]([C:10]1[CH:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[N:14]2[C:15](=[O:18])[NH:16][N:17]=[C:13]2[N:12]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[CH:20]=2)[C:11]=1[CH3:29])=[O:32]
Reactant: CC1=C(C(=O)O)C(c2ccc(C#N)cc2)n2c(n[nH]c2=O)N1c1cccc(C(F)(F)F)c1
Reactant: CN(C)CCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC1=C(C(=O)OCCCN(C)C)C(c2ccc(C#N)cc2)n2c(n[nH]c2=O)N1c1cccc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a solution of Example 9 (42 mg, 0.095 mmol) in DMF (1 mL), was added diiosopropylethylamine (33 μL, 0.19 mmol) followed by HATU (72 mg, 0.19 mmol). After 1 hour, N,N-dimethylpropanolamine (67 μL, 0.57 mmol) was added, and the reaction mixture was stirred at 60° C. for 16 hours. The reaction mixture was allowed to cool to RT then partitioned between EtOAc and water. The organic layer was separated, and the aqueous layer further extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and evaporated in vacuo. The resulting residue was purified by silica gel chromatography eluting with a gradient of 0-6% (2 M NH3 in MeOH) in DCM to give the title compound as a white solid (15 mg).