Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15](O)=[O:16])[CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:54]([C:58]1[CH:64]=[CH:63][C:61]([NH2:62])=[CH:60][CH:59]=1)([CH3:57])([CH3:56])[CH3:55]>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:62][C:61]3[CH:63]=[CH:64][C:58]([C:54]([CH3:57])([CH3:56])[CH3:55])=[CH:59][CH:60]=3)=[O:16])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: Nc1ncc2c(n1)CCN(c1cccc(C(=O)O)c1)C2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(NC(=O)c2cccc(N3CCc4nc(N)ncc4C3)c2)cc1
Temperature: 50 °C
Reaction time: 17.5 h
Yield: 82.2 %

Procedure:
A mixture of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzoic acid (27 mg, 0.10 mmol), N,N-diisopropylethylamine (0.087 mL, 0.50 mmol), and HBTU (42 mg, 0.11 mmol) in 0.9 mL DMF was briefly warmed to approx. 50° C. to dissolve solids, then continued stirring at room temperature. After 7 minutes 4-tert-butylaniline (0.024 mL, 0.15 mmol) was added and the reaction continued at room temperature for 17.5 hours. The reaction mixture was partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting solid was triturated with an EtOAc/hexane mixture to give the title compound as an off-white solid (33 mg, 81%). 1H NMR (DMSO-d6) δ: 10.08 (s, 1H), 8.13 (s, 1H), 7.65-7.70 (m, 2H), 7.50 (s, 1H), 7.32-7.40 (m, 4H), 7.21 (dt, J=7.0, 2.4 Hz, 1H), 6.41 (s, 2H), 4.29 (s, 2H), 3.65 (t, J=5.9 Hz, 2H), 2.77 (t, J=5.9 Hz, 2H), 1.28 (s, 9H)
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH:3]=[CH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].N1C=CC=CC=1.[F:17][C:18]1[C:26]([CH3:27])=[C:25]([F:28])[C:24]([F:29])=[C:23]([N+:30]([O-:32])=[O:31])[C:19]=1[C:20](Cl)=[O:21]>C(OCC)(=O)C>[CH3:1][N:2]([CH3:10])[CH:3]=[C:4]([C:20](=[O:21])[C:19]1[C:23]([N+:30]([O-:32])=[O:31])=[C:24]([F:29])[C:25]([F:28])=[C:26]([CH3:27])[C:18]=1[F:17])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: Cc1c(F)c(F)c([N+](=O)[O-])c(C(=O)Cl)c1F
Reactant: CCOC(=O)C=CN(C)C
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=CN(C)C)C(=O)c1c(F)c(C)c(F)c(F)c1[N+](=O)[O-]
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 100.5 %

Procedure:
1.4 g (0.01 mol) of ethyl 3-dimethylaminoacrylate, 15 mg of ethyl acetate and 0.8 mg (0.01 mol) of pyridine were loaded and cooled below 5° C., and a liquid mixture of 3 g (0.01 mol) of 2,4,5-trifluoro-3-methyl-6-nitrobenzoyl chloride and 5 ml of ethyl acetate was added dropwise while the temperature was maintained at 0 to 5° C. The resulting mixture was stirred at 5° C. for 1 hour and then stirred at room temperature (25° C.) overnight (12 hours). The precipitated pyridine hydrochloride was filtered off, and the filtrate was concentrated under reduced pressure to give 3.62 g of ethyl 3-dimethylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate with a 87% purity (in terms of the percentage of the peak area in HPLC) as the residue.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:44])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH2:32][CH2:33][O:34][CH3:35])[N:23]=4)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[C:1]([CH:3]1[CH2:4][N:5]([C:7](=[O:44])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH2:32][CH2:33][O:34][CH3:35])[N:23]=4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:6]1)#[N:2]
Reactant: COCCn1nc(-c2cnc3c(n2)c(C(=O)N[C@H](C)C(=O)N2CC(C#N)C2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Solvent: NCCN
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCn1nc(-c2cnc3[nH]cc(C(=O)N[C@H](C)C(=O)N4CC(C#N)C4)c3n2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.4 %

Procedure:
In a round-bottomed flask, 2-[6-chloro-1-(2-methoxy-ethyl)-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (50 mg, 0.079 mmol) was dissolved in dichloromethane (0.5 ml) and trifluoroacetic acid (0.25 ml, 3.24 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was dissolved in dichloromethane (0.5 ml) and ethylenediamine (0.32 ml, 4.74 mmol) was added. The reaction was stirred at room temperature for 1.5 h then quenched with water and diluted with ethyl acetate. The resultant suspension was filtered, washed with hot water and ethyl acetate and dried under high vacuum to provide 19 mg (48%) of 2-[6-chloro-1-(2-methoxy-ethyl)-1H-indazol-3-yl]-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a light yellow powder. MS: (M+H)+=507; 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 12.88 (br. s., 1H), 9.16 (s, 1H), 8.72 (dd, J=8.6, 3.0 Hz, 1H), 8.49 (dd, J=8.6, 4.8 Hz, 2H), 8.00 (s, 1H), 7.23-7.30 (m, 1H), 4.52-4.79 (m, 5H), 4.19-4.28 (m, 1H), 4.08-4.16 (m, 1H), 3.85 (t, J=5.3 Hz, 3H), 3.24 (s, 3H), 1.41 (t, J=6.6 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3](=O)[O:4][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:12])[C:10]=2[CH:11]=1.[CH3:14][NH2:15]>>[CH3:14][N:15]1[C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:12])[C:10]=2[CH:11]=[C:2]([CH3:1])[C:3]1=[O:4]
Reactant: Cc1cc2c(oc1=O)CCCC2=O
Reactant: CN
Product: Cc1cc2c(n(C)c1=O)CCCC2=O

Procedure:
Prepared analogously to Example 5(b) from 3-methyl- 5,6,7,8-tetrahydro-cumarin-5-one and methanolic methylamine solution a ambient temperature. After evaporation of the methanolic ammonia the residue is recrystallised from water with the addition of charcoal.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:7][C:8]([N:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]([CH3:21])[C:13](=[O:22])[C:12]2[CH:23]=[N:24][C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:26][C:11]1=2)=[O:9]>C1(C)C=CC=CC=1>[CH3:21][N:14]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:10]([C:8](=[O:9])[CH2:7][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:11]2[N:26]=[C:25]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:24]=[CH:23][C:12]=2[C:13]1=[O:22]
Reactant: CN1C(=O)c2cnc(-c3ccccc3)nc2N(C(=O)CCl)c2ccccc21
Reactant: C1CCNC1
Solvent: Cc1ccccc1
Product: CN1C(=O)c2cnc(-c3ccccc3)nc2N(C(=O)CN2CCCC2)c2ccccc21

Procedure:
1.35 g (19 mmol) of pyrrolidine are added slowly at 40° C. to a solution of 3 g (7 mmol) of 11-chloroacetyl-6-methyl-2-phenyl-5,6-dihydropyrimido[4,5-b][1,5]benzodiazepin-5-one in 30 ml of absolute toluene, while stirring. The mixture is stirred for a further 6 hours at 60° C. After filtration the solvent is removed on a rotary evaporator, and the residue is purified by chromatography on neutral silica gel using 99:1 chloroform/methanol as the eluant. After removing the solvent, the residue is stirred with methanol and finally recrystallized from ethanol; yield 1.1 g (34%), m.p. 196° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH2:11]Br.[CH3:13][C:14]([O-:16])=[O:15].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH2:11][O:16][C:14](=[O:15])[CH3:13]
Reactant: O=[N+]([O-])c1cccc(Br)c1CBr
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1c(Br)cccc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 98.1 %

Procedure:
To a solution of 1-bromo-2-bromomethyl-3-nitro-benzene (3.39 g, 11.53 mmol) in DMF (50 ml) was added KOAc (7.6 g, 77.4 mmol). The reaction was heated at 70° C. for an hour. After cooling to room temperature, the mixture was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, and dried over MgSO4. Acetic acid 2-bromo-6-nitro-benzyl ester (3.1 g) was obtained as a brown oil after concentration under vacuum (˜100%). 1H NMR (CDCl3, 300 MHz) δ: 2.06(s, 3H), 5.46 (s, 2H), 7.377(t, J=8.1 Hz), 7.778(dd, J=1.23 Hz, 8.14 Hz), 7.856(dd, J=1.23 Hz, 8.07 Hz).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6](O)=[O:7])[C:3]([C:9]([OH:11])=O)=[CH:2]1.[CH2:12]([NH2:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[CH2:12]([N:24]1[C:9](=[O:11])[C:3]2=[CH:2][S:1][CH:5]=[C:4]2[C:6]1=[O:7])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCCN
Reactant: O=C(O)c1cscc1C(=O)O
Product: CCCCCCCCCCCCN1C(=O)c2cscc2C1=O
Yield: 55 %

Procedure:
The title compound was synthesized as described hereinabove using thiophene-3,4-dicarboxylic acid (10.00 g, 58.08 mmol) and 1-dodecylamine (16.14 g, 87.12 mmol) to afford 10.27 g of the title product as a white solid (Y=55%). 1H NMR (400 MHz, CDCl3, ppm) δ: 7.80 (s, 2H); 3.60 (t, 2H, J=7.3 Hz); 1.65-1.62 (m, 2H); 1.30-1.24 (m, 18H); 0.87 (t, 3H, J=6.5 Hz); 13C NMR (100 MHz, CDCl3, ppm) δ: 162.92; 136.91; 125.71; 38.75; 32.15; 29.87; 29.85; 29.81; 29.75; 29.59; 29.45; 28.72; 27.12; 22.93; 14.39.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[C:24]2[C:5]([CH2:6][CH2:7][C@@:8]32[CH2:13][C:12](=[O:14])[N:11]([CH3:15])[C:10]([NH:16]C(=O)OC(C)(C)C)=[N:9]3)=[CH:4][CH:3]=1.[F:26][C:27]([F:35])([F:34])[C:28]1([C:31](O)=[O:32])[CH2:30][CH2:29]1>>[NH2:16][C:10]1[N:11]([CH3:15])[C:12](=[O:14])[CH2:13][C@@:8]2([C:24]3[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:31]([C:28]4([C:27]([F:35])([F:34])[F:26])[CH2:30][CH2:29]4)=[O:32])[CH:25]=3)[CH2:6][CH2:7]2)[N:9]=1
Reactant: O=C(O)C1(C(F)(F)F)CC1
Reactant: CN1C(=O)C[C@]2(CCc3ccc(N)cc32)N=C1NC(=O)OC(C)(C)C
Product: CN1C(=O)C[C@]2(CCc3ccc(NC(=O)C4(C(F)(F)F)CC4)cc32)N=C1N

Procedure:
The coupling of tert-butyl [(1S)-6-amino-1′-methyl-6′-oxo-2,3,5′,6′-tetrahydro-1′H-spiro[indene-1,4′-pyrimidin]-2′-yl]carbamate (intermediate F6) and 1-trifluoromethyl-cyclopropanecarboxylic acid followed by deprotection of the intermediate yielded the title compound as a white solid. MS (ESI): m/z=381.2 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][N:15]=[CH:16][CH:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][CH2:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)[CH2:7]1)=[O:5])C.[OH-].[Na+].[Cl:34]CCl.Cl>C(O)C>[ClH:34].[CH:28]1[C:19]2[CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH:17](/[CH:16]=[N:15]\[O:14][CH2:13][CH2:12][N:8]3[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]3)[C:18]=2[CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCON=CC2c3ccccc3CCc3ccccc32)C1
Reactant: ClCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCO/N=C\C2c3ccccc3CCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The above ester (5.0 g, 12 mmol) was dissolved in ethanol (100 ml) and a 2 N aqueous sodium hydroxide solution (27 ml) was added. The mixture was stirred at room temperature for 16 h. The solvent was evaporated in vacuo to give an oily residue. Dichloromethane (160 ml) was added and the mixture was cooled on an ice-bath. A concentrated hydrochloric acid solution (5.5 ml) was added. The mixture was stirred vigorously for a few minutes and the phases were separated. The organic phase was dried over magnesium sulphate and the solvent was evaporated in vacuo to give 4.1 g of the title compound as a foam. The material isolated consists of an approx. 1:5 mixture of the E/Z isomers.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH:10]2[CH:14]([O:15][CH3:16])[CH2:13][NH:12][CH2:11]2)=[O:8])=[CH:4][CH:3]=1.[CH3:17][CH:18]1[C:23]2[S:24][C:25]([C:27](O)=[O:28])=[N:26][C:22]=2[CH2:21][CH2:20][N:19]1[CH3:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH3:16][O:15][CH:14]1[CH2:13][N:12]([C:27]([C:25]2[S:24][C:23]3[CH:18]([CH3:17])[N:19]([CH3:30])[CH2:20][CH2:21][C:22]=3[N:26]=2)=[O:28])[CH2:11][CH:10]1[NH:9][C:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:8]
Reactant: COC1CNCC1NC(=O)c1ccc(Cl)s1
Reactant: CC1c2sc(C(=O)O)nc2CCN1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COC1CN(C(=O)c2nc3c(s2)C(C)N(C)CC3)CC1NC(=O)c1ccc(Cl)s1

Procedure:
Prepared analogously to Example 1b from (3SR,4SR)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-methoxy-pyrrolidine and (RS)-4,5-dimethyl-4,5,6,7-tetrahydro-thiazolo[5.4-c]pyridine-2-carboxylic acid (prepared analogously to WO2004058728) with HATU as coupling reagent.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH3:26])[C:13]([NH:15][N:16]1[CH:20]=[CH:19][C:18]([Br:21])=[C:17]1[C:22]([O:24]C)=O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:27][C:28]([F:37])([F:36])[C:29]1[N:34]=[C:33]([NH2:35])[CH:32]=[CH:31][CH:30]=1>>[Br:21][C:18]1[CH:19]=[CH:20][N:16]([NH:15][C:13](=[O:14])[C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH3:26])[C:17]=1[C:22](=[O:24])[NH:35][C:33]1[CH:32]=[CH:31][CH:30]=[C:29]([C:28]([F:36])([F:27])[F:37])[N:34]=1
Reactant: Nc1cccc(C(F)(F)F)n1
Reactant: COC(=O)c1c(Br)ccn1NC(=O)[C@H](C)NC(=O)OCc1ccccc1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)Nn1ccc(Br)c1C(=O)Nc1cccc(C(F)(F)F)n1
Yield: 50.7 %

Procedure:
The title compound was prepared from (S)-methyl 1-(2-(benzyloxycarbonylamino)propanamido)-3-bromo-1H-pyrrole-2-carboxylate (2.00 g, 4.7 mmol) and 6-(trifluoromethyl)pyridin-2-amine (3.00 g, 18.5 mmol) following the experimental procedure described in Preparation 44a. 1.32 g (51% yield) of the desired compound were obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([OH:28])=O)[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:74][C:75]([NH2:78])([CH3:77])[CH3:76]>C(Cl)Cl.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([NH:78][C:75]([CH3:77])([CH3:76])[CH3:74])=[O:28])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Reactant: CC(C)(C)N
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Reaction time: 0.5 h

Procedure:
A suspension of 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (70 mg, 0.14 mmol), PyBOP® (40 mg, 0.077 mmol), DIEA (24 μL, 0.14 mmol) in dry CH2Cl2:DMF (2:0.1 mL) was stirred at RT for 15 minutes. To this solution of activated acid was added 2-methylpropan-2-amine (6.7 mg, 0.091 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® were added. After stirring the solution for 15 minutes, 0.65 equivalents of 2-methylpropan-2-amine were added and the mixture was stirred for an additional 30 minutes. The solvent was removed in vacuo and the crude product was purified using prep HPLC (25-55—90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-tert-butylacetamide. (36 mg, 0.061 mmol, 55%).
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11](Cl)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:24][CH:25]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]1.O>CS(C)=O.C(Cl)(Cl)Cl>[C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]([N:27]3[CH2:28][CH2:29][CH2:30][CH:25]([CH3:24])[CH2:26]3)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1CCCNC1
Reactant: CC(C)(C)c1nc2cc(Cl)c([N+](=O)[O-])cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: CC1CCCN(c2cc3nc(C(C)(C)C)sc3cc2[N+](=O)[O-])C1

Procedure:
A solution of 2.7 g of 2-tert-butyl-5-chloro-6-nitrobenzothiazole described in example 5, in 25 ml of dimethyl sulfoxide is stirred and heated at 140° for 11 hours with 2.6 g of anhydrous potassium carbonate and 1 g of 3-methylpiperidine, cooled and poured into water. The material obtained is dissolved in chloroform and filtered through a silica gel column. The filtrate is evaporated to give 2-tert-butyl-5-[3-methylpiperidin-1-yl]-6-nitrobenzothiazole as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:18][OH:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][C:28]1[C:33]([F:34])=[CH:32][C:31]([C:35]2[O:36][CH:37]=[CH:38][N:39]=2)=[C:30]([F:40])[CH:29]=1.ClC1C=CC(S(N(CC2C=CC(C3OC=CN=3)=C(F)C=2F)[C@@H]2CCCC[C@H]2CO)(=O)=O)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:27][C:28]2[CH:29]=[C:30]([F:40])[C:31]([C:35]3[O:36][CH:37]=[CH:38][N:39]=3)=[CH:32][C:33]=2[F:34])[C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:18][OH:19])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=S(=O)(N[C@@H]1CCCC[C@H]1CO)c1ccc(Cl)cc1
Reactant: Fc1cc(-c2ncco2)c(F)cc1CBr
Agent: O=C([O-])[O-]
Agent: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncco2)c(F)c1F)[C@@H]1CCCC[C@H]1CO
Agent: [Cs+]
Product: O=S(=O)(c1ccc(Cl)cc1)N(Cc1cc(F)c(-c2ncco2)cc1F)[C@@H]1CCCC[C@H]1CO
Yield: 30.9 %

Procedure:
The title compound was synthesized from 4-chloro-N-((1R,2R)-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (90 mg, 0.30 mmol), cesium carbonate (117 mg, 0.36 mmol), and 2-(4-(bromomethyl)-2,5-difluorophenyl)oxazole (99 mg, 0.36 mmol) according to the procedure described for 4-chloro-N-(2,3-difluoro-4-(oxazol-2-yl)benzyl)-N-((1R,2R)-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (Example 20) to give 4-chloro-N-(2,5-difluoro-4-(oxazol-2-yl)benzyl)-N-((1R,2R)-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (46 mg, 31%). 1H NMR (400 MHz, CDCl3) δ ppm 7.77 (s, 1H), 7.74 (d, J=8.56 Hz, 2H), 7.68 (dd, J=9.95, 5.67 Hz, 1H), 7.52 (dd, J=9.95, 5.67 Hz, 1H), 7.49 (d, J=8.56 Hz, 2H), 7.29 (s, 1H), 4.52 (d, J=16.00 Hz, 1H), 4.37 (d, J=16.00 Hz, 1H), 3.53-3.65 (m, 2H), 3.12 (d, J=11.08 Hz, 1H), 2.57 (d, J=1.01 Hz, 1H), 1.58-1.77 (m, 3H), 1.36-1.53 (m, 2H), 0.98-1.21 (m, 4H). Analytical HPLC R.T.=22.02 min. MS [M+H]+=497. HRMS [M+H]+ calc'd 497.1113, found 497.1100.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1F)[CH3:2].[NH:13]1[CH:17]=[CH:16][N:15]=[C:14]1[CH2:18][N:19]([CH3:21])[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.CC(=O)OCC>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:13]1[CH:17]=[CH:16][N:15]=[C:14]1[CH2:18][N:19]([CH3:21])[CH3:20])[CH3:2]
Reactant: CCOC(=O)c1ccccc1F
Reactant: CN(C)Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccccc1-n1ccnc1CN(C)C
Temperature: 120 °C
Reaction time: 16 h
Yield: 17.8 %

Procedure:
A mixture of 2-fluoro-benzoic acid ethyl ester (200 mg; 1.19 mmol; 10 eq.), (1H-imidazol-2-ylmethyl)-dimethyl-amine (149 mg; 1.19 mmol; 1 eq.) and cesium carbonate (775 mg; 2.38 mmol; 2 eq.) in DMSO (3 mL) was stirred at 120° C. for 16 hours. The mixture was diluted with EA, washed with water (3×), dried over magnesium sulfate and concentrated in vacuo to afford the title compound (58 mg, 18%) as a white solid. HPLC (max plot) 95.7%; Rt 1.80 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]([CH3:20])([CH3:19])[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:21]([O:23][CH3:24])=[O:22])[CH:15]=3)[NH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)C(C)C)(C)C.[CH:34]1([C:40](Cl)=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>ClCCl>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([CH:9]2[C:18]([CH3:19])([CH3:20])[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:21]([O:23][CH3:24])=[O:22])[CH:15]=3)[NH:10]2)=[CH:3][C:2]=1[NH:1][C:40]([CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:41]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(Cl)c(N)c1)N2
Reactant: O=C(Cl)C1CCCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(Cl)c(NC(=O)C3CCCCC3)c1)N2
Reaction time: 1.5 h
Yield: 94.7 %

Procedure:
To a solution of methyl 2-(3-amino-4-chlorophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (200 mg, 0.58 mmol) in 8 mL of dichloromethane, was added N,N-diisopropylethylamine (150 mg, 1.16 mmol) under nitrogen atmosphere. Then a solution of cyclohexanecarbonyl chloride (127 mg, 0.87 mmol) was added via syringe with an ice bath. The mixture was stirred for 1.5 h. The mixture was purified by column chromatography to afford 250 mg of methyl 2-(4-chloro-3-(cyclohexanecarboxamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a crude product. (Yield: 95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]=O)=[CH:5][CH:4]=1.[C:13]([CH2:15][C:16]([O:18][CH3:19])=[O:17])#[N:14]>C(O)(=O)C.N1CCCCC1>[C:13](/[C:15](=[CH:11]\[CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)/[C:16]([O:18][CH3:19])=[O:17])#[N:14]
Reactant: COC(=O)CC#N
Reactant: COc1ccc(CCC=O)cc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: COC(=O)/C(C#N)=C/CCc1ccc(OC)cc1
Yield: 72.3 %

Procedure:
A solution of 13d (0.616 g, 3.75 mmol) in 0.51 mL glacial acetic acid was treated with NCCH2CO2CH3 (0.338 g, 3.75 mmol, 0.3 mL, 1.0 equiv), then a premixed solution of piperidine (0.0011 g, 0.128 mmol, 13 mL, 3.4 mol %) and 125 mL of acetic acid at room temperature (24 h). The reaction mixture was quenched by the addition of saturated aqueous NaHCO3 (15 mL, pH>7) and extracted with EtOAc (3×15 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. SGC chromatotron (SiO2, 1 mm, 0-10% EtOAc/hexanes) afforded 15d (0.665 g, 0.920 g theoretical, 72%). For 15d: 1H NMR (CDCl3, 400 MHz) d 7.63 (t, 1H, J=7.5 Hz, CH=C), 7.09 (d, 2H, J=8.5 Hz, Ar C2-H and C6-H), 6.83 (d, 2H, J=8.5 Hz, Ar C3-H and C5-H), 3.83 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 2.70-2.90 (m, 4H, ArCH2CH2); IR (neat) nmax 2955, 1837, 2359, 2341, 1732, 1612, 1513, 1436, 1270, 1248, 1178, 1116, 1061, 1039, 823, 761, 668 cm-1. See FIG. 19c.
Reaction SMILES: [NH2:1][CH2:2][N:3]1[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[CH2:5][C:4]1=[O:11].Cl[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=1.C(N(CC)CC)C>O1CCOCC1>[N+:19]([C:18]1[C:13]([NH:1][CH2:2][N:3]2[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[CH2:5][C:4]2=[O:11])=[N:14][CH:15]=[CH:16][CH:17]=1)([O-:21])=[O:20]
Reactant: CCCC1CC(=O)N(CN)C1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCCC1CC(=O)N(CNc2ncccc2[N+](=O)[O-])C1
Yield: 52.6 %

Procedure:
A mixture of 1-(aminomethyl)-4-propylpyrrolidin-2-one x76 (1 eq, 17.09 mmol, 2.67 g), 2-chloro-3-nitropyridine (1 eq, 17.09 mmol, 2.709 g) and triethylamine (1.1 eq, 18.8 mmol, 1.902 g, 2.62 ml) in dioxane (20 ml) is refluxed 48 h. After cooling, the crude mixture is filtrated and the dioxane is distilled under vacuum. The residue is purified by preparative chromatography to afford 2.5 g of 1-{[(3-nitropyridin-2-yl)amino]methyl}-4-propylpyrrolidin-2-one x77.