Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Br:11][CH:12]([OH:14])[CH3:13]>>[Br-:11].[OH:14][CH2:12][CH2:13][N+:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[S:3][C:2]=1[CH3:1]
Reactant: CC(O)Br
Reactant: Cc1nc2ccccc2s1
Product: Cc1sc2ccccc2[n+]1CCO
Product: [Br-]

Procedure:
A solution of 2-methylbenzothiazole (5.87 g) and bromoethanol (49.2 g) were stirred in an oil bath at 110° C. for 18 hours. Added ethyl acetate (100 mL) to the reaction mixture and decanted. The residual solid was then dissolved in methanol (50 mL) and precipitated with ethyl acetate (300 mL). The solid was again recrystallized from methanol-ethyl acetate (15 mL/150 mL), washed with ethyl acetate (2×25 mL) and dried in an oven under high vacuum at 50° C. overnight. The yield was 4.21 g (39%). TLC (silica gel, 4:1 methylene chloride-methanol) Rf=0.34.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([O:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=3[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:26])=[CH:12][CH:13]=[N:14]2)=[CH:9][C:8]=1[O:33][CH3:34].[C:35](=[O:38])([O-])[O-].[K+].[K+].O.[CH3:42][N:43](C)C=O>>[OH:38][CH2:35][CH2:42][NH:43][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([O:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=3[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:26])=[CH:12][CH:13]=[N:14]2)=[CH:9][C:8]=1[O:33][CH3:34]
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCCCl
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Agent: [K+]
Solvent: O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCCNCCO
Temperature: 80 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
(2-{[7-(4-Chlorobutoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (compound 142) (60 mg), 4-aminoethanol (24 mg), and potassium carbonate (90 mg) were suspended in N,N-dimethylformamide (2 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate, and the solvent was removed therefrom by distillation under the reduced pressure. The residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (33 mg, yield 51%).
Reaction SMILES: Cl[CH:2]1[C:7]([I:10])(CC)[CH:6]=[N:5][CH:4]=[N:3]1.[C:11]([C@@H:15]1[CH2:20][CH2:19][C@H:18]([NH2:21])[CH2:17][CH2:16]1)([CH3:14])([CH3:13])[CH3:12].[CH2:22](N(CC)CC)[CH3:23]>O.C1(C)C=CC=CC=1>[C:11]([C@@H:15]1[CH2:16][CH2:17][C@H:18]([NH:21][C:6]2[C:7]([I:10])=[C:2]([CH2:22][CH3:23])[N:3]=[CH:4][N:5]=2)[CH2:19][CH2:20]1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)[C@H]1CC[C@@H](N)CC1
Reactant: CCN(CC)CC
Reactant: CCC1(I)C=NC=NC1Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1I

Procedure:
7.25 g (30 mmol) of 4-chloro-5-iodo-5-ethylpyrimidine (EP 470 600), 5.6 g (36 mmol) of cis-4-tert-butylcyclohexylamine and 6.1 g of triethylamine were heated at from 80° to 90° C. for 4 hours without solvent. After cooling, the mixture was taken up in water/toluene and the organic phase was dried and concentrated. The crude product was purified by chromatography on silica gel using petroleum ether/ethyl acetate (7:3), to give 7.4 g (56.7% of theory) of a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([OH:15])=O)=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.[N:16]1([CH2:22][C:23]2[CH:27]=[C:26]([NH2:28])[NH:25][N:24]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C.O>[N:16]1([CH2:22][C:23]2[CH:27]=[C:26]([NH:28][C:13]([C:3]3[C:2]([NH2:1])=[N:7][C:6]([C:8]([F:9])([F:10])[F:11])=[C:5]([Br:12])[N:4]=3)=[O:15])[NH:25][N:24]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: Nc1cc(CN2CCCCC2)n[nH]1
Reactant: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)Nc1cc(CN2CCCCC2)n[nH]1

Procedure:
A mixture, comprising 3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (Intermediate 2)(0.349 g, 1.221 mmol), 3-(piperidin-1-ylmethyl)-1H-pyrazol-5-amine (Intermediate 8) (0.220 g, 1.221 mmol), HATU (0.464 g, 1.221 mmol) and N-methylmorpholine (0.241 ml, 2.441 mmol) in DMF (5 ml) was stirred for 30 minutes at RT. The reaction mixture was diluted with water (20 ml) and the resulting yellow precipitate was filtered under vacuum and washed with water (20 ml). The resulting residue was loaded onto a SCX-2 cartridge eluting with MeOH followed by 7M NH3 in MeOH. The methanolic ammonia fractions were concentrated in vacuo and the residue was triturated with EtOAc/iso-hexane to yield the title compound.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[F:18][C:19]([F:32])([F:31])[C:20]1[N:21]=[C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[S:23][CH:24]=1>>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:28]1[CH2:29][CH2:30][N:25]([C:22]2[S:23][CH:24]=[C:20]([C:19]([F:32])([F:18])[F:31])[N:21]=2)[CH2:26][CH2:27]1)=[O:9])([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: FC(F)(F)c1csc(N2CCNCC2)n1
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2nc(C(F)(F)F)cs2)CC1
Yield: 55 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-(4-trifluoromethyl-thiazol-2-yl)-piperazine. The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in pentane to yield the title compound as a crystalline white solid (yield 55%). MS (m/e): 478.0 (M+H+, 100%).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]1([C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:19][CH:18]2[C:20]#N)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.S(=O)(=O)(O)[OH:29]>CCCCCC.C1(C)C=CC=CC=1>[C:11]1([C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:19][CH:18]2[CH:20]=[O:29])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#CC1CC1(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=CC1CC1(c1ccccc1)c1ccccc1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
A solution of diisobutylaluminum hydride in hexane (25%; 212 mL) was added over 30 minutes to a solution of 2,2-diphenylcyclopropanecarbonitrile (45.4 g) in dry toluene (400 mL) maintained at -40° C. during the addition. After the reaction had been stirred at room temperature for 1 hour, it was rechilled to 0°-5° C. and 2N sulfuric acid (400 mL) was added dropwise. The two phase system was stirred at ambient temperature for 1 hour then the layers were separated and the aqueous phase was extracted with ethyl acetate (2×300 mL). The organic layers were washed with Rochelle salt solution (5%; 2×200 mL), then were dried (Na2SO4) and evaporated to give 2,2-diphenylcyclopropanecarboxaldehyde as a solid, mp 71°-73° C. A sample was crystallized from benzene-hexane to provide the purified aldehyde, mp 75°-76° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[O:6][C:7]=1[CH3:8].[OH:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:24]([C:23]1[CH:26]=[CH:27][C:20]([O:19][CH2:2][C:3]2[N:4]=[C:5]([C:9]3[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=3)[C:12]([O:14][CH3:15])=[O:13])[O:6][C:7]=2[CH3:8])=[CH:21][CH:22]=1)=[O:25]
Reactant: O=Cc1ccc(O)cc1
Reactant: COC(=O)c1cccc(-c2nc(CCl)c(C)o2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2nc(COc3ccc(C=O)cc3)c(C)o2)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
A mixture of methyl 3-(4-chloromethyl-5-methyl-1,3-oxazol-2-yl)benzoate (2.0 g), 4-hydroxybenzaldehyde (0.87 g), potassium carbonate (0.98 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give methyl 3-{4-[(4-formylphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzoate as colorless crystals (2.33 g, yield 94%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 103-104° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[F:18][C:19]1[C:27]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:25]=[C:24]([F:32])[C:20]=1[C:21](O)=[O:22]>>[F:18][C:19]1[C:27]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:26][CH:25]=[C:24]([F:32])[C:20]=1[C:21]([N:15]1[CH2:16][CH2:17][N:12]([C:3]2[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:7][C:2]=2[F:1])[CH2:13][CH2:14]1)=[O:22]
Reactant: CS(=O)(=O)c1ccc(F)c(C(=O)O)c1F
Reactant: CS(=O)(=O)c1ccc(N2CCNCC2)c(F)c1
Product: CS(=O)(=O)c1ccc(N2CCN(C(=O)c3c(F)ccc(S(C)(=O)=O)c3F)CC2)c(F)c1

Procedure:
This compound was prepared in analogy to example 5 from 1-(2-fluoro-4-methanesulfonyl-phenyl)-piperazine and 2,6-difluoro-3-methanesulfonyl-benzoic acid. MS (m/e): 477.0 (MH+, 67%)
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[CH3:27][NH:28][C:29](=[O:46])[C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][C:31]=1[CH3:45]>>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH:7]([CH3:26])[CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:33]4[CH:34]=[CH:35][C:30]([C:29]([NH:28][CH3:27])=[O:46])=[C:31]([CH3:45])[CH:32]=4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)[N:15]=1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1C
Product: CNC(=O)c1ccc(-c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)C(C)C3)cc1C

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 129, Step 4 starting from 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine and N,2-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide. LCMS (M+H)+: m/z=486.298.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2([CH:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:20]=4)[CH2:15][CH2:14][NH:13]3)[CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[ClH:1].[ClH:1].[N:7]1[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=1[C:8]1([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:20]=3)[CH2:15][CH2:14][NH:13]2)[CH2:11][CH2:10][CH2:9]1
Reactant: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3cccc(Cl)n3)CCC1)NCC2
Agent: [Pd]
Solvent: CO
Product: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccccn3)CCC1)NCC2
Product: Cl
Temperature: 25 °C
Reaction time: 36 h

Procedure:
N-[2-({1-[1-(6-Chloropyridin-2-yl)cyclobutyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}oxy)ethyl]propane-1-sulfonamide (9 mg) were dissolved in methanol (1 ml). 10% Palladium on charcoal (5 mg) was added and the reaction mixture was stirred under an atmosphere of hydrogen at room temperature for 36 hours. The catalyst was removed by filtration and washed with methanol. The solvent was evaporated in vacuo. 5N isopropanolic hydrochloric acid (0.5 ml) was added. The solvent was evaporated in vacuo. Yield: 9 mg.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:17][CH:16]=2)=[O:13])[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.[C:38](O)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C1CCC(N=C=NC2CCCCC2)CC1>ClCCl.C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([C:38](=[O:45])[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH2:24][CH2:23]3)=[CH:17][CH:16]=2)=[O:13])[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccccc1
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)Nc1ccc(OC2CCNCC2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cn1nc(C(C)(C)C)cc1NC(=O)Nc1ccc(OC2CCN(C(=O)c3ccccc3)CC2)cc1
Temperature: 22 °C
Reaction time: 19 h
Yield: 93.4 %

Procedure:
To an ice-cooled solution of 1-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-3-[4-(piperidin-4-yloxy)-phenyl]-urea (82.2 mg, 0.22 mmol), 1-hydroxybenzotriazole (HOBt, 50.1 mg, 0.37 mmol), and benzoic acid (38.8 mg, 0.32 mmol) in dichloromethane-THF (1:1, 2 mL) is added DCC (52.0 mg, 0.25 mmol). The reaction mixture is stirred at 22° C. for 19 hours. The crude product is purified on a silica gel chromatography with ethyl acetate-hexanes to provide a white solid (97.7 mg, 93.4% yield, ES+(m/z) 476.1 [M+H]).
Reaction SMILES: [NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:12]([OH:14])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(OCC)(=O)C>[NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:12]([O:14][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)OCc1ccccc1
Yield: 70 %

Procedure:
BocSer(Bzl) 60 g (0.2 mol) was added to 400 ml of ethyl acetate, to which triethylamine 21 g (0.2 mol) and benzyl bromide 35.4 g (0.2 mol) were added and reacted under refluxing condition for 4 hours. After cooled, the salt produced was separated by filtration. The filtrate was washed with an aqueous NaHCO3 solution and an aqueous NaCl solution and then dried over Na2SO4 and concentrated to dryness to obtain 54 g of white powder (Yield: 68%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[NH:34][C:35]1[S:36][CH:37]=[CH:38][N:39]=1>>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:22]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:19])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:21])[CH3:20])=[O:23])=[C:28]([NH:34][C:35]2[S:36][CH:37]=[CH:38][N:39]=2)[CH:29]=1
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reactant: NCc1ccc(F)cc1Nc1nccs1
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1Nc1nccs1)c(OCc1ccccc1)c2=O

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and N-(2-(aminomethyl)-5-fluorophenyl)thiazol-2-amine, derived from reduction of intermediate 123, 4-fluoro-2-(thiazol-2-ylamino)benzonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm: 9.92 (1H, s), 9.10 (1H, t, J=6.3 Hz), 8.19 (1H, dd, J=2.8, 12.3 Hz), 7.41-7.38 (2H, m), 7.32-7.28 (5H, m), 6.99 (1H, d, J=3.8 Hz), 6.71 (1H, ddd(dt), J=2.8, 8.3), 5.05 (2H, s), 4.45 (2H, d, J=6.3 Hz), 4.01-3.98 (2H, m), 3.88-3.85 (2H, m), 1.54 (6H, s) LCMS (+ESI, M+H+) m/z 536.
Reaction SMILES: [C:1]([Cl:6])(=O)[C:2](Cl)=O.[Cl:7][C:8]1[CH:9]=[C:10]([C:15]([OH:17])=O)[C:11](=[O:14])[NH:12][N:13]=1.C[N:19]([CH:21]=O)C>C1COCC1>[Cl:6][C:1]1[CH:2]=[CH:11][C:10]([CH2:21][NH:19][C:15]([C:10]2[C:11](=[O:14])[NH:12][N:13]=[C:8]([Cl:7])[CH:9]=2)=[O:17])=[CH:9][CH:8]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(Cl)n[nH]c1=O
Reactant: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Cl)cc1)c1cc(Cl)n[nH]c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalyl chloride was added to a solution a 8.73 g of 6-chloro-3-oxo-2,3-dihydro-pyridazine-4-carboxylic acid and 1 ml DMF in 250 ml THF at 5-10° C. and the mixture was stirred at room temperature for 2 h. Afterwards, it was evaporated to dryness, the residue dissolved in 450 ml THF and 13.8 g potassium carbonate and a solution of 7.2 g 4-chloro-benzyl amide in THF were added. The solvent was distilled off after 2 h of stirring at room temperature, the residue suspended in 100 ml water and a pH of 6.4 was adjusted. The obtained precipitate was sucked off, suspended again in 50 ml water and the pH is adjusted to 3. Afterwards, the precipitate was sucked off and dried over phosphorous pentoxide in an desiccator.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1C(C)(C)C.O.[C:19]([OH:23])(=O)[CH:20]=[O:21].O>ClCCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([C:6]([CH3:11])([CH3:7])[CH3:5])[C:9]2[O:12][C:20](=[O:21])[CH:19]([OH:23])[C:10]=2[CH:11]=1
Reactant: COC(=O)CCc1ccc(O)cc1C(C)(C)C
Reactant: O=CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCCl
Product: COC(=O)CCc1cc2c(c(C(C)(C)C)c1)OC(=O)C2O
Yield: 200 %

Procedure:
23.6 g of 3-(2-tert-butyl-4-hydroxy-phenyl)-propionic acid methyl ester (US 423070-A2), 10.1 g of glyoxylic acid monohydrate and 0.08 g of p-toluenesulfonic acid are boiled in 80 ml of 1,2-dichloroethane for 7 hours using a water separator. The reaction solution is then cooled, washed three times with 50 ml of water each time and freed of solvent using a rotary evaporator. 29.2 g of 3-(7-tert-butyl-3-hydroxy-2-oxo-2,3-dihydro-benzofuran-5-yl)-propionic acid methyl ester are obtained in the form of a yellowish oil. That yellowish oil is placed in 50 ml of toluene with 15 ml of thionyl chloride and 3 drops of DMF and the reaction mixture is then slowly heated to 100° C. at such a rate that the evolution of HCl and SO2 remains vigorous yet controllable. The reaction mixture is then stirred at that temperature for a further hour. Approximately 50 ml of liquid are then distilled off in order to remove the excess thionyl chloride. The residue is diluted with 160 ml of toluene and, at room temperature, 14 ml of triethylamine are added dropwise thereto. The thick, red reaction mixture is then heated under reflux for 30 min. After cooling to room temperature, the triethylamine hydrochloride which has precipitated is filtered off and the filtrate is concentrated to an oily consistency using a rotary evaporator. The isoxindigo is crystallised out by adding 100 ml of acetonitrile, is filtered off, washed with acetonitrile and dried. 7.4 g (27% of the theoretical yield) of 3-[7,7′-di-tert-butyl-2,2′-dioxo-[3,3′]bibenzofuranyliden-5-yl]-5,5′-propionic acid methyl ester (LVIa) are obtained.
Reaction SMILES: [CH3:1][C:2]1[S:19][C:5]2[O:6][C:7]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:8]=3[NH:9][C:10](=O)[C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[CH3:1][C:2]1[S:19][C:5]2[O:6][C:7]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:8]=3[N:9]=[C:10]([N:38]3[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]3)[C:4]=2[CH:3]=1
Reactant: CN1CCNCC1
Reactant: Cc1cc2c(s1)Oc1cc([N+](=O)[O-])ccc1NC2=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Cc1cc2c(s1)Oc1cc([N+](=O)[O-])ccc1N=C2N1CCN(C)CC1

Procedure:
In the same manner as in Example 125 and using 2-methyl-8-nitrothieno[2,3-b][1,5]benzoxazepin-4(5H)-one, phosphorus oxychloride, N,N-dimethylaniline and 1-methylpiperazine, 2-methyl-4-(4-methylpiperazin-1-yl)-8-nitrothieno[2,3-b][1,5]benzoxazepine is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:20])[C:6]=1[N:7]1[CH2:11][CH2:10][C@@H:9]([NH:12]C(=O)OC(C)(C)C)[CH2:8]1.C(OC([NH:28][C:29]1[S:33][C:32]([C:34]2[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:35]=2[F:41])=[N:31][C:30]=1[C:42](O)=[O:43])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[NH2:28][C:29]1[S:33][C:32]([C:34]2[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:35]=2[F:41])=[N:31][C:30]=1[C:42]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:20])[C:6]=1[N:7]1[CH2:11][CH2:10][C@@H:9]([NH2:12])[CH2:8]1)=[O:43]
Reactant: Cn1ncc(N)c1N1CC[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CC[C@@H](N)C1
Yield: 32 %

Procedure:
Following the procedures as described in Example 113, (R)-tert-butyl 1-(4-amino-1-methyl-1H-pyrazol-5-yl)pyrrolidin-3-ylcarbamate, 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid, and HATU were reacted to give 126 as a white solid (38 mg, 32%) over two steps. 1H NMR (400 MHz, DMSO) δ 7.67 (d, J=19.5, 1H), 7.62-7.45 (m, 3H), 7.28 (t, J=8.7, 2H), 3.63 (s, 3H), 3.53 (s, 1H), 3.20 (dt, J=8.9, 4.4, 2H), 2.84 (d, J=10.2, 2H), 2.05-1.84 (m, 2H), 1.75 (s, 2H). ESIMS m/z=420.1 (M+1)
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:15][CH2:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.C(OCC)(=O)C>[CH2:18]([O:17][CH2:16][CH2:15][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[CH:12][CH:11]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCCOCc1ccccc1
Reactant: Oc1ccc(C2CCCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: c1ccc(COCCOc2ccc(C3CCCCC3)cc2)cc1
Temperature: 60 °C
Reaction time: 23 h
Yield: 90.1 %

Procedure:
A suspension of 4-cyclohexylphenol (2.5 g), benzyl 2-bromoethyl ether (3.0 g) and potassium carbonate (2.4 g) in N,N-dimethylformamide (50 mL) was stirred at 60° C. for 23 hours. The reaction solution was diluted with water and ethyl acetate. The organic layer was washed with saturated aqueous potassium carbonate solution and saturated ammonium chloride (×2), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a colorless oil (3.9 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][N:11]([C:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:14])[CH2:10][C@H:9]2[N:21]([CH3:32])[C:22](=[O:31])[O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:42](Cl)(=[O:44])[CH3:43].CO>C(Cl)Cl>[F:30][C:27]1[CH:26]=[CH:25][C:24]([O:23][C:22](=[O:31])[N:21]([C@H:9]2[C@H:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:12][N:11]([C:13]([CH:15]3[CH2:20][CH2:19][N:18]([C:42](=[O:44])[CH3:43])[CH2:17][CH2:16]3)=[O:14])[CH2:10]2)[CH3:32])=[CH:29][CH:28]=1
Reactant: CC(=O)Cl
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCNCC2)C[C@H]1c1ccc(Cl)cc1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCC(C(=O)N2C[C@@H](N(C)C(=O)Oc3ccc(F)cc3)[C@H](c3ccc(Cl)cc3)C2)CC1
Reaction time: 5 h
Yield: 51.8 %

Procedure:
A mixture of 94 mg (0.204 mmol) 4-fluorophenyl (3S,4R)-4-(4-chlorophenyl)-1-(piperidine-4-carbonyl)pyrrolidin-3-yl(methyl)carbamate and 132 mg (1.02 mmol) DIPEA in 5 mL DCM was added 24.1 mg (0.3 mmol) acetyl chloride and stirred for 5 h. Methanol was added and stirred over night. The reaction mixture was extracted with sat NaHCO3 and the aqueous layer extracted with DCM. The combined organic layers were dried with Na2SO4, filtered off and concentrated in vacuum. The residue was subjected to purification by column chromatography on silica eluting with a gradient formed from DCM, methanol and NH3aq. The product containing fractions were evaporated to yield 53 mg (52%) of the title compound as light yellow foam. MS m/e: 502.2 [M+H]+.