Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([CH3:12])=[C:7]2[C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1.[CH3:20][O:21][C:22](=[O:32])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30]Br)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([CH3:12])=[C:7]2[C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[O:19][CH2:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][C:22]([O:21][CH3:20])=[O:32])=[CH:29][CH:28]=1
Reactant: Cc1nnc2c(Cl)cccc2c1-c1cccc(O)c1
Reactant: COC(=O)Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)Cc1ccc(COc2cccc(-c3c(C)nnc4c(Cl)cccc34)c2)cc1
Yield: 82.9 %

Procedure:
A mixture of 3-(8-chloro-3-methylcinnolin-4-yl)phenol (0.21 g, 0.78 mmol), 4-bromomethylphenyl acetic acid methyl ester (0.42 g, 1.64 mmol), and cesium carbonate (1.70 g, 5.2 mmol) in acetone (15 mL) was refluxed for 2 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic residue was purified by silica gel chromatography using 5-50% EtOAc/hexanes as eluent to provide the title compound (0.28 g) as a gum. MS (ESI) m/z 433; HRMS (ESI, [M+H]+) 433.1335.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[F:20][C:21]([F:33])([F:32])[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[CH:24][CH:23]=1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:29](=[O:30])[CH2:28][C:25]3[CH:24]=[CH:23][C:22]([C:21]([F:32])([F:20])[F:33])=[CH:27][CH:26]=3)[N:11]=2)=[CH:13][CH:14]=1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Product: O=C(Cc1ccc(C(F)(F)F)cc1)Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O

Procedure:
The product of Example 86A and 2-[4-(trifluoromethyl)phenyl]acetic acid were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.40-8.42 (m, 1H), 7.93-8.04 (m, 2H), 7.72-7.74 (m, 3H), 7.59-7.69 (m, 6H), 3.83-3.84 (bs, 2H); MS (ESI−) M/Z 456 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][CH:12]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:20][S:21]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)(=[O:23])=[O:22].COC(OC)OC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][CH2:12][N:27]3[CH2:28][CH2:29][N:24]([S:21]([CH3:20])(=[O:23])=[O:22])[CH2:25][CH2:26]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: O=CCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: COC(OC)OC
Product: CS(=O)(=O)N1CCN(CCc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.3 %

Procedure:
To a solution of crude (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-acetaldehyde (300 mg) and 1-methanesulfonyl-piperazine (243 mg) in 1,2-dichloroethane (10 mL) at room temperature was added trimethylorthoformate (0.33 mL). The reaction mixture was stirred at room temperature for 1 h and then sodium triacetoxyborohydride (534 mg) was added. The reaction mixture was stirred at room temperature for 16 h and then quenched with saturated aqueous sodium carbonate solution (20 mL) and extracted into dichloromethane (2×20 mL). The combined organics were washed with aqueous brine solution (2×20 mL), dried (MgSO4), concentrated and purified using column chromatography to give 2-chloro-6-[2-(4-methanesulfonyl-piperazin-1-yl)-ethyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidine as a white solid (100 mg).
Reaction SMILES: [NH:1]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[C@H:2]([C:5]([OH:7])=O)[CH2:3][OH:4].[NH2:18][C@H:19]([C:28]([O:30][CH3:31])=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1.ON1C(=O)CCC1=O.CCN=C=NCCCN(C)C>CN(C=O)C>[NH:1]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[C@H:2]([C:5]([NH:18][C@H:19]([C:28]([O:30][CH3:31])=[O:29])[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=1)=[O:7])[CH2:3][OH:4]
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: O=C(N[C@@H](CO)C(=O)O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 92.4 %

Procedure:
Z-Ser-OH 23.9 g and 23.2 g of H-Tyr-OMe were dissolved in 50 mL of DMF, 12.7 g of HOSu and 20 mL of WSC were added to the solution, then the mixture was stirred at 0° C. for 5 minutes then at room temperature overnight. After confirmation with ninhydrin, the reaction mixture was concentrated under reduced pressure. Ethyl acetate 500 mL was added to the residue, and the mixture was washed twice with 200 mL of 1N hydrochloric acid, twice with 200 mL of saturated aqueous sodium bicarbonate, twice with saturated saline, in this order. The ethyl acetate layer was concentrated under reduced pressure. The residue was solidified by treatment with hexane. Thus 38.44 g of Z-Ser-Tyr-OMe (92.3% yield) was obtained.
Reaction SMILES: Cl.[CH3:2][N:3]([C@@H:28]1[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]1)[C:4]1[N:5]=[C:6]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:21])=[CH:16][CH:15]=2)[C:7]([C:10]([NH2:12])=[O:11])=[N:8][CH:9]=1.CCN(C(C)C)C(C)C.[C:43]([Cl:47])(=[O:46])[CH:44]=[CH2:45]>CN1C(=O)CCC1>[C:43]([N:30]1[CH2:31][CH2:32][CH2:33][C@@H:28]([N:3]([CH3:2])[C:4]2[N:5]=[C:6]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)=[O:21])=[CH:16][CH:15]=3)[C:7]([C:10]([NH2:12])=[O:11])=[N:8][CH:9]=2)[CH2:29]1)(=[O:46])[CH:44]=[CH2:45].[ClH:47]
Reactant: C=CC(=O)Cl
Reactant: CN(c1cnc(C(N)=O)c(Nc2ccc(C(=O)N3CCOCC3)cc2)n1)[C@@H]1CCCNC1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)N1CCC[C@@H](N(C)c2cnc(C(N)=O)c(Nc3ccc(C(=O)N4CCOCC4)cc3)n2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (R)-5-(methyl(piperidin-3-yl)amino)-3-(4-(morpholine-4-carbonyl)phenylamino)pyrazine-2-carboxamide hydrochloride (92) (40 mg, 0.084 mmol) in NMP (3 mL) was added DIEA (150 μL, 0.84 mmol) and then acryloyl chloride (23 mg, 0.25 mmol). The mixture was stirred at RT for 1.5 h, quenched with TFA (0.2 mL), diluted with 2 mL water, and subjected to reverse phase preparative HPLC to isolate the title compound (93) as an HCl salt (25 mg). MS found for C25H31N7O4 as (M+H)+ 494.1, (M−H)− 492.3. UV: λ=275, 280, 313, 343, 369 nm.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1>>[C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][CH:19]3[CH2:20][CH2:21][O:16][CH2:17][CH2:18]3)=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc(C#Cc2ccccc2)cn1
Reactant: O=C1CCOCC1
Product: C(#Cc1ccc(NC2CCOCC2)nc1)c1ccccc1

Procedure:
The title compound, MS: m/e=279.3 (M+H+), can be prepared in accordance with the general method of example 13, step 2 from 5-phenylethynyl-pyridin-2-ylamine (example 13, step 1) and tetrahydro-4H-pyran-4-one.
Reaction SMILES: C([O:8][CH2:9][C:10]([O:12][CH2:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([CH2:26][O:27][C:28](=[O:38])[CH2:29][O:30]CC1C=CC=CC=1)=[O:25])=[O:15])=[O:11])C1C=CC=CC=1>CN(C=O)C.[Pd]>[OH:8][CH2:9][C:10]([O:12][CH2:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([CH2:26][O:27][C:28](=[O:38])[CH2:29][OH:30])=[O:25])=[O:15])=[O:11]
Reactant: O=C(COC(=O)COCc1ccccc1)NCCCCCCNC(=O)COC(=O)COCc1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: O=C(COC(=O)CO)NCCCCCCNC(=O)COC(=O)CO
Temperature: 70 °C
Reaction time: 72 h

Procedure:
Benzyloxy-acetic acid {6-[2-(2-benzyloxy-acetoxy)-acetyl amino]-hexylcarbamoyl}-methyl ester (250 g) was dissolved in DMF (600 ml) in a pressure vessel (Autoclave), 50% wet palladium on carbon (10%, 75 g) was added and the mixture was stirred under hydrogen atmosphere (8 Kg) for 72 hours at 70° C. The catalyst was removed by filtration and 80% of the DMF was distilled off. The crude product was precipitated by adding to Methanol and filtered and dried to get pure (Hydroxy-acetic acid {6-[2-(2-hydroxy-acetoxy)-acetylamino]-hexylcarbamoyl}-methyl ester) (90 g) as a white powder with a melting point of 156-158° C. The pure product was characterized by 1HNMR (CDCl3+DMSO-d6) δ 1.22 (m, 2H, CH2), 1.38 (m, 2H, CH2), 3.06 (m, 2H, CH2), 4.15 (d, 2H, CH2), 4.48 (s, 2H, CH2), 5.42 (t, 1H, OH), 7.98 (bt, 1H, NH).
Reaction SMILES: [O:1]1CCO[CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([O:31][CH2:32][O:33][CH3:34])[CH2:18][C@@H:19]2[O:27][C:28](=[O:30])[CH3:29])=[CH:14][CH:13]=3)[CH2:10][CH2:9]1)[CH3:7]>CC(C)=O.Cl(O)(=O)(=O)=O>[C:28]([O:27][C@@H:19]1[C@@:20]2([CH3:21])[C:15](=[CH:14][CH:13]=[C:12]3[C@@H:22]2[CH2:23][CH2:24][C@@:25]2([CH3:26])[C@H:11]3[CH2:10][CH2:9][C@@H:8]2[CH:6]([CH:2]=[O:1])[CH3:7])[CH2:16][C@@H:17]([O:31][CH2:32][O:33][CH3:34])[CH2:18]1)(=[O:30])[CH3:29]
Reactant: COCO[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCCO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(C)=O
Product: COCO[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Yield: 44.1 %

Procedure:
In 10 ml of acetone was dissolved 100 mg of 20-(1,3-dioxolan-2-yl)-1α-acetoxy-3β-(methoxymethyl)oxypregna-5,7-diene, followed by addition of one drop of 70% perchloric acid, and the mixture was refluxed in an atmosphere of argon gas for 2 hours. The reaction mixture was then worked up in the same manner as Example 156 to give 40 mg of 1α-acetoxy-3β-(methoxymethyl)oxypregna-5,7-diene-20-carbaldehyde showing the following physical properties. 1H-NMR spectrum (90 MHz) δTMSCDCl 3: 0.66 (s, 3H), 1.00 (s, 3H), 1.16 (d, J=6.2 Hz, 3H), 2.07 (s, 3H), 3.35 (s, 3H), 4.30 (m, 1H), 4.65 (br. s, 2H), 4.99 (1H), 5.35 (m, 1H), 5.70 (m, 1H), 9.57 (d, J=3.5 Hz, 1 H) IR spectrum (KBr): 1735, 1725 cm-1
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[C:4]([C:15]2[CH:20]=[N:19][CH:18]=[CH:17][N:16]=2)[N:3]=1.[F:21][CH:22]([F:31])[O:23][C:24]1[CH:25]=[C:26]([NH2:30])[CH:27]=[CH:28][CH:29]=1.CCN(CC)CC>C1COCC1>[F:21][CH:22]([F:31])[O:23][C:24]1[CH:25]=[C:26]([NH:30][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[C:4]([C:15]3[CH:20]=[N:19][CH:18]=[CH:17][N:16]=3)[N:3]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: O=[N+]([O-])c1ccc2nc(-c3cnccn3)nc(Cl)c2c1
Reactant: Nc1cccc(OC(F)F)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc2nc(-c3cnccn3)nc(Nc3cccc(OC(F)F)c3)c2c1
Temperature: 75 °C
Reaction time: 18 h
Yield: 92.2 %

Procedure:
A mixture of 4-chloro-6-nitro-2-(pyrazin-2-yl)quinazoline (1.00 g, crude, 3.7 mmol, 1.0 eq.), 3-(difluoromethoxy)benzenamine (600 mg, 3.7 mmol, 1.0 eq.) and Et3N (1.00 g, 10 mmol, 3.0 eq) in THF (80 mL) was stirred at 75° C. for 18 h. After cooling, the volatiles were removed in vacuo and the residue was washed with H2O (100 mL×2). The solid was dried in vacuo to afford 1.40 g of N-(3-(difluoromethoxy)phenyl)-6-nitro-2-(pyrazin-2-yl)quinazolin-4-amine as a black solid (90.2% of two steps). LCMS m′ z=411.0 (M+1) (Method A) (retention time=1.61 min).
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[CH2:14][O:15][Si](C(C)(C)C)(C)C)[NH:7][C:6]1=[O:23])[CH3:3].Cl.[CH3:25][NH:26][S:27](=[O:36])([C:29]1[CH:34]=[CH:33]C(N)=[CH:31][CH:30]=1)=[O:28]>C(O)C>[OH:15][CH2:14][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:13]=1[C:5](=[CH:4][NH:2][C:3]1[CH:33]=[CH:34][C:29]([S:27]([NH:26][CH3:25])(=[O:36])=[O:28])=[CH:30][CH:31]=1)[C:6](=[O:23])[NH:7]2
Reactant: CN(C)C=C1C(=O)Nc2cccc(CO[Si](C)(C)C(C)(C)C)c21
Reactant: CNS(=O)(=O)c1ccc(N)cc1
Agent: Cl
Solvent: CCO
Product: CNS(=O)(=O)c1ccc(NC=C2C(=O)Nc3cccc(CO)c32)cc1
Temperature: 25 °C
Yield: 39.3 %

Procedure:
A solution of 1.2 g (3.7 mmol) of 3-methylsulfanyl-4-(t-butyldimethylsilyloxy)-methyl-1,3-dihydro-indol-2-one in THF (25 mL) was stirred with saturated ammonium chloride solution (20 mL), and activated zinc dust (5 g) was added. The mixture was stirred for 60 h at rt. The organic phase was separated, dried over MgSO4 and concentrated to give 1.16 g of impure 4-t-butyldimethylsilyloxy)methyl-1,3-dihydro-indol-2-one as an off-white solid: 1H NMR (DMSO-d6): δ 0.11 (s, 6H), 0.86 (s, 9H), 3.42 (s, 2H), 4.67 (s, 2H), 6.74 (d, J=7.7 Hz, 1H), 695 (d, J=7.7 Hz, 1H) 7.18 (t, J=7.7 Hz, 1H), 10.40 (s, 1H). A solution of 0.64 g (2.3 mmol) of 4-(t-butyldimethylsilyloxy)methyl-1,3-dihydro-indol-2-one in DMF dimethylacetal (5 mL) was heated to 100° C. for 1 h. The excess DMF dimethylacetal was removed under high vacuum, and the resulting dark oil was chromatographed on silica gel, eluting with EtOAc, to give 0.34 g (44%) of 3-dimethylaminomethylene-4-(t-butyldimethyl-silyloxy)methyl-1,3-dihydro-indol-2-one as a white solid: 1H NMR (DMSO-d6): δ −0.03 (s, 6H), 0.81 (s, 9H), 3.29 (s, 6H), 4.64 (s, 2H), 6.66 (d, J=7.3 Hz, 1H), 6.73 (d, J=7.3 Hz, 1H), 6.79 (t, J=7.3 Hz, 1H), 7.76 (s, 1H), 9.97 (s, 1H) ); APCI−MS m/z 333 (M+1)+. A solution of 0.115 g (0.34 mmol) of 3-dimethylaminomethylene-4-(t-butyldimethylsilyloxy)methyl-1,3-dihydro-indol-2-one in ethanol (10 mL) was treated with 0.076 g (0.34 mmol) N-methylsulfanilamide hydrochloride. The solution was refluxed for 0.5 h and cooled to rt. The resulting yellow precipitate was isolated by filtration, washed with ethanol and dried to yield 0.048 g (38%) of the title compound: 1H NMR (DMSO-d6): δ 2.37 (d, J=5.0 Hz, 3H), 4.67 (s, 2H), 5.3 (bs, 1H), 6.78 (d, J=7.5 Hz, 1H), 6.93 (d, J=7.5 Hz, 1H), 6.99 (t, J=7.5 Hz, 1H), 7.33 (q, J=5.0 Hz, 1H), 7.44 (d, J=8.6 Hz, 2H), 7.71 (d, J=8.6 Hz, 2H), 8.32 (d, J=12.2 Hz, 1H), 10.67 (s, 1H), 11.26 (d, J=12.2 Hz, 1H); APCI−MS m/z 358 (M−1)−. Anal. Calcd for C17H17N3O4S: C, 56.81, H, 4.77; N, 11.69, S, 8.92. Found C, 56.89, H, 4.81; N, 11.70; S, 8.84.
Reaction SMILES: [CH:1]([C:3]1[CH:27]=[CH:26][C:6]([C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][C:16]3=[O:17])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1)=O.[C:28]([CH:32]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:30][CH3:31])=[O:29]>CO>[CH3:31][O:30][C:28]([CH:32]=[CH:1][C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][C:16]3=[O:17])[CH2:11][CH2:10]2)=[O:8])=[CH:26][CH:27]=1)=[O:29]
Reactant: O=Cc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CO
Product: COC(=O)C=Cc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 145.2 %

Procedure:
1-[1-(4-Formylbenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (4.77 g) is dissolved in methanol (100 ml) and thereto is added carbomethoxymethylenetriphenylphosphorane (5.3 g) and the mixture is stirred at room temperature for 1 hour. The solvent is concentrated and the residue is purified roughly by silica gel column chromatography (solvent: n-hexane:ethyl acetate=1:1) to give a mixture (8 g) of 1-{1-[4-(2-methoxycarbonylvinyl)benzoyl]4-piperidinyl}-3,4-dihydrocarbostyril and triphenylphosphineoxide.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][C:8]([C:12]3[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=3)=[CH:9][CH:10]=2)[N:5]=[C:4]([O:22]C)[CH:3]=1.[F:24][C:25]([F:34])([F:33])[C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.Cl.CCOCC>C(O)(C)C>[F:24][C:25]([F:33])([F:34])[C:26]1[CH:27]=[CH:28][C:29]([NH:30][C:2]2[C:11]3[C:6](=[N:7][C:8]([C:12]4[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=4)=[CH:9][CH:10]=3)[N:5]=[C:4]([OH:22])[CH:3]=2)=[CH:31][CH:32]=1
Reactant: COc1cc(Cl)c2ccc(-c3ncccc3C(F)(F)F)nc2n1
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)O
Product: Oc1cc(Nc2ccc(C(F)(F)F)cc2)c2ccc(-c3ncccc3C(F)(F)F)nc2n1

Procedure:
Heat 4-chloro-2-methoxy-7-(3-trifluoromethyl-pyridin-2-yl)-[1,8]naphthyridine (600 mg, 1.8 mmol), 4-trifluoromethylaniline (322 mg, 2.0 mmol) and 2M hydrochloric acid in ether (1 mL, 2.0 mmol) in isopropanol (15 mL) at 80° C. for 16 hours. Cool the mixture and collect the precipitate by filtration. Partition the solid between ethyl acetate and saturated sodium bicarbonate solution. Separate the layers and extract the aqueous layer with further ethyl acetate. Wash the combined organic extracts with brine, dry (MgSO4) and evaporate to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([NH2:11])[CH2:7][CH2:6]1)=[O:4].CCN(CC)CC.[Cl:19][C:20]1[CH:21]=[N:22][C:23]([CH3:29])=[C:24]([CH:28]=1)[C:25](Cl)=[O:26]>C1COCC1>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:25]([C:24]2[C:23]([CH3:29])=[N:22][CH:21]=[C:20]([Cl:19])[CH:28]=2)=[O:26])[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Reactant: Cc1ncc(Cl)cc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](NC(=O)c2cc(Cl)cnc2C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trans-4-Amino-cyclohexanecarboxylic acid methyl ester (2.14 g, 11.05 mmol) is suspended in THF (50 mL) and Et3N (2.79 g, 27.6 mmol) and cooled to 0° C. 5-chloro-2-methylnicotinoyl chloride (step 1) (2.20 g, 11.05 mmol) is slowly added portionwise and the RM is stirred at r.t. for 2 hours. LCMS showed mainly product. The reaction mixture is partitioned between EtOAc and 1M HCl. The organic phase is washed with water and brine, dried over MgSO4, filtered and the solvent is removed in vacuo to afford the title product which is used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 8.53 (1H, d), 7.42 (1H, 5), 7.80 (1H, d), 3.70 (1H, m), 3.60 (3H, s), 2.49 (3H, s), 2.29 (1H, m), 1.95 (4H, m), 1.42 (2H, m), 1.29 (2H, m); [MH]+311.26.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]12[CH2:16][O:15][C@H:14]([C:17]([F:20])([F:19])[F:18])[CH:13]1[CH2:12][O:11][NH:10]2>C(O)(=O)C.CCOC(C)=O.[Zn]>[NH2:10][C@@:9]1([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[CH2:16][O:15][C@H:14]([C:17]([F:19])([F:18])[F:20])[C@H:13]1[CH2:12][OH:11]
Reactant: Fc1cccc(C23CO[C@H](C(F)(F)F)C2CON3)c1F
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: N[C@@]1(c2cccc(F)c2F)CO[C@H](C(F)(F)F)[C@H]1CO
Temperature: 0 °C
Reaction time: 20 h
Yield: 98.1 %

Procedure:
(4S)-6a-(2,3-difluorophenyl)-4-(trifluoromethyl)hexahydrofuro[3,4-c]isoxazole (3.16 g) was dissolved in acetic acid (20 mL) and the reaction mixture cooled to 0° C. Zinc (5.0 g) was added, and the reaction was allowed to warm and stir at RT for 20 h. The reaction mixture was then diluted with EtOAc (50 mL) and filtered through Celite®, washing with a further 100 mL of EtOAc. The combined organic portions were evaporated, dissolved in CHCl3 (20 mL), and ammonia (28% aq., 25 mL) was added slowly. The layers were separated, and the aqueous portion was further extracted with CHCl3 (2×25 mL). The combined organic extracts were dried over anhydrous MgSO4 and evaporated to afford the title compound (3.12 g) which was used in the subsequent step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 2.93 (ddd, J=7.8, 5.1, 2.8 Hz, 1H), 3.85 (dd, J=12.4, 5.1 Hz, 1H), 4.03 (dd, J=9.1, 2.8 Hz, 1H), 4.14 (dd, J=12.3, 2.7 Hz, 1H), 4.35 (d, J=9.1 Hz, 1H), 4.68 (quin, J=7.3 Hz, 1H), 7.09-7.25 (m, 2H), 7.25-7.34 (m, 1H)
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[N-:12]=[N+:13]=[N-:14].[Na+]>CN(C=O)C>[N:12]([C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2)=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: Clc1nccc2ncccc12
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1nccc2ncccc12
Temperature: 80 °C
Reaction time: 4 h
Yield: 96 %

Procedure:
A solution of 5-chloro-1,6-naphthyridine (500 mg, 3.04 mmol) in DMF (5 mL) was stirred at room temperature. Sodium azide (592 mg, 9.12 mmol) was added to the mixture, and the mixture was stirred at 80° C. for 4 h. The mixture was cooled to room temperature and filtered through Celite to remove a white solid. The filtrate was diluted with EtOAc (25 mL) and washed with brine (5×5 mL). The combined organic layers were dried with Na2SO4, filtered, and the solvent was removed under reduced pressure to yield 5-azido-1,6-naphthyridine as a yellow solid, which was used in the next step without further purification (500 mg, yield 96%). ESI MS: m/z 172 [M+H]+.
Reaction SMILES: CN(C=O)C.[CH3:6][C@@H:7]1[NH:12][CH2:11][CH2:10][N:9]([C:13]2[N:14]=[N:15][C:16]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[C:17]3[CH:22]=[CH:21][N:20]=[CH:19][C:18]=23)[CH2:8]1.[F:33][C:34]1([F:52])[CH2:39][CH2:38][N:37]([C:40](OC2C=CC([N+]([O-])=O)=CC=2)=[O:41])[CH2:36][CH2:35]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[F:33][C:34]1([F:52])[CH2:39][CH2:38][N:37]([C:40]([N:12]2[CH2:11][CH2:10][N:9]([C:13]3[N:14]=[N:15][C:16]([C:23]4[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:27][CH:28]=4)=[C:17]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=34)[CH2:8][C@@H:7]2[CH3:6])=[O:41])[CH2:36][CH2:35]1
Reactant: C[C@H]1CN(c2nnc(-c3ccc(C(F)(F)F)cc3)c3ccncc23)CCN1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCC(F)(F)CC1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H]1CN(c2nnc(-c3ccc(C(F)(F)F)cc3)c3ccncc23)CCN1C(=O)N1CCC(F)(F)CC1
Temperature: 75 °C

Procedure:
DMF (3 mL) was added to (S)-4-(3-methylpiperazin-1-yl)-1-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazine 47 (150 mg, 402 μmol), 4-nitrophenyl 4,4-difluoropiperidin-1-carboxylate 41 (230 mg, 803 μmol), potassium carbonate (167 mg, 1.2 mmol), 4-dimethylaminopyridine (9.8 mg, 80 μmol). The reaction was heated to 75° C. for 72 h. The reaction was diluted with ethyl acetate (70 mL) and washed with 1×10 mL water, 1×10 mL NaHCO3, and 1×10 mL brine. The organic layer was dried over MgSO4, filtered, and concentrated. Purification by column chromatography afforded (S)-(4,4-difluoropiperidin-1-yl)(2-methyl-4-(1-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyridazin-4-yl)piperazin-1-yl)methanone 48. MS 520.2 (calc'd) 521.2 (M+H, found).
Reaction SMILES: Br[C:2]1[C:3](F)=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1.[CH3:24][C:25]1[O:29][N:28]=[C:27]([C@:30]([OH:34])([C:32]#[CH:33])[CH3:31])[N:26]=1>>[OH:34][C@:30]([C:27]1[N:26]=[C:25]([CH3:24])[O:29][N:28]=1)([CH3:31])[C:32]#[C:33][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1
Reactant: CNC(=O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(Br)cc1-2
Reactant: C#C[C@@](C)(O)c1noc(C)n1
Product: CNC(=O)c1c(C(N)=O)nc2n1CCOc1ccc(C#C[C@@](C)(O)c3noc(C)n3)cc1-2

Procedure:
10-Bromo-9-fluoro-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide (0.05 g) was reacted with (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol similar to as described in Procedure F to afford 8.4 mg of 10-[(3R)-3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1-ynyl]-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following reverse phase hplc purification. MS (Q1) 437 (M)+. 1H NMR (400 MHz, DMSO) δ 11.05 (q, J=4.1 Hz, 1H), 8.56 (d, J=2.0 Hz, 1H), 8.33 (s, 1H), 7.88 (s, 1H), 7.40 (dd, J=8.5, 2.1 Hz, 1H), 7.07 (d, J=8.5 Hz, 1H), 6.68 (s, 1H), 5.02-4.93 (m, 2H), 4.58-4.45 (m, 2H), 2.81 (d, J=4.5 Hz, 3H), 2.61 (s, 3H), 1.84 (s, 3H).