Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[OH:21][C:22]1[CH:23]=[CH:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:28]([C:25]3[CH:24]=[CH:23][C:22]([OH:21])=[CH:27][N:26]=3)=[O:29])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(O)cn1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1)c1ccc(O)cn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 5-hydroxy-2-pyridinecarboxylic acid (CAN 15069-92-8) as starting materials; LC-MS (UV peak area/ESI) 96.3%, 422.0523 (M−H)−.
Reaction SMILES: Br[C:2](Br)([C:6]([CH3:9])([CH3:8])[CH3:7])[C:3](O)=[O:4].[NH2:11][NH:12][C:13]([NH:15][NH2:16])=[S:14].CO>O>[NH2:16][N:15]1[C:3](=[O:4])[C:2]([C:6]([CH3:9])([CH3:8])[CH3:7])=[N:11][N:12]=[C:13]1[SH:14]
Reactant: CC(C)(C)C(Br)(Br)C(=O)O
Reactant: NNC(=S)NN
Solvent: CO
Solvent: O
Product: CC(C)(C)c1nnc(S)n(N)c1=O
Temperature: 0 °C

Procedure:
A mixture of 2,2-dibromo-3,3-dimethylbutyric acid, 55 parts, and thiocarbohydrazide, 22 parts, in 500 parts of (1:1) methanol and water was heated to reflux for five hours. Upon cooling the reaction mixture to 0° C., a solid formed and was collected. The solid, 4-amino-6-t-butyl-3-mercapto-1,2,4-triazin-5-one, was obtained in 78% of theory (29 parts).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH2:16]>C(O)CC>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([NH:16][CH2:15][CH2:14][N:13]([CH3:17])[CH3:12])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN(C)CCN
Solvent: CCCO
Product: Cc1ccc(NCCN(C)C)c([N+](=O)[O-])c1
Yield: 11.2 %

Procedure:
A mixed solution of 4-chloro-3-nitrotoluene (1.30 g) and N,N-dimethylethylenediamine (1.34 g) in 1-propanol (20 ml) was refluxed for 24 hours and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate and the solution was successively washed with water (×2) and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent: chloroform:methanol=30:1) to give 0.19 g of N-(4-methyl-2-nitrophenyl)-N',N'-dimethylethylenediamine.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[CH3:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.C[N:40](C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[Cl-].[NH4+]>O.C(OCC)(=O)C.CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH2:40])=[O:28])=[CH:24][C:23]=4[CH3:31])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Reactant: Cc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C(N)=O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.33 h
Yield: 69.2 %

Procedure:
A mixture of 0.0755 g (0.175 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methyl-benzoic acid (I-184), 4 mL of dimethylformamide, 0.0904 g (0.231 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate and 0.15 mL (0.859 mmole) of diisopropylethylamine was stirred for 20 minutes, then 0.0196 g (0.366 mmole) of ammonium chloride was added. The reaction mixture was stirred for 1.5 hours and then 150 mL of ethyl acetate and 25 mL of water was added. The organic layer was washed with 25 mL of ammonium chloride solution, 25 mL of water, 25 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0521 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methyl-benzamide (I-193).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[C:6]([N:8]2[CH2:12][CH2:11][N:10]([CH3:13])[C:9]2=[O:14])[CH:7]=1.[CH3:31][CH:32]1[NH:36][C:35](=[O:37])[CH2:34][CH2:33]1>>[CH3:29][C:28]1[C:23]([N:20]2[CH2:21][CH2:22][N:17]([C:15]([C:5]3[CH:4]=[CH:3][C:2]([N:36]4[C:35](=[O:37])[CH2:34][CH2:33][CH:32]4[CH3:31])=[CH:7][C:6]=3[N:8]3[CH2:12][CH2:11][N:10]([CH3:13])[C:9]3=[O:14])=[O:16])[CH2:18][CH2:19]2)=[N:24][CH:25]=[C:26]([CH3:30])[CH:27]=1
Reactant: CC1CCC(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3N3CCN(C)C3=O)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CCC4C)cc3N3CCN(C)C3=O)CC2)c(C)c1
Yield: 12.8 %

Procedure:
Using 1-{5-chloro-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-3-methylimidazolidin-2-one (116 mg) described in Preparation Example 241 and 5-methylpyrrolidin-2-one (40 mg) and by the reaction and treatment in the same manner as in Example 666, the title compound (17 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:18](=[O:21])(=[O:20])[NH2:19])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:22][C:23]([CH3:27])([CH3:26])[C:24]#[CH:25]>>[CH3:22][C:23]([CH3:27])([CH3:26])[C:24]#[C:25][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:18](=[O:21])(=[O:20])[NH2:19])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1ccccc1NS(=O)(=O)c1cccc(Br)c1
Reactant: C#CC(C)(C)C
Product: CC(C)(C)C#Cc1cccc(S(=O)(=O)Nc2ccccc2S(N)(=O)=O)c1
Yield: 27 %

Procedure:
The title compound was synthesized as described for Example 179a) in 27% yield, starting from 3-bromo-N-(2-sulfamoylphenyl)benzenesulfonamide and 3,3-dimethyl-1-butyne.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].C[Si]([C:23]#[C:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]([CH3:36])[C:32]([O:34][CH3:35])=[O:33])(C)C>C1COCC1>[C:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]([CH3:36])[C:32]([O:34][CH3:35])=[O:33])#[CH:23]
Reactant: COC(=O)C(C)c1ccccc1C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccccc1C(C)C(=O)OC
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 89.5 %

Procedure:
A solution of TBAF (1 M solution in THF; 2.28 mL, 2.28 mmol) was added to a solution of methyl 2-(2-((trimethylsilyl)ethynyl)phenyl)propanoate (I50) (0.297 g, 1.14 mmol) in THF (10 mL) at 0° C. The reaction was stirred for 50 minutes at 0° C. then concentrated under reduced pressure and the residue taken up in EtOAc (20 mL). The organic solution was washed with saturated NaHCO3 (20 mL), water (20 mL) and dried over Na2SO4. The solvent was removed in vacuo to yield a brown oily residue. The oil was purified using column chromatography on silica gel (0-5% EtOAc in cyclohexane) to afford the title compound (I51) (0.192 g, 89%) as a pale yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.53-7.48 (m, 1H), 7.36-7.28 (m, 2H), 7.24-7.20 (m, 1H), 4.31 (q, J=7.2 Hz, 1H), 3.67 (s, 3H), 3.28 (s, 1H), 1.50 (d, J=7.2 Hz, 3H). LCMS Method C: rt 5.92 min; m/z 189 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20]Br)[CH3:17].[I-].[Na+]>CN(C=O)C.CCOC(C)=O>[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20][NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[C:8]([CH3:9])[C:2]=1[CH3:1])[CH3:17]
Reactant: Cc1cccc(N)c1C
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(CNc1cccc(C)c1C)OCC
Temperature: 110 °C
Reaction time: 96 h

Procedure:
To a solution of 2,3-dimethylaniline (2.0 mL, 16.6 mmol) in 30 mL of dry DMF at room temperature was added cesium carbonate (5.4 g, 17 mmol), then bromoacetaldehyde diethylacetal (2.50 mL, 16.6 mmol). The solution was warmed to 110° C., and stirred for four days. Sodium iodide (100 mg, 0.6 mmol) was added, and the reaction stirred for an additional 24 hours. The reaction mixture was poured into EtOAc, washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled product as a brown oil which was used directly in the next step without further purification.
Reaction SMILES: [NH:1]1[C:8](=[O:9])[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=2)[CH:13]=1)=O>CO>[CH3:29][O:28][C:26](=[O:27])[C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12]([CH:10]=[C:7]3[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1][C:8]3=[O:9])=[CH:13]2)=[CH:31][CH:30]=1
Reactant: O=C1CC(=O)NC(=O)N1
Reactant: COC(=O)c1ccc(Cn2cc(C=O)c3ccccc32)cc1
Solvent: CO
Product: COC(=O)c1ccc(Cn2cc(C=C3C(=O)NC(=O)NC3=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of barbituric acid (1.28 g; 0.01 mol) and methyl 4-((3-formyl-1H-indol-1-yl)methyl)benzoate (2.93 g; 0.01 mol) in methanol (50 ml) were stirred at room temperature. After 10 min the reaction mixture became a solid suspension and the color of reaction mixture changed to yellow color solid suspension. The suspension continued to stir at room temperature for 5 hrs. Solid product was separated by filtration and washed several times with cold methanol (3×5 ml). The isolated yellow solid recrystallized from methanol gave (2) as a yellow crystalline product; m.p. >300° C.; 1H NMR (DMSO-d6): δ 3.82 (s, 3H), 5.79 (s, 2H), 7.33-7.36 (m, 2H), 7.40-7.42 (d, 2H), 7.61-7.63 (m, 1H), 7.91-7.93 (m, 1H), 7.94-7.95 (d, 2H), 8.68 (s, 1H), 9.62 (s, 1H), 11.06 (bs, 1H), 11.14 (bs, 1H); 13C NMR (DMSO-d6): δ 49.9, 52.1, 109.2, 110.7, 111.8, 117.8, 122.9, 123.7, 127.4, 129.0, 129.5, 129.6, 136.2, 141.4, 141.7, 142.6, 150.1, 162.8, 164.1, 165.5.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:11]1[N:12]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[N:13]=[C:14]2[C:19]=1[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[NH2:38][C:39]1[CH:46]=[CH:45][C:42]([C:43]#[N:44])=[CH:41][C:40]=1[F:47]>C1COCC1>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([N:12]2[C:11]([CH:4]([CH:5]3[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]3)[C:3]([NH:38][C:39]3[CH:46]=[CH:45][C:42]([C:43]#[N:44])=[CH:41][C:40]=3[F:47])=[O:2])=[C:19]3[C:14]([CH2:15][CH2:16][CH2:17][CH2:18]3)=[N:13]2)=[CH:21][CH:22]=1
Reactant: N#Cc1ccc(N)c(F)c1
Reactant: COC(=O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc(NC(=O)C(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)c(F)c1
Reaction time: 0.5 h

Procedure:
To a stirred solution of [rac]-[2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-cyclohexyl-acetic acid methyl ester (250 mg, 0.64 mmol) in dry THF was added LiHMDS (1.0 M solution in THF; 4.5 ml, 4.5 mmol) at −30° C. and stirring continued for another 30 min at that temperature. 4-Amino-3-fluoro-benzonitrile (90.64 mg, 0.768 mmol; CAS Reg. No. 115661-37-5) in THF (1 ml) was then added at that temperature and slowly brought to room temperature. Reaction mixture was then stirred at room temperature for 13 h. TLC shows formation of a new spot. LC-MS of the crude material shows formation of desired product. Reaction mixture was quenched with saturated NH4Cl and the aqueous layer was extracted with EtOAc (3×5 ml). Combined organic layers were washed with brine and concentrated under reduced pressure to give crude material (260 mg); which was then purified by column chromatography [SiO2 (230-400 mesh), EtOAc:hexane 30:70] to give the title compound (130 mg, 42%) as light yellow solid.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[NH2:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:26][C:27]#[N:28]>C1COCC1>[C:27]([CH2:26][C:20]1[C:19]2[C:23](=[CH:24][CH:25]=[C:17]([NH:16][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:18]=2)[NH:22][CH:21]=1)#[N:28]
Reactant: N#CCc1c[nH]c2ccc(N)cc12
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: N#CCc1c[nH]c2ccc(NC(=O)c3ccccc3)cc12
Reaction time: 18 h

Procedure:
A solution of 2.0 g (0.014 mole) of benzoyl chloride in THF was treated with 10 ml pyridine followed by 2.43 g (0.014 mole) of 5-aminoindole-3-acetonitrile, Example 1, and stirred 18 hr. The solvent was removed in vacuo and crude product recrystallized from EtOH to give product used directly in next step below.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[C:17](Br)[CH:16]=[CH:15][C:14]=2[F:20])=[CH:8][C:7]=1[CH3:21].[CH2:23]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:26]=1)[CH3:24]>>[CH2:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:17]2[CH:16]=[CH:15][C:14]([F:20])=[C:13]([CH:18]=2)[O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:22])=[C:7]([CH3:21])[CH:8]=2)=[C:27]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:26]=1)[CH3:24]
Reactant: CCc1ccc(O)c(Oc2ccccc2)c1
Reactant: COC(=O)CCc1ccc(Oc2cc(Br)ccc2F)cc1C
Product: CCc1ccc(Oc2ccc(F)c(Oc3ccc(CCC(=O)O)c(C)c3)c2)c(Oc2ccccc2)c1

Procedure:
The title compound is prepared according to Example 13, Step C by using 3-[4-(5-bromo-2-fluoro-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester and 4-ethyl-2-phenoxy-phenol to afford 15 mg (11%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C30H27FO5 486, found 487 (M+1, 100%).
Reaction SMILES: [CH2:1]([CH:3]([NH:6][OH:7])[CH2:4][CH3:5])[CH3:2].[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[O:19])=[CH:13][CH:12]=1)([O-:10])=[O:9]>>[CH2:1]([CH:3]([N:6]([OH:7])[C:18]([NH:17][C:14]1[CH:13]=[CH:12][C:11]([N+:8]([O-:10])=[O:9])=[CH:16][CH:15]=1)=[O:19])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)NO
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Product: CCC(CC)N(O)C(=O)Nc1ccc([N+](=O)[O-])cc1

Procedure:
Using the method of Compound 39 Part C, N-(1-ethylpropyl)hydroxylamine (Compound 39 Part B, 1.15 g, 11.3 mmol) was reacted with 4-nitrophenyl isocyanate (1.85 g, 11.3 mmol) to provide 1.95 g of the desired product as a solid, m.p. 169°-170° C. Analysis: Calculated for C12H17N3O4 : %C, 53.92; %H, 6.41; %N, 15.72; Found: %C, 53.85; %H, 6.36; %N, 15.55.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1.C([O-])(O)=O.[Na+]>COCCOC.CCO.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:27][C@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:32]3[CH:33]=[N:28][CH:29]=[N:30][CH:31]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: OB(O)c1cncnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](O)C2)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](O)C2)c(-c2cncnc2)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
(S)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 33.1, 2.4. g, 5.38 mmol) and pyrimidin-5-ylboronic acid (1.33 g, 10.76 mmol) were dissolved in a mixture of DME (15 mL) and EtOH (2.1 mL). A solution of 2 M aq. NaHCO3 (8.07 mL, 16.14 mmol) was added, the RM was flushed with argon, then Pd(PPh3)2Cl2 (0.453 g, 0.645 mmol) was added and the RM was stirred under argon at 90° C. for 2 h. After cooling to RT, the RM was dissolved in EtOAc and washed with brine. The organic phase was dried over Na2SO4 and evaporated to dryness under reduced pressure. The residue was purified by flash chromatography (Silica gel column, 200 g, DCM/MeOH from 2% to 5% MeOH). Treatment with Si-Thiol (1 g) in MeOH and a further purification by flash chromatography (RediSep® Silica gel column, EtOAc/MeOH from 0 to 20% MeOH) afforded the title compound as white crystalline solid. HPLC (Condition 4) tR=4.63 min, HPLC Chiral (CHIRALPAK® AD-H, 250×4.6 mm, eluent: EtOH, 0.5 mL/min, UV 210 nm) tR=31.72 min, UPLC-MS (Condition 3) tR=0.91 min, m/z=446.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.78 (m, 1H) 1.79-1.89 (m, 1H) 2.87 (d, J=11.73 Hz, 1H) 3.21 (m, J=11.10, 4.90 Hz, 2H) 3.37 (m, J=7.40 Hz, 1H) 4.19 (br. s, br. s, 1H) 4.87 (d, J=3.52 Hz, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.75-7.89 (m, 2H) 8.08 (d, J=2.35 Hz, 1H) 8.70-8.83 (m, 1H) 8.87 (s, 2H) 9.18 (s, 1H) 10.16 (s, 1H).
Reaction SMILES: ClCCl.[O:4]1[C:9]2[CH:10]=[CH:11][C:12]([CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH:17]3[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:13][C:8]=2[O:7][CH2:6][CH2:5]1.[CH3:27][O:28][C:29]1[CH:38]=[C:37]2[C:32]([C:33]([CH3:43])=[CH:34][C:35](=[O:42])[N:36]2[CH2:39][CH:40]=O)=[CH:31][CH:30]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O.C(Cl)(Cl)Cl.C(O)(=O)C>[O:4]1[C:9]2[CH:10]=[CH:11][C:12]([CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][N:19]([CH2:40][CH2:39][N:36]4[C:37]5[C:32](=[CH:31][CH:30]=[C:29]([O:28][CH3:27])[CH:38]=5)[C:33]([CH3:43])=[CH:34][C:35]4=[O:42])[CH2:18][CH:17]3[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:13][C:8]=2[O:7][CH2:6][CH2:5]1
Reactant: COc1ccc2c(C)cc(=O)n(CC=O)c2c1
Reactant: CCOC(=O)C1CNCCN1CCc1ccc2c(c1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C1CN(CCn2c(=O)cc(C)c3ccc(OC)cc32)CCN1CCc1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 64.8 %

Procedure:
To 2.5 mL of dichloromethane solution containing 0.14 g of ethyl 1-(2-(2,3-dihydro-1,4-benzodioxin-6-yl)ethyl)piperazine-2-carboxylate and 0.10 g of (7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)acetaldehyde, 25 μL of acetic acid were added and stirred at room temperature for 50 min. Then, 0.14 g of sodium triacetoxyborohydride was added, and stirred at room temperature for 1 hour. To the reaction mixture, chloroform and water were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:acetone=50 1], to give 0.15 g of ethyl 1-(2-(2,3-dihydro-1,4-benzodioxin-6-yl)ethyl)-4-(2-(7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperazine-2-carboxylate as a colorless foam.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([O:23][CH3:24])=[O:22])=[C:18]([CH3:25])[C:17]4[CH:26]=[C:27](F)[CH:28]=[CH:29][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:38](C1C=C(OC)C=CC=1C1NC2C(C=1C1CCCCC1)=CC=C(C(OC(C)(C)C)=O)C=2)(=[O:40])C>>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([O:23][CH3:24])=[O:22])=[C:18]([CH3:25])[C:17]4[CH:26]=[C:27]([O:40][CH3:38])[CH:28]=[CH:29][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C1=C(C)c2cc(F)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC(C)(C)C)cc3n2C1
Reactant: COc1ccc(-c2[nH]c3cc(C(=O)OC(C)(C)C)ccc3c2C2CCCCC2)c(C(C)=O)c1
Product: COC(=O)C1=C(C)c2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC(C)(C)C)cc3n2C1

Procedure:
The title product 10-tert-butyl 6-methyl 13-cyclohexyl-3-methoxy-5-methyl-7H-indolo[2,1-a][2]benzazepine-6,10-dicarboxylate 16a was synthesized by following a similar procedure to that used for the synthesis of 10-tert-butyl 6-methyl 13-cyclohexyl-3-fluoro-5-methyl-7H-indolo[2,1-a][2]benzazepine-6,10-dicarboxylate 20a, using tert-butyl 2-(2-acetyl-4-methoxyphenyl)-3-cyclohexyl-1H-indole-6-carboxylate 37d instead of tert-butyl 2-(2-acetyl-4-fluorophenyl)-3-cyclohexyl-1H-indole-6-carboxylate 33c.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:12]2[CH:18]=[CH:17][C:16](=[O:19])[N:15]([CH2:20][CH2:21][CH2:22][C:23]([N:25]3[CH2:32][CH2:31][C:28]4([CH2:30][CH2:29]4)[C@H:27]([OH:33])[CH2:26]3)=[O:24])[CH2:14][C@H:13]2[CH3:34])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].C(O)(=O)C>CO.O=[Pt]=O.O=[Pt]=O.[H][H]>[Cl:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:18][CH2:17][C:16](=[O:19])[N:15]([CH2:20][CH2:21][CH2:22][C:23]([N:25]3[CH2:32][CH2:31][C:28]4([CH2:29][CH2:30]4)[C@H:27]([OH:33])[CH2:26]3)=[O:24])[CH2:14][C@H:13]2[CH3:34])[CH:5]=[CH:6][C:7]=1[C:8]([F:10])([F:9])[F:11]
Reactant: C[C@@H]1CN(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)C(=O)C=CN1c1ccc(C(F)(F)F)c(Cl)c1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CO
Product: C[C@@H]1CN(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)C(=O)CCN1c1ccc(C(F)(F)F)c(Cl)c1
Reaction time: 48 h
Yield: 113.6 %

Procedure:
A solution of 0.066 g (0.1 mmol) of (R)-1-(3-chloro-4-trifluoromethyl-phenyl)-4-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-2-methyl-1,2,3,4-tetrahydro-[1,4]diazepin-5-one (61% ds) (example 65) in 2 ml MeOH was treated with 0.007 g of PtO2 and was stirred over H2-atmosphere for 2 days. After filtration and evaporation, the crude compound was again hydrogenated in 2 ml of MeOH and 0.007 ml (0.1 mmol) of acetic acid with 0.007 g of PtO2/H2 over night. After filtration and evaporation, the residue was reevaporated (3 times) with toluene and the solvent was removed under vacuum to give 0.057 g (86%) of the titled compound as white foam. MS: 502.21 (MH+, Cl).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:10]3[N:19]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:18]([CH2:24][CH2:25][CH3:26])=[N:17][C:11]=3[C:12]([NH2:16])=[N:13][C:14]=2[CH:15]=1.[C:27](Cl)(=[O:31])[CH:28]([CH3:30])[CH3:29].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[NH2:16][C:12]1[C:11]2[N:17]=[C:18]([CH2:24][CH2:25][CH3:26])[N:19]([CH2:20][CH:21]([CH3:22])[CH3:23])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:1][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])=[CH:15][C:14]=2[N:13]=1
Reactant: CC(C)C(=O)Cl
Reactant: CCCc1nc2c(N)nc3cc(OCCCN)ccc3c2n1CC(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c(N)nc3cc(OCCCNC(=O)C(C)C)ccc3c2n1CC(C)C
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
A solution of 7-(3-aminopropoxy)-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine (0.500 g, 1.41 mmol) in chloroform (15 mL) was cooled to 0° C. Isobutyryl chloride (0.147 mL, 1.40 mmol) was added dropwise, and the reaction was stirred for 30 minutes. The reaction was diluted with chloroform and poured into 3% aqueous sodium carbonate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting white solid was recrystallized from acetonitrile to yield 0.450 g of N-{3-[4-amino-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-yloxy]propyl}-2-methylpropanamide as feathery, white crystals, mp 179-181° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12]([OH:14])[CH3:13]>>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][N:9]2[C:12](=[O:14])[CH:13]3[CH:5]([CH2:4][CH2:3][CH2:2][CH2:11]3)[C:6]2=[O:7])=[O:7])=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccc(Br)cc1
Reactant: CCO
Product: O=C(NN1C(=O)C2CCCCC2C1=O)c1ccc(Br)cc1
Yield: 52 %

Procedure:
A mixture of cis-cyclohexanedicarboxylic anhydride (150 mg, 0.97 mmol) and 4-bromobenzoic hydrazide (220 mg, 1.02 mmol) in ethanol (10 mL) was heated under argon overnight. The solvent was removed via rotary evaporation. Purification by column chromatography on silica gel using 1/1 hexane/ethyl acetate as eluent provided 179 mg (52%) of the desired product as a white solid.