Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:9]=[C:10]([CH2:15][OH:16])[CH:11]=[N:12][C:13]=1[CH3:14].C(N(CC)C(C)C)(C)C>CS(C)=O.C(Cl)Cl>[Cl:7][C:8]1[CH:9]=[C:10]([CH:15]=[O:16])[CH:11]=[N:12][C:13]=1[CH3:14]
Reactant: Cc1ncc(CO)cc1Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: Cc1ncc(C=O)cc1Cl
Reaction time: 8 h
Yield: 88 %

Procedure:
Sulphur trioxide pyridene complex (1010 mg, 6.35 mmol) was suspended in dry DMSO (1.126 ml, 15.87 mmol). Then pyridine (0.513 ml, 6.35 mmol) was added and after 15 min under stirring, this solution was slowly added to other containing a mixture of (5-chloro-6-methyl-3-pyridinyl)methanol (for a synthesis see WO2006/137485 A1 Example 255) (500 mg, 3.17 mmol) and N,N-diisopropylethylamine (1.939 ml, 11.10 mmol) in a mixture of DMSO (1.12 ml) and DCM (4 ml) at 0° C. After 1 h under stirring, the ice bath was removed and the reaction was left at room temperature overnight. DCM was evaporated under vacuum, H2O and Et2O (1:1) were added and the aqueous layer was extracted several times with Et2O. Organic layers were washed with brine, dried (Na2SO4), filtered and concentrated to afford 5-chloro-6-methyl-3-pyridinecarbaldehyde (435 mg, 88%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]2[CH:27]=[CH:26][C:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25][C:19]=3[CH:18]=2)[C:11](=[O:28])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:31](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.C([O-])(O)=O.[Na+]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]2[CH:27]=[CH:26][C:20]3[CH2:21][CH2:22][N:23]([CH3:31])[CH2:24][CH2:25][C:19]=3[CH:18]=2)[C:11](=[O:28])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: O=c1cc(OCc2ccccc2)ccn1CCc1ccc2c(c1)CCNCC2
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CN1CCc2ccc(CCn3ccc(OCc4ccccc4)cc3=O)cc2CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 100 mg (0.27 mmol) 4-benzyloxy-1-[2-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-ethyl]-1H-pyridin-2-one (preparation 23.2) in 5.0 mL THF is added 43 μL (0.53 mmol) aqueous 37% formaldehyde solution. The mixture is acidified with acetic acid and then 62 mg (0.29 mmol) sodium triacetoxy-borohydride is added. The reaction mixture is stirred 3 h at RT and is diluted with aqueous saturated NaHCO3-solution. The mixture is stirred additional 1 h at RT, the layers are separated and the aqueous phase is extracted three times with DCM/MeOH. The combined organic phase is dried over MgSO4, filtered and the solvent is evaporated to afford the product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([O:11]C)=O)=[CH:4][CH:3]=1.[OH-].[Na+].Cl.BrC1C=CC(C(C)(C)C(O)=O)=CC=1.[CH3:31][CH:32]([CH3:35])[CH2:33][NH2:34].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([NH:34][CH2:33][CH:32]([CH3:35])[CH3:31])=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C)CN
Reactant: COC(=O)C(C)(C)c1ccc(Br)cc1
Agent: CC(C)(C(=O)O)c1ccc(Br)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)CNC(=O)C(C)(C)c1ccc(Br)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
Methyl 2-(4-bromophenyl)-2-methylpropanoate (1.29 ml, 5 mmol) was added to 30 ml of 1M aq. NaOH and the mixture was stirred at 60° C. overnight. The solution was acidified with 6M aq. HCl (pH 2) and extracted with EtOAc. The organic extract was washed with brine, dried over MgSO4 and concentrated on vacuum. The crude 2-(4-bromophenyl)-2-methylpropanoic acid was coupled without further purification with 2-methylpropan-1-amine (0.5 ml, 5 mmol) in presence of EDC (1.1 g, 5.5 mmol) and HOBt (675 mg, 5 mmol) in 8 ml of DMF at rt overnight. The mixture was dried down on vacuum and extracted with EtOAc and washed with saturated NaHCO3, 10% citric acid and brine. Organic extracts were dried over MgSO4 and concentrated on vacuum to give 2-(4-bromophenyl)-N-isobutyl-2-methylpropanamide as a white solid (1.4 g, 94%). (M+H, 298).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[CH:11][C:12]3[O:13][CH:14]=[C:15]([CH2:17]Cl)[N:16]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[N:19]1([CH2:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[CH:23]=[CH:22][N:21]=[N:20]1.[I-].[K+].C[O-].[Na+]>CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[CH:11][C:12]3[O:13][CH:14]=[C:15]([CH2:17][O:34][C:31]4[CH:32]=[CH:33][C:28]([CH2:27][CH2:26][CH2:25][CH2:24][N:19]5[CH:23]=[CH:22][N:21]=[N:20]5)=[CH:29][CH:30]=4)[N:16]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: ClCc1coc(C=Cc2ccc3c(c2)OCO3)n1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Agent: C[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Product: C(=Cc1nc(COc2ccc(CCCCn3ccnn3)cc2)co1)c1ccc2c(c1)OCO2

Procedure:
0.264 g (1.00 mmol) 2-(2-Benzo[1,3]dioxol-5-yl-vinyl)-4-chloromethyl-oxazole, 0.217 g 1.00 mmol) 4-(4-[1,2,3]Triazol-1-yl-butyl)-phenol, 0.166 g (1.00 mmol) potassium iodide and 0.191 ml (1.00 mmol) of a 30% sodium methylate solution were added to 50.0 ml methanol and heated to reflux for 8 h. After removal of solvent, partitioning of the residue between 50 ml ethyl acetate and 15 ml water, the organic phase was washed with 10 ml water, 10 ml 0.1 N NaOH, 15 ml water twice and dried over sodium sulphate. The solution was concentrated to a volume until crystallisation of the product started. After leaving for 1 h at room temperature the precipitate was filtered, washed with diethyl ether and dried at 40° C. in vacuo. Yield 0.17 g (38%) 4.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]([NH:16][C:17]([C:19]3([C:22]4[CH:30]=[CH:29][C:25]5[O:26][CH2:27][O:28][C:24]=5[CH:23]=4)[CH2:21][CH2:20]3)=[O:18])[CH:10]=2)=[CH:5][CH:4]=1.[CH3:31][CH:32]([CH3:36])[CH2:33][CH:34]=O.COCCOC.[BH4-].[Na+]>ClCCl.O>[O:26]1[C:25]2[CH:29]=[CH:30][C:22]([C:19]3([C:17]([NH:16][C:11]4[CH:10]=[C:9]([C:6]5[CH:5]=[CH:4][C:3]([CH2:2][NH:1][CH2:34][CH2:33][CH:32]([CH3:36])[CH3:31])=[CH:8][CH:7]=5)[C:14]([CH3:15])=[CH:13][CH:12]=4)=[O:18])[CH2:20][CH2:21]3)=[CH:23][C:24]=2[O:28][CH2:27]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(CN)cc1
Reactant: CC(C)CC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(CNCCC(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 12.1 %

Procedure:
N-(4′-(Aminomethyl)-6-methylbiphenyl-3-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (40 mg, 0.10 mmol), 3-methylbutanal (8.6 mg, 0.10 mmol) and Ti(OPr)4 (82 μL, 0.30 mmol) were dissolved in dichloromethane (1.0 mL) and mono-glyme (1.0 mL) and allowed to stir at 25° C. for 16 hours. NaBH4 (5.7 mg, 0.15 mmol) was added and the reaction was stirred for an additional 1 h. The reaction was diluted to 5 mL with dichloromethane before water (5 mL) was added. The reaction was filtered through celite to remove the titanium salts and the layers separated. The organic extracts were dried over Na2SO4 and evaporated. The crude product was purified by reverse phase HPLC to afford 1-(benzo[d][1,3]dioxol-5-yl)-N-(4′-((isopentylamino)methyl)-6-methylbiphenyl-3-yl)cyclopropanecarboxamide (5.7 mg, 10%). ESI-MS m/z calc. 470.3. found 471.5 (M+1)+; retention time 2.76 minutes.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]=2)O1.Br[C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[C:26]([F:31])[CH:25]=1.C(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:28][C:27]1[CH:29]=[CH:30][C:24]([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][CH:10]=2)=[CH:25][C:26]=1[F:31]
Reactant: Nc1ccc(Br)cc1F
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(N)c(F)c2)CC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 100.8 %

Procedure:
tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (197, 1.95 g, 6.32 mmol), 4-bromo-2fluoroaniline (1.00 g, 5.26 mmol), Pd(dppf)Cl2.DCM (0.43 g, 0.526 mmol), K2CO3 (1.45 g, 10.5 mmol) were mixed in 40 mL dioxane and 20 mL water. The mixture was degassed with N2 stream for 3 min and stirred at 90° C. in N2 atmosphere for overnight. The mixture was cooled to RT, concentrated in vacuo, diluted with 120 mL EtOAc, washed with water ×2, dried, concentrated, and subjected to silica flash column to isolate tert-butyl 4-(4-amino-3-fluorophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (198, 1.55 g, quantitative yield) using 0 to 25% EtOAc in hexane. It was dissolved in 150 mL iPrOH, and to it was hydrogenated with 10% Pd/C using a balloon for overnight. The mixture was filtered through celite, concentrated in vacuo to afford tert-butyl 4-(4-amino-3-fluorophenyl)piperidine-1-carboxylate (199) in quantitative yield.
Reaction SMILES: [H-].[Na+].I.[N:4]1[C:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[O:15][CH2:16][C:7]=2[S:6][C:5]=1[NH2:17].Cl.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1>O1CCCC1>[N:4]1[C:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[O:15][CH2:16][C:7]=2[S:6][C:5]=1[NH:17][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: Nc1nc2c(s1)COc1ccccc1-2
Agent: Cl
Agent: I
Agent: [H-]
Solvent: C1CCOC1
Product: O=C(Nc1nc2c(s1)COc1ccccc1-2)c1ccncc1
Reaction time: 0.25 h
Yield: 14.4 %

Procedure:
Added sodium hydride (19 mg; 0.8 mmol) to a stirred suspension of 4H-Chromeno[4,3-d]thiazol-2-ylamine hydroiodide 19 (90 mg; 0.27 mmol) in dry tetrahydrofuran under nitrogen at room temperature. After 15 minutes, isonicotinoyl chloride hydrochloride (62 mg; 0.35 mmol) was added and the mixture allowed to stir for 3 hr. at room temperature and then concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The extracts were dried (sodium sulfate), filtered and concentrated in vacuo. Purification using reverse phase HPLC (eluent: acetonitrile/water/0.1% trifluoroacetic acid) provided 12 mg of N-(4H-Chromeno[4,3-d]thiazol-2-yl)-isonicotinamide 20 as the trifluoroacetate salt. ES-HRMS m/e calcd for C16H11N3OS (M+H) 310.0645, found 310.0646.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[CH2:10]2)(=[O:3])[CH3:2].[CH2:22](I)[CH2:23][CH3:24]>>[C:1]([N:4]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([N:15]([CH2:16][CH2:17][CH3:18])[CH2:19][CH2:20][CH3:21])[CH2:10]2)[CH2:22][CH2:23][CH3:24])(=[O:3])[CH3:2]
Reactant: CCCI
Reactant: CCCN(CCC)C1CCc2c(cccc2NC(C)=O)C1
Product: CCCN(C(C)=O)c1cccc2c1CCC(N(CCC)CCC)C2

Procedure:
Starting from 2.88 g (0.010 mol) of 5-acetylamino-2-di-n-propylamino-tetraline (Example 4.3.4) and 2.04 g (0.012 mol) of n-propyliodide, the title compound is obtained analogously to Example 4.7.1 in the form of a non-crystallising gum in a yield of 2.70 g (89.4% of theory) and with an Rf value of 0.67 (solvent mixture as specified in 4.7.1).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].Br[CH2:7][C:8]([NH:10][C:11]1[C:28]([OH:29])=[C:27]2[C:14]([CH2:15][CH:16]3[C:25]([C:26]2=[O:30])=[C:24]([OH:31])[C:23]2([OH:32])[CH:18]([CH:19]([N:38]([CH3:40])[CH3:39])[C:20]([OH:37])=[C:21]([C:34]([NH2:36])=[O:35])[C:22]2=[O:33])[CH2:17]3)=[C:13]([N:41]([CH3:43])[CH3:42])[CH:12]=1)=[O:9]>CN1C(=O)N(C)CCC1.C(#N)C>[CH3:40][N:38]([CH3:39])[C@H:19]1[C@H:18]2[C@:23]([OH:32])([C:24]([OH:31])=[C:25]3[C@H:16]([CH2:17]2)[CH2:15][C:14]2[C:27](=[C:28]([OH:29])[C:11]([NH:10][C:8](=[O:9])[CH2:7][N:3]([O:4][CH3:5])[CH3:2])=[CH:12][C:13]=2[N:41]([CH3:42])[CH3:43])[C:26]3=[O:30])[C:22](=[O:33])[C:21]([C:34]([NH2:36])=[O:35])=[C:20]1[OH:37]
Reactant: CNOC
Reactant: CN(C)c1cc(NC(=O)CBr)c(O)c2c1CC1CC3C(N(C)C)C(O)=C(C(N)=O)C(=O)C3(O)C(O)=C1C2=O
Agent: Cl
Solvent: CC#N
Solvent: CN1CCCN(C)C1=O
Product: CON(C)CC(=O)Nc1cc(N(C)C)c2c(c1O)C(=O)C1=C(O)[C@]3(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]3C[C@@H]1C2
Yield: 51.2 %

Procedure:
The compound of the example is prepared by the procedure of Example 1 using 10 g of N,O-dimethylhydroxylamine hydrochloride (neutralized by NaOH, extracted with methylene chloride), and 1.0 g of 9-(2-bromo-acetylamino)-4,7-bis-dimethylamino-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-naphthacene-2-carboxylic acid amide in 8 ml DMPU and 2.5 ml acetonitrile to give 0.495 g of the product.
Reaction SMILES: N1C=CN=C1.P(Cl)(Cl)(OC1C=CC=CC=1)=O.[CH2:17]([O:24][C:25]([NH:27][C@H:28]([C:33]([OH:35])=O)[CH2:29][CH:30]([CH3:32])[CH3:31])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[NH2:36][C@@H:37]([CH2:45][CH:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1)[C@H:38]([C:40]1[O:41][CH:42]=[CH:43][CH:44]=1)[OH:39]>ClCCl.O1CCCC1.CN(C)C=O>[CH2:17]([O:24][C:25]([NH:27][C@H:28]([C:33]([NH:36][C@@H:37]([CH2:45][CH:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1)[C@H:38]([C:40]1[O:41][CH:42]=[CH:43][CH:44]=1)[OH:39])=[O:35])[CH2:29][CH:30]([CH3:31])[CH3:32])=[O:26])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: N[C@@H](CC1CCCCC1)[C@@H](O)c1ccco1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: O=P(Cl)(Cl)Oc1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)c1ccco1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 84 %

Procedure:
To a solution of 1.4 g of imidazole in 18 ml of dichloromethane is added 0.90 ml of phenyl dichlorophosphate in 6 ml of dichloromethane. The mixture is stirred for 20 minutes, cooled to 0° C. and a solution of 0.60 g of imidazole, 2.4 ml of N,N-dimethylformamide and 1.6 g of Nα -[(benzyloxy)carbonyl]-L-leucine in 6 ml of tetrahydrofuran added. The mixture is stirred at 0°C. for 40 minutes and then 1.30 g of (S)-2-amino-3-cyclohexyl-(R)-1-(2-furanyl)propan-1-ol added. The mixture is stirred at 0° C. to 25° C. (ice bath allowed to melt) overnight and the solvent removed. The residue is dissolved in 20 ml of ethyl acetate and washed with water, 2N citric acid, sodium bicarbonate solution and dried (MgSO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the pad washed with several volumes of ethyl acetate. The filtrate is concentrated under vacuum to give 2.3 g of N-[N-(benzyloxy)carbonyl-L-leucyl]-(S)-2-amino-3-cyclohexyl-(R)-1-(2-furanyl)propan-1-ol as an oil. The preceding compound (1.85 g) and 1.0 g of ammonium formate in 24 ml of methanol under nitrogen is warmed on a steam bath and then the solution is chilled to 0° C. To the mixture (without stirring) is added (by pipette) 0.96 g of 10% palladium on carbon suspended in 5 ml of ethanol. The mixture is stirred at 0° C. for one hour, diatomaceous earth added and the mixture filtered. The filter pad is washed with methanol and the filtrate evaporated to dryness. The residue is partitioned between ammonium hydroxide and dichloromethane. The organic layer is separated, dried (MgSO4) and the solvent removed to give 1.24 g of a gum. Crystallization from 5 ml of diisopropyl ether gives 0.74 g of N-(L-leucyl)-(S)-2-amino-3-cyclohexyl-(R)-1-(2-furanyl)propan-1-ol as colorless crystals, mp 83°-84° C. [α]D26 -17°±1 (c, 1.031, CH3OH).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH2:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C@@H:28]([NH2:35])[C@H:27]1[OH:36].C([BH3-])#N.[Na+]>C(O)(=O)C.C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][C:14]=2[CH2:23][NH:35][C@@H:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:26][C@@H:27]2[OH:36])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN[C@@H]2c3ccccc3C[C@@H]2O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2′-Formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.153 g, 0.43 mmol), (1R,2S)-(+)-cis-1-amino-2-indanol (0.065 g, 0.43 mmol), sodium cyanoborohydride (0.041 g, 0.65 mmol), and acetic acid (3 drops) were combined in CH2Cl2 (1.5 mL), and the reaction was stirred for 30 minutes at room temperature. The mixture was diluted with CH2Cl2 and saturated aqueous NaHCO3, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound.
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[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[NH2:66][CH2:67][CH2:68][CH2:69][N:70]1[CH2:75][CH2:74][CH:73]([OH:76])[CH2:72][CH2:71]1>O.C(=O)(O)[O-].[Na+].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]([NH:66][CH2:67][CH2:68][CH2:69][N:70]5[CH2:71][CH2:72][CH:73]([OH:76])[CH2:74][CH2:75]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: NCCCN1CCC(O)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NCCCN2CCC(O)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.08 h
Yield: 83.4 %

Procedure:
A mixture of 0.045 g (0.1 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-methoxybenzoic acid (I-22), 0.042 g (0.110 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.052 ml (0.300 mmole) of ethyldiisopropyl amine and 1.0 mL of dimethylformamide was stirred for 5 minutes and then 0.019 g (0.12 mmole) 1-(3-Amino-propyl)-piperidin-4-ol was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluting with water-acetonitrile (gradient, 0:100-80:20) to give 0.049 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)-N-[3-(4-hydroxy-piperidin-1-yl)-propyl]-3-methoxy-benzamide (I-105) as a white solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.O.ON1C2C=CC=CC=2N=N1.[CH2:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][NH:26]1>CN(C=O)C>[CH2:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][N:26]1[C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[N:7][CH:6]=2)[N:1]=1)=[O:13]
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=C(O)c1ccc2cnccc2n1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc2cnccc2n1)N1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
To a stirring mixture of 2-[1,6]naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in anhydrous DMF (1.0 mL) at room temperature was added sequentially 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), 1,2,3,4-tetrahydroisoquinoline (55.6 μL, 0.431 mmol) and 1-(3dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (61.8 mg, 0.316 mmol). The resulting mixture was allowed to stir at room temperature overnight and it was found to be clear. The solvent was removed under vacuum. Flash column chromatography of the residue (100% ethyl acetate) afforded the desired product as a white solid (79.1 mg, 95%): m.p. 98-100° C.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][N:6]([CH3:9])[CH:7]=[O:8].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:29]=[CH:30][C:31]=1[N+:32]([O-:34])=[O:33])[C:15]([C:17]1[N:21]2[CH:22]=[CH:23][CH:24]=[C:25](C(O)=O)[C:20]2=[CH:19][N:18]=1)=[O:16].CNC>ClCCl.O1CCCC1>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:29]=[CH:30][C:31]=1[N+:32]([O-:34])=[O:33])[C:15]([C:17]1[N:21]2[CH:22]=[CH:23][CH:24]=[C:25]([C:7]([N:6]([CH3:9])[CH3:5])=[O:8])[C:20]2=[CH:19][N:18]=1)=[O:16]
Reactant: CN(C)C=O
Reactant: COc1cc(C(=O)c2ncc3c(C(=O)O)cccn23)ccc1[N+](=O)[O-]
Agent: CNC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2ncc3c(C(=O)N(C)C)cccn23)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.17 ml (2.36 mmol) of thionyl chloride and then 30 μl of N,N-dimethylformamide are added to 0.318 g (0.88 mmol) of 3-(3-methoxy-4-nitrobenzoyl)imidazo[1,5-a]pyridine-8-carboxylic acid obtained in example 183 in 10 ml of dichloromethane. The mixture is heated at reflux for 2 hours. The reaction medium is concentrated under reduced pressure. The residue obtained is added to 5 ml of a 2N solution of dimethylamine in tetrahydrofuran. After stirring at ambient temperature for 18 h, the reaction medium is concentrated under reduced pressure. The residue is taken up in dichloromethane. The organic phase is washed with a 1N aqueous hydrochloric acid solution and then with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel, elution being carried out with dichloromethane and then a dichloromethane/methanol (99/1) mixture. 0.19 g of a yellow solid is collected. Melting point: 176° C.; 1H NMR (d6-DMSO): 4.02 (3H, s), 7.39 (1H, t), 7.53 (1H, d), 7.83 (1H, s), 8.0-8.12 (3H, m), 9.75 (1H, d)