Azzindani/Open_Reaction_Data huggingface dataset:
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[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26]([OH:28])=O)=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:35][N:36]1[CH2:41][CH2:40][N:39]([CH2:42][C:43]2[CH:49]=[CH:48][C:46]([NH2:47])=[CH:45][CH:44]=2)[CH2:38][CH2:37]1>>[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[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26]([NH:47][C:46]5[CH:45]=[CH:44][C:43]([CH2:42][N:39]6[CH2:38][CH2:37][N:36]([CH3:35])[CH2:41][CH2:40]6)=[CH:49][CH:48]=5)=[O:28])=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Agent: Cl
Product: COc1cc(C(=O)Nc2ccc(CN3CCN(C)CC3)cc2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was prepared in a manner analogous to compound 149 from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoic acid and 4-((4-methylpiperazin-1-yl)methyl)aniline hydrochloride with yield 48 mg (37%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.62 (br. s., 4H) 1.73 (br. s., 2H) 1.98 (m, 2H) 2.14 (s, 3H) 2.17-2.45 (m, 8H) 3.40 (s, 2H) 3.94 (s, 3H) 4.09 (t, J=12 Hz, 2H) 4.84 (t, J=8.08 Hz, 1H) 7.16-7.37 (m, 3H) 7.66 (d, J=8.34 Hz, 2H) 8.10 (s, 1H) 8.19-8.39 (m, 2H) 10.13 (s, 1H). [M+H] calc'd for C33H39F3N8O3, 653. found 653.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[F:19])[CH:14]=O.[CH2:20]=[C:21]([CH3:23])[CH3:22].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C.C(OCC)(=O)C>[Cl:10][C:11]1[CH:12]=[C:13]([CH:14]2[CH2:20][C:21]([CH3:23])([CH3:22])[C:3]3[C:2](=[CH:7][N:6]=[C:5]([C:8]#[N:9])[CH:4]=3)[NH:1]2)[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: C=C(C)C
Reactant: N#Cc1ccc(N)cn1
Reactant: O=Cc1ccc(F)c(Cl)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC1(C)CC(c2ccc(F)c(Cl)c2)Nc2cnc(C#N)cc21
Temperature: 85 °C
Reaction time: 18 h
Yield: 4.8 %

Procedure:
To a stirred solution of 5-amino-pyridine-2-carbonitrile (9.3 g, 78.4 mmol) and 3-chloro-4-fluoro-benzaldehyde (12.3 g, 78.4 mmol) in acetonitrile (150 mL) were added isobutene (21.0 mL, 313.5 mmol) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (5.8 g, 9.5 mmol). The resulting mixture was stirred at 85° C. for 18 h in sealed tube. The mixture was diluted with ethyl acetate (300 mL) and washed with water (100 mL×2) and brine (100 mL×2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10-50% ethyl acetate in petroleum ether) to afford 2-(3-chloro-4-fluoro-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-[1,7]naphthyridine-6-carbonitrile (1.2 g, 5.0%) as a light yellow solid: MS (ESI) M+1=316.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@@H:4]([NH:14][C:15]([C:17]1[CH:21]=[C:20]([OH:22])[N:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:18]=1)=[O:16])[CH2:5][CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[H-].[Na+].Br[CH2:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]>CN(C=O)C.[Cl-].[Na+].O>[CH3:1][O:2][C:3](=[O:29])[C@@H:4]([NH:14][C:15]([C:17]1[CH:21]=[C:20]([O:22][CH2:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[N:19]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:18]=1)=[O:16])[CH2:5][CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: COC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1cc(O)n(-c2ccccc2)n1
Reactant: CC(C)(C)C(=O)CBr
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1cc(OCC(=O)C(C)(C)C)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 6.5 g of (S)-2-[(5-Hydroxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-pentanedioic acid 5-tert-butyl ester 1-methyl ester in 175 ml of DMF was cooled to 0° C. Then, 644 mg of sodium hydride (60% in mineral oil) was added portionwise over 20 min. Further 20 min after completion of the addition 2.9 g of 1-Bromo-3,3-dimethyl-butan-2-one was added and the reaction mixture was allowed to warm to RT. After striring for 16 h the reaction mixture was diluted with brine and extracted with DCM. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 3.3 g.
Reaction SMILES: BrCC1C=CC=CC=1F.ClC1N=C2NN=CC2=CN=1.Cl[C:21]1[N:26]=[C:25]2[N:27]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[F:37])[N:28]=[CH:29][C:24]2=[CH:23][N:22]=1.C[N:39]1[CH:43]=[C:42]([NH2:44])[CH:41]=[N:40]1>>[F:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][N:27]1[C:25]2=[N:26][C:21]([NH:44][C:42]3[CH:43]=[N:39][NH:40][CH:41]=3)=[N:22][CH:23]=[C:24]2[CH:29]=[N:28]1
Reactant: Cn1cc(N)cn1
Reactant: Fc1ccccc1Cn1ncc2cnc(Cl)nc21
Agent: Clc1ncc2cn[nH]c2n1
Agent: Fc1ccccc1CBr
Product: Fc1ccccc1Cn1ncc2cnc(Nc3cn[nH]c3)nc21

Procedure:
The following compound was made according to the procedures in Example 1 (Step ii) using 1-(bromomethyl)-2-fluorobenzene and 6-chloro-1H-pyrazolo[3,4-d]pyrimidine followed by Example 1 (Step i) using 6-chloro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidine and 1-methyl-1H-pyrazol-4-amine:
Reaction SMILES: [H-].[Na+].[PH:3](=[O:6])([O-:5])[O-:4].[CH2:7]([Li])[CH2:8][CH2:9]C.Br[CH2:13][C:14]#CC.[CH2:17]1[CH2:21][O:20][CH2:19][CH2:18]1>CCCCCC>[CH3:9][CH:8]([CH3:7])[C:19](=[O:20])[CH2:18][CH2:17][C:21]#[C:13][CH3:14].[PH:3](=[O:4])([O-:6])[O-:5]
Reactant: [Li]CCCC
Reactant: CC#CCBr
Reactant: C1CCOC1
Agent: O=[PH]([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: CC#CCCC(=O)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of dry sodium hydride (3.13 g, 124.07 mmol) in dry THF (100 ml) at room temperature was added dropwise a solution of dimethyl 2-oxopropyl)-phosphonate (20.61 g, 124.07 mmol) in dry THF (50 ml) under N2. The reaction mixture was stirred for 1 h, then cooled in an ice-bath and treated with a solution of n-butyllithium (7.95 g, 124.07 mmol) in hexane, causing a dark brown solution to be formed. Stirring was continued for 1 h at 0° C., followed by dropwise addition of 1-bromo2-butyne.1 (15 g, 112.79 mmol) in THF (30 ml). The reaction mixture was gradually warmed to room temperature and after 1 h (TLC monitoring) the reaction mixture was quenched with ice-water, HCl 1M to pH about 4 and extracted, twice, with ethyl acetate. The organic layer was washed with brine and chromatographed on silica gel using EtOAc as eluent. Rf=0.38 (silica gel, ethylacetate), yield 18 g (73%).
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]([CH3:7])=[N:4][C:3]=1[C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:11]([OH:13])=O.Cl.[NH:19]1[CH2:22][CH:21]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[CH2:20]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:1][C:2]1[N:6]=[C:5]([CH3:7])[NH:4][C:3]=1[C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:11]([N:19]1[CH2:22][CH:21]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[CH2:20]1)=[O:13]
Reactant: Cc1nc(-c2cc(C(=O)O)ccc2C)c(Cl)[nH]1
Reactant: N#Cc1ccc(C2CNC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c(-c2cc(C(=O)N3CC(c4ccc(C#N)cc4)C3)ccc2C)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 18.9 %

Procedure:
A mixture of 3-(5-chloro-2-methyl-1H-imidazol-4-yl)-4-methylbenzoic acid (compound 7.3, ˜0.038 mmol), 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2, 8.6 mg, 0.044 mmol), EDCI (12 mg, 0.063 mmol), HOBt (8 mg, 0.044 mmol) and DIEA (28 μl, 0.16 mmol) in DMF (1 mL) was stirred at room temperature for 16 hours. The reaction was diluted with water and extracted with EtOAc. The organic phase was washed with brine (how much), dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel preparative TLC (8% MeOH in DCM) to yield the title compound as a foam (2.8 mg, 19% over 2 steps). m/z (ES+) 391 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 10.62 (s, 1H), 7.69 (d, J=8.3 Hz, 2H), 7.54-7.40 (m, 3H), 7.37 (d, J=1.9 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 4.80-4.58 (m, 2H), 4.41-4.19 (m, 2H), 4.03-3.92 (m, 1H), 2.49 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[CH3:25][O:26][C:27]1[CH:41]=[CH:40][C:30]([O:31][C:32]2[CH:33]=[C:34]([CH2:38][NH2:39])[CH:35]=[CH:36][CH:37]=2)=[CH:29][CH:28]=1.[NH2:42][C:43]1[N:52]=[C:51]([N:53]2[CH2:58][CH2:57][N:56]([CH3:59])[CH2:55][CH2:54]2)[C:50]2[C:45](=[CH:46][C:47]([C:60](O)=[O:61])=[CH:48][CH:49]=2)[N:44]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[NH2:42][C:43]1[N:52]=[C:51]([N:53]2[CH2:54][CH2:55][N:56]([CH3:59])[CH2:57][CH2:58]2)[C:50]2[C:45](=[CH:46][C:47]([C:60]([NH:39][CH2:38][C:34]3[CH:35]=[CH:36][CH:37]=[C:32]([O:31][C:30]4[CH:40]=[CH:41][C:27]([O:26][CH3:25])=[CH:28][CH:29]=4)[CH:33]=3)=[O:61])=[CH:48][CH:49]=2)[N:44]=1
Reactant: CN1CCN(c2nc(N)nc3cc(C(=O)O)ccc23)CC1
Reactant: COc1ccc(Oc2cccc(CN)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Oc2cccc(CNC(=O)c3ccc4c(N5CCN(C)CC5)nc(N)nc4c3)c2)cc1
Reaction time: 1 h
Yield: 54 %

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.030 g, 0.078 mmol) was added to a solution of crude 1-[3-(4-methoxyphenoxy)phenyl]methanamine (0.045 g) and 2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxylic acid (0.015 g, 0.052 mmol) in N,N-dimethylformamide (2.0 mL) with N,N-diisopropylethylamine (0.027 mL, 0.16 mmol) at r.t. The reaction was stirred for 1 h. The product was purified without workup by RP-HPLC (pH=10) to give the desired product (0.014 g, 44%) as a white amorphous solid. Analytical LCMS (M+H)+: m/z=499.0.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([OH:13])[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:3]1.C[O-].[Na+].CN([CH:26]=[O:27])C>>[CH2:15]([O:27][CH2:26][O:13][C:5]1[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:3][N:2]([CH3:1])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:14][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: Cn1nc(-c2ccccc2)c(O)c1-c1ccccc1
Reactant: CN(C)C=O
Agent: C[O-]
Agent: [Na+]
Product: CCCCCCCOCOc1c(-c2ccccc2)nn(C)c1-c1ccccc1

Procedure:
The temperature is maintained at -20° C to -10° C during the addition. When the exotherm subsides, the addition of gas is discontinued and the reaction mixture allowed to warm up to 5°-10° C. The reaction mixture is washed with chilled water (100 ml) and the organic layer separated. The organic layer is filtered through calcium chloride and added to a solution of the sodium salt of 1-methyl-3,5-diphenyl-4-pyrazolol in DMF. The 4-pyrazolol solution is prepared by stirring 1-methyl-3,5-diphenyl-4-pyrazolol (10 g, 0.04 mole) with sodium methoxide (2.16 g, 0.04 mole) and dry DMF (100 ml).
Reaction SMILES: [C:1]([O:4][C:5]1[N:6]=[C:7]([CH2:19]Br)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH3:16])=[C:10]([O:17][CH3:18])[CH:9]=2)(=[O:3])[CH3:2].[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.[K]>CN(C=O)C.CCOCC.O>[C:1]([O:4][C:5]1[N:6]=[C:7]([CH2:19][N:25]2[C:21](=[O:31])[C:22]3[C:23](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:24]2=[O:26])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH3:16])=[C:10]([O:17][CH3:18])[CH:9]=2)(=[O:3])[CH3:2]
Reactant: COc1cc2cc(OC(C)=O)nc(CBr)c2cc1OC
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: COc1cc2cc(OC(C)=O)nc(CN3C(=O)c4ccccc4C3=O)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a stirred solution of 1-(bromomethyl)-6,7-dimethoxyisoquinolin-3-yl acetate SIL 32162 (2.57 g, 7.56 mmol) in dry DMF (60 mL) in a 250 mL round-bottomed flask equipped with a magnetic stirrer was added potassium phthalimide (2.43 g, 13.12 mmol) and the mixture was stirred overnight at RT and then diluted with Et2O (150 mL) and H2O (40 mL). A solid appeared and was isolated by filtration. The aqueous phase was isolated and diluted with Et2O (100 mL) before vigorous stirring for 15 min, which gave a new amount of solid that was isolated by filtration (done 3 times). The solids were then combined, further washed with Et2O (100 mL) and dried overnight under vacuum in presence of P2O5, which gave 2.10 g of 1-((1,3-dioxoisoindolin-2-yl)methyl)-6,7-dimethoxyisoquinolin-3-yl acetate SIL 32166 as an off-white solid (68%).
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:18]1[CH:19]=[C:20]2[C:31]3([CH2:35][O:34][C:33]([NH2:36])=[N:32]3)[C:30]3[C:25](=[N:26][CH:27]=[C:28]([O:37][CH2:38][C:39]([O:42][CH3:43])([CH3:41])[CH3:40])[CH:29]=3)[O:24][C:21]2=[CH:22][CH:23]=1.O>C1COCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[C:7]([C:18]2[CH:19]=[C:20]3[C:31]4([CH2:35][O:34][C:33]([NH2:36])=[N:32]4)[C:30]4[C:25](=[N:26][CH:27]=[C:28]([O:37][CH2:38][C:39]([O:42][CH3:43])([CH3:40])[CH3:41])[CH:29]=4)[O:24][C:21]3=[CH:22][CH:23]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1cccnc1F
Reactant: COC(C)(C)COc1cnc2c(c1)C1(COC(N)=N1)c1cc(Br)ccc1O2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(C)(C)COc1cnc2c(c1)C1(COC(N)=N1)c1cc(-c3cccnc3F)ccc1O2

Procedure:
A vial charged with 2-fluoropyridin-3-ylboronic acid (0.156 g, 1.105 mmol), palladiumtetrakis (0.043 g, 0.037 mmol), potassium carbonate (0.255 g, 1.842 mmol), and 7-bromo-3-(2-methoxy-2-methylpropoxy)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (0.160 g, 0.368 mmol) was dissolved in 3 mL THF and 0.5 mL water and was heated to 110° C. 2 hours. The reaction mixture was diluted with EtOAc and dried over MgSO4. The organcis were concentrated then purified directly by column chromatography yielding 7-(2-fluoropyridin-3-yl)-3-(2-methoxy-2-methylpropoxy)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[C:20](O)[C:19]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:18][N:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].P(Cl)(Cl)([Cl:33])=O>>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[C:20]([Cl:33])[C:19]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:18][N:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCCCCCOc1ccc(-c2ncc(OCc3ccccc3)c(O)n2)cc1
Product: CCCCCCCCOc1ccc(-c2ncc(OCc3ccccc3)c(Cl)n2)cc1

Procedure:
Ethyl benzyloxyacetate (B) was obtained by esterifying benzyloxyacetic acid as obtained from benzyl alcohol and chloroacetic acid by a conventional Williamson synthesis. (B) (9.7 g) and 3.7 g of ethyl formate were dissolved in 25 ml of ether, and stirred in the presence of sodium for 2 hours, and ether was distilled away to obtain sodium 2-benzyloxy-2-ethoxycarbonylethylenolate (C). To this compound was added a solution as prepared by dissolving 14.2 g of 4-decyloxybenzamidine hydrochloride (synthesized from 4-decyloxycyanobenzene by a conventional method) in 80 ml of ethanol and adding 1.2 g of sodium, and the mixture was refluxed for 2 hours. The solvent was distilled away to obtained 2-(4-octyloxyphenyl)-4-hydroxy-5-benzyloxypyrimidine (D). (D) (2 g) together with phosphorus oxychloride was refluxed for 3 hours to obtain 2-(4-octyloxyphenyl)-4-chloro-5-benzyloxypyrimidine (E).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH2:12])[CH:5]=[CH:4][CH:3]=1.[CH3:13]C(=O)CCCCCCCCCCC>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[NH:1]1[C:2]2=[C:11]3[C:6](=[CH:5][CH:4]=[CH:3]2)[CH:7]=[CH:8][CH:9]=[C:10]3[NH:12][CH2:13]1
Reactant: CCCCCCCCCCCC(C)=O
Reactant: Nc1cccc2cccc(N)c12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: c1cc2c3c(cccc3c1)NCN2
Yield: 174.3 %

Procedure:
A stirred mixture of 26.05 g of 1,8-diaminonaphthalene, 32.66 g of 2-tridecanone, 55 mg of p-toluenesulfonic acid monohydrate, and 250 mL of toluene was heated to reflux under a nitrogen atmosphere using a Dean-Stark trap to remove the water evolved from the reaction for 5 hr. The mixture was then washed with saturated sodium bicarbonate solution, dried over anhydrous potassium carbonate, filtered, and the solvent removed under reduced pressure. The product was distilled to yield 48.86 g of dihydroperimidine intermediate, bp 192°-213° C. at 0.3 to 0.4 torr.
Reaction SMILES: [CH3:1][O:2][Si:3]([CH2:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])([O:6][CH3:7])[O:4][CH3:5].[C:14]([OH:21])(=[O:20])/[CH:15]=[CH:16]\[C:17]([OH:19])=[O:18]>CO>[C:14]([O-:21])(=[O:20])/[CH:15]=[CH:16]\[C:17]([O-:19])=[O:18].[CH3:1][O:2][Si:3]([CH2:8][CH2:9][CH2:10][NH+:11]([CH3:13])[CH3:12])([O:4][CH3:5])[O:6][CH3:7].[CH3:1][O:2][Si:3]([CH2:8][CH2:9][CH2:10][NH+:11]([CH3:13])[CH3:12])([O:4][CH3:5])[O:6][CH3:7]
Reactant: O=C(O)/C=C\C(=O)O
Reactant: CO[Si](CCCN(C)C)(OC)OC
Solvent: CO
Product: CO[Si](CCC[NH+](C)C)(OC)OC
Product: O=C([O-])/C=C\C(=O)[O-]

Procedure:
5.0 g of trimethoxysilylpropyldimethylamine and 18 g of methanol were charged into a 100 mL flask to be dissolved. While stirring the resultant mixed solution with a magnetic stirrer, to the mixed solution, a solution in which 4.2 g of maleic acid was dissolved in 24 g of methanol was gradually added at room temperature in a nitrogen atmosphere. The reaction mixture was stirred for half a day and therefrom, methanol was distilled off under reduced pressure. The resultant concentrate was dropped into 100 mL of diethyl ether and therefrom, trimethoxysilylpropyldimethylamine and maleic acid as by-products were removed. This purification was repeated three times and then remaining diethyl ether was distilled off under reduced pressure, followed by dissolving the resultant concentrate in methanol to obtain a 30% methanol solution of trimethoxysilylpropyldimethylammonium maleate.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[N:9][N:10]([CH2:11][CH3:12])[C:6]=2[N:5]=[C:4]2[C:13](=[O:22])[C:14]3[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=3[CH2:16][CH2:17][C:3]=12.C(N(CC)CC)C.C(OCC)(=O)C>[Pd].C(O)C>[Cl:1][C:2]1[C:7]2[CH:8]=[N:9][N:10]([CH2:11][CH3:12])[C:6]=2[N:5]=[C:4]2[CH:13]([OH:22])[C:14]3[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=3[CH2:16][CH2:17][C:3]=12
Reactant: CCn1ncc2c(Cl)c3c(nc21)C(=O)c1ccccc1CC3
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCn1ncc2c(Cl)c3c(nc21)C(O)c1ccccc1CC3
Reaction time: 6 h

Procedure:
20.2 g. of 4-chloro-1-ethyl-5,6-dihydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11(1H)-one (0.065 mol.) and 13 g. of triethylamine (0.13 mol.), dissolved in 400 ml. of ethyl acetate and 75 ml. of absolute ethanol, are catalytically hydrogenated in the presence of 2 g. of palladium on charcoal (10%) at room temperature. In about 6 hours, the theoretical amount of hydrogen is absorbed. The catalyst is then filtered off, the filtrate evaporated in vacuo and the residue extracted with 200 ml. of ether. The ethereal extract is washed with water, dried with Na2SO4 and the ether removed. The resulting material is recrystallized from petroleum ether (60°-70°) to yield 12.7 g. (62.5%) of 4-chloro-1-ethyl-1,5,6,11-tetrahydro[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11-ol; m.p. 128°-130°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH:20]1([C:23](Cl)=[O:24])[CH2:22][CH2:21]1>ClCCl>[C:8]([C:4]1[CH:3]=[C:2]([NH:1][C:23]([CH:20]2[CH2:22][CH2:21]2)=[O:24])[CH:7]=[CH:6][CH:5]=1)(=[O:10])[CH3:9]
Reactant: O=C(Cl)C1CC1
Reactant: CC(=O)c1cccc(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)c1cccc(NC(=O)C2CC2)c1

Procedure:
A mixture of 13.524 g of m-aminoacetophenone and 14.224 g of diisopropylethylamine in 300 ml of dichloromethane was stirred with cooling. An 11.45 g portion of cyclopropanecarboxylic acid chloride was added and the mixture was stirred at room temperature overnight. The solid was collected, giving 17.30 g of N-(3-acetylphenyl)cyclopropanecarboxamide, mp 136°-137° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:21]1([CH2:27][C:28](Cl)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.FC(F)(F)S(O)(=O)=O.[OH-].[Na+]>C(Cl)Cl>[CH2:13]([N:20]1[C:28](=[O:29])[CH2:27][C:21]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:7]1[C:6]1[CH:9]=[CH:10][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:4][CH:5]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: NCc1ccccc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C1Cc2ccccc2C(c2ccc(C(F)(F)F)cc2)N1Cc1ccccc1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
4-(Trifluoromethyl)benzaldehyde (1.87 mL, 14.0 mmol) and benzylamine (1.53 mL, 14.0 mmol) were dissolved into 40 mL of DCM and 4 Å molecular sieve was added. The mixture was left under nitrogen for 3 days. Molecular sieve was removed via filtration. 25 mL of DCM was used to wash the filter cake. To the filtrate, phenylacetyl chloride (1.90 mL, 14.4 mmol) was added and the pale yellow solution was stirred for 2 h. Then trifluoromethanesulfonic acid (6.20 mL, 70.1 mmol) was added. The mixture was stirred for 1.5 h then poured into a mixture of ice (˜100 mL) and 5N sodium hydroxide (˜50 mL). The phases were separated and the aqueous phase was extracted with DCM. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to afford a yellow oil. The crude product was purified by silica gel chromatography (0-30% EtOAc in hexanes) twice to afford the title compound as a light yellow semi-solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.56-7.74 (m, 4H) 7.41 (d, J=6.87 Hz, 1H) 7.13-7.33 (m, 8H) 5.80 (s, 1H) 5.30 (d, J=15.20 Hz, 1H) 3.81-4.01 (m, 2H) 3.66-3.78 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[N:19]1([CH:26]=[O:27])[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH:26]([N:19]1[CH2:25][CH2:24][CH2:23][N:22]([C:2]2[N:3]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]3[C:9]([C:10]=2[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:21][CH2:20]1)=[O:27]
Reactant: O=Cc1c(Cl)n(-c2ccccc2)c2ccccc12
Reactant: O=CN1CCCNCC1
Product: O=Cc1c(N2CCCN(C=O)CC2)n(-c2ccccc2)c2ccccc12
Yield: 97 %

Procedure:
2-Chloro-1-phenyl-1H-indole-3-carboxaldehyde is reacted with [1,4]diazepane-1-carboxaldehyde as described in Example 1 to afford 2-(4-formyl-[1,4]diazepan-1-yl)-1-phenyl-1H-indole-3-carboxaldehyde (97% yield) as a yellow solid. LC/MS: MS 348 (M+H); RT 2.77 min; (CDCl3): 10.26 (1H, d), 8.22 (1H, d), 8.00 (0.5H, s), 7.86 (0.5H, s) 7.47-7.69(3H, m), 7.23-7.38 (3H, m), 7.17(1H, t), 6.97 (1H, d), 3.25-3.70 (8H, m), 1.50-1.73(2H, m).