Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]([CH2:9][O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]3=[N:21][N:22]=[C:23]([C:24]4[CH:28]=[C:27]([CH3:29])[O:26][N:25]=4)[N:13]3[N:12]=2)=[CH:7][N:6]=[N:5]1.[NH:30]([CH3:32])[CH3:31]>CN(C=O)C>[CH3:31][N:30]([CH2:2][CH2:3][N:4]1[C:8]([CH2:9][O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]3=[N:21][N:22]=[C:23]([C:24]4[CH:28]=[C:27]([CH3:29])[O:26][N:25]=4)[N:13]3[N:12]=2)=[CH:7][N:6]=[N:5]1)[CH3:32]
Reactant: CNC
Reactant: Cc1cc(-c2nnc3c4ccccc4c(OCc4cnnn4CCBr)nn23)no1
Solvent: CN(C)C=O
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4cnnn4CCN(C)C)nn23)no1
Yield: 44.2 %

Procedure:
A solution of 6-({[1-(2-bromoethyl)-1H-1,2,3-triazol-5-yl}methyl}oxy)-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[3,4-α]phthalazine (125 mg, 0.27 mmol) in DMF (5 ml) and Me2NH (2.0 M in THF, 4 ml, 8 mmol) were heated at 80° C. for 4 h in a sealed tube. The reaction mixture was concentrated under reduced pressure and then taken up in MeOH/CH2Cl2 and dry loaded onto silica. The mixture was purified by column chromatography on silica using 1.5% MeOH/CH2Cl2 containing 1% NH3 as eluent to yield the desired phthalazine (50 mg, 44%). 1H NMR (360 MHz, CDCl3) δ 8.69 (1H, d, J=8.0 Hz), 8.18 (1H, d, J=8.0 Hz), 8.07 (1H, s), 7.98 (1H, t, J=7.6 Hz), 7.82 (1H, t, J=7.6 Hz), 6.85 (1H, s), 5.86 (2H, s), 4.66 (2H, t, J=6.9 Hz), 2.92 (2H, m), 2.59 (3H, s), 2.32 (6H, s). m/z (ES+) 420 (M+H+).
Reaction SMILES: [Cl:1][C:2]([F:25])([F:24])[C:3]([C:20]([Cl:23])([F:22])[F:21])([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14](=[O:19])[CH2:15][C:16](=O)[CH3:17])[CH2:9][CH2:8]2)[OH:4]>S(=O)(=O)(O)O>[Cl:23][C:20]([F:21])([F:22])[C:3]([C:5]1[CH:13]=[C:12]2[C:11]3=[C:7]([CH2:8][CH2:9][N:10]3[C:14](=[O:19])[CH:15]=[C:16]2[CH3:17])[CH:6]=1)([OH:4])[C:2]([Cl:1])([F:24])[F:25]
Reactant: CC(=O)CC(=O)N1CCc2cc(C(O)(C(F)(F)Cl)C(F)(F)Cl)ccc21
Agent: O=S(=O)(O)O
Product: Cc1cc(=O)n2c3c(cc(C(O)(C(F)(F)Cl)C(F)(F)Cl)cc13)CC2

Procedure:
By the method of Example 7, αα-bis(chlorodifluoromethyl)2,3-dihydro-1H-indole-5-methanol is converted to α,α-bis(chlorodifluoromethyl)-1-(1,3-dioxobutyl)-2,3-dihydro-1H-indole-5-methanol, which is cyclized by heating in sulfuric acid to give 1,2-dihydro-8-[2-chloro-2,2-difluoro-1-hydroxy-1-(chlorodifluoromethyl)ethyl]-6-methyl-4H-pyrrolo[3,2,1-ij]quinolin-4-one, m.p. 256°-257°.
Reaction SMILES: [NH2:1][C:2]([CH3:23])([CH3:22])[CH2:3][C:4]1[N:5]([CH2:18][CH2:19][O:20][CH3:21])[N:6]=[C:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:9]=[C:8]2[NH2:17].[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[F:34])[C:28](Cl)=[O:29]>>[NH2:17][C:8]1[C:7]2=[N:6][N:5]([CH2:18][CH2:19][O:20][CH3:21])[C:4]([CH2:3][C:2]([NH:1][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][C:33]([F:34])=[C:25]([F:24])[CH:26]=3)([CH3:23])[CH3:22])=[C:16]2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: COCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)N
Product: COCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)NC(=O)c1ccc(F)c(F)c1

Procedure:
Using the general method of Example 599, 1-(2-amino-2-methylpropyl)-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-4-amine (0.52 g, 1.66 mmol, prepared as described in Example 590) was reacted with 3,4-difluorobenzoyl chloride. The crude product was purified as described in Example 599 to provide 382 mg of N-{2-[4-amino-2-(methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-1,1-dimethylethyl}-3,4-difluorobenzamide as a white solid, mp 199-200° C. MS (ESI) m/z 454 (M+H)+; Anal. Calcd for C24H25F2N5O2: C, 63.57; H, 5.56; N, 15.44. Found: C, 63.37; H, 5.50; N, 15.58.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[C:9]2=[N:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:8]2[C:7](=[O:17])[N:6]([CH3:18])[CH2:5]1.[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:18][N:6]1[CH2:5][CH:4]([CH2:3][CH2:2][N:28]2[CH2:29][CH2:30][N:25]([C:20]3[N:19]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:26][CH2:27]2)[C:9]2=[N:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:8]2[C:7]1=[O:17]
Reactant: CN1CC(CCCl)c2nc3ccccc3n2C1=O
Reactant: c1cnc(N2CCNCC2)nc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN1CC(CCN2CCN(c3ncccn3)CC2)c2nc3ccccc3n2C1=O

Procedure:
To 60 mL of toluene was added 4.0 g (0.0152 mol) of 4-(2-chloroethyl)-3,4-dihydro-2-methylpyrimido[1,6-a]benzimidazol-1(2H)-one, 6.0 g (0.033 mol) of 1-(2-pyrimidyl)piperazine, and 4.0 g (0.04 mol) of triethylamine. The reaction mixture was heated at reflux for 2 days and subsequently washed with 2×50 mL of 1N NaOH, dried over Na2SO4, filtered, and concentrated by rotary evaporation. Crystallization from ethyl acetate afforded 4.0 g, 67% of analytically pure crystals, mp 161°-62° C.
Reaction SMILES: [C:1]([C:6]1[N:7]=[C:8]([CH2:13][CH2:14][CH3:15])[NH:9][C:10]=1[C:11]#[N:12])(=[O:5])[CH:2]([CH3:4])[CH3:3].[C:16]([N:35]1[C:39]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[C:46]2[CH:53]=[CH:52][C:49]([CH2:50]Br)=[CH:48][CH:47]=2)=[N:38][N:37]=[N:36]1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CC(C)([O-])C.[K+]>>[C:1]([C:6]1[N:7]=[C:8]([CH2:13][CH2:14][CH3:15])[N:9]([CH2:50][C:49]2[CH:48]=[CH:47][C:46]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=3[C:39]3[N:35]([C:16]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:36]=[N:37][N:38]=3)=[CH:53][CH:52]=2)[C:10]=1[C:11]#[N:12])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CCCc1nc(C(=O)C(C)C)c(C#N)[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCCc1nc(C(=O)C(C)C)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 59 %

Procedure:
Following a procedure similar to that described in Example 74(a), but using 0.97 g of 4-isobutyryl-2-propylimidazole-5-carbonitrile (prepared as described in Preparation 39), 2.90 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide and 0.56 g of potassium t-butoxide, 1.90 g of the title compound was obtained as crystals, melting at 133°-134° C.
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C:6]1[C:7]([N+:15]([O-:17])=[O:16])=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10].[CH3:18]O>>[OH:5][C:6]1[C:7]([N+:15]([O-:17])=[O:16])=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([O:11][CH3:18])=[O:10]
Reactant: O=C(O)c1cccc(O)c1[N+](=O)[O-]
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a methanol solution (15 mL) at 0° C. was dropwise added thionyl chloride (6.4 mL, 0.088 mol). After 15 minutes, 3-hydroxy-2-nitrobenzoic acid (4 g, 0.022 mol) was added and the resulting mixture was stirred at room temperature for 72 hours. Volatile was removed under vacuo and the residue was partitioned between water and ethyl acetate. The organic layer was separated, washed with water and saturated sodium chloride, and was dried over sodium sulfate. After concentration, the crude product was recrystallized from dichloromethane and hexane to gave 4.5 g of methyl 3-hydroxy-2-nitrobenzoate.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:22]([O:24][C:25](=[O:31])[C:26](OCC)=[O:27])[CH3:23]>CCOCC>[CH2:22]([O:24][C:25](=[O:31])[C:26](=[O:27])[CH:9]1[C:8](=[O:11])[CH2:7][CH2:6][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:10]1)[CH3:23]
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CCOC(=O)C(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOCC
Product: CCOC(=O)C(=O)C1CC2(CCC1=O)OCCO2

Procedure:
According to the procedure of Example 2, a solution of 1,4-dioxaspiro[4.5]decane-8-one Compound 22a in ether was added to a solution of LHMDS in ether at −78° C. The diethyloxalate Compound 2b was added to the mixture and reacted to produce an oxo-(8-oxo-1,4-dioxa-spiro[4.5]dec-7-yl)-acetic acid ethyl ester Compound 22b.
Reaction SMILES: [C:1]([NH:9][CH2:10][C:11](=[N:19][NH:20][C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=1)=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14](Cl)[CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].[ClH:39]>CO>[C:1]([NH:9][CH2:10][CH:11]([NH:19][NH:20][C:21]([NH:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][C:31]([F:33])([F:34])[F:32])=[CH:28][CH:29]=1)=[O:22])[C:12]1[CH:17]=[CH:16][C:15]([Cl:39])=[CH:14][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl
Reactant: O=C(NN=C(CNC(=O)c1ccccc1)c1cccc(Cl)c1)Nc1ccc(OC(F)(F)F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=C(NNC(CNC(=O)c1ccccc1)c1ccc(Cl)cc1)Nc1ccc(OC(F)(F)F)cc1

Procedure:
In 10 ml of methanol was suspended 0.30 g (0.59 mmole) of 2-[2-benzoylamino-l-(3-chlorophenyl)ethylidene]-N-(4-trifluoromethoxyphenyl)hydrazinecarboxamide, and 0.07 g (1 mmole) of sodium cyanoborohydride was added to the resulting suspension. The resulting mixture was adjusted to pH 4 to 6 with a methanolic solution of hydrogen chloride at room temperature and subjected to reaction.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:17][CH2:18][CH2:19][OH:20].NC1C=C(O[C@H](C)COC)C(C#N)=CN=1>>[NH2:1][C:2]1[CH:9]=[C:8]([O:20][CH2:19][CH2:18][O:17][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][O:11]2)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: N#Cc1cnc(N)cc1F
Reactant: OCCOC1CCCCO1
Agent: COC[C@@H](C)Oc1cc(N)ncc1C#N
Product: N#Cc1cnc(N)cc1OCCOC1CCCCO1

Procedure:
From intermediate 21 and (racemic) 2-((tetrahydro-2H-pyran-2-yl)oxy)ethanol, reacted in an analogous manner to the preparation of intermediate 146. (UPLC-MS 7) tR 0.70; ESI-MS 264.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO.CCOCC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:12][OH:13])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C=O)cc1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: COc1ccc(CO)cc1OCc1ccccc1

Procedure:
A solution of 0.35 mol of the compound obtained in Step 1 in 400 ml of methanol and 1.5 equivalents of sodium borohydride is stirred for 6 hours at ambient temperature and then 500 ml of acidified water are slowly added. The precipitate obtained is taken up in ether; the organic phase is subsequently extracted, dried, filtered and then evaporated off under reduced pressure, allowing the expected product to be isolated.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([Cl:16])=[C:11](Cl)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][O-:19].[Na+]>CN(C)P(N(C)C)(N(C)C)=O>[Cl:16][C:12]1[C:13]([Cl:15])=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][C:11]=1[O:19][CH3:18]
Reactant: C[O-]
Reactant: Clc1cc(OCc2ccccc2)cc(Cl)c1Cl
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1cc(OCc2ccccc2)cc(Cl)c1Cl
Temperature: 0 °C
Reaction time: 20 h
Yield: 14.9 %

Procedure:
A mixture of 3,4,5-trichlorophenol benzyl ether (7.5 g, 0.026 mole) and sodium methoxide (1.7 g, 0.032 mole) in hexamethylphosphoramide (60 ml) was heated with stirring on a steam bath for 20 hours. The reaction mixture was poured into ice water, extracted into ether, washed with water, brine, and dried over magnesium sulfate. The solvent was evaporated at reduced pressure and the residual oil chromatographed on silica gel (320 g) eluting with ethyl acetate-hexane; 1:4 to obtain 1.1 g of 2,3-dichloro-5-benzyloxyanisole which melted at 79°-81° C.
Reaction SMILES: [NH:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[N+:17]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.[Pd]>[NH2:17][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:8]=1[NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:12]([OH:14])=[O:13]
Reactant: O=C(O)c1ccc(Nc2ccccc2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cc(C(=O)O)ccc1Nc1ccccc1
Reaction time: 12 h

Procedure:
A solution of the 4-anilino-3-nitrobenzoic acid (20.1 mmol) in THF (100 mL) was charged with 10% Pd/C (500 mg) and the reaction flask evacuated and subsequently charged with H2 (g) three times. The mixture was stirred vigorously for 12 h after which time it was filtered through diatomaceous earth and the filtrate concentrated in vacuo to give the desired 3-amino-4-anilinobenzoic acid: e.g. 3-amino-4-[(3-hydroxyphenyl)amino]benzoic acid.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C(OCC)(=O)C>[CH2:25]([O:24][C:22](=[O:23])[C:21](=[P:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH3:27])[CH3:26]
Reactant: CCOC(=O)C(C)Br
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.9 %

Procedure:
1.6 Kg (6.10 mol) triphenyl phosphine was dissolved in 10 L ethyl acetate and 1.0 Kg of ethyl 2-bromopropionate was added into the above solution. The reaction mixture was stirred at room temperature for 2 days. White solid was filtered off and the precipitate was washed with ethyl acetate. The resulting compound was dissolved in methanol and treated with saturated aqueous potassium carbonate. After stirring for 2 h, the yellow solid was filtered off and washed with water to give 1.5 Kg (75%) of desired product.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]=O)[N:6]=1.[CH3:9][O:10][C:11](=[O:32])[CH:12]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>O1CCCC1.O>[CH3:9][O:10][C:11](=[O:32])[CH:12]=[CH:7][C:5]1[N:6]=[C:2]([Br:1])[S:3][CH:4]=1
Reactant: O=Cc1csc(Br)n1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C=Cc1csc(Br)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.8 %

Procedure:
Dissolve 2-bromothiazole-4-carbaldehyde (3.00 g, 15.62 mmol) in tetrahydrofuran (52 mL) and add methyl(triphenylphosphoranylidene)acetate (5.33 g. 15.62 mmol). Stir the mixture overnight at room temperature. Dilute the mixture with water and extract twice using diethyl ether. Dry the combined organics over sodium sulfate, filter, and concentrate. Purify via silica gel chromatography using a 0-30% gradient of EtOAc/hexanes to give 3.13 g (81%) of the title compound as a white solid.
Reaction SMILES: [NH:1]([C:8]1[CH:16]=[C:15]([C:17](O)=[O:18])[C:14]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:13][C:9]=1[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(NC2C=C(C(O)=O)C(NC3C=CC(C)=CC=3)=CC=2C(O)=O)=CC=1>>[CH:24]1[CH:25]=[C:26]2[C:17]([C:15]3[C:14]([NH:20][C:21]2=[CH:22][CH:23]=1)=[CH:13][C:9]1[C:10]([C:7]2[C:2]([NH:1][C:8]=1[CH:16]=3)=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:11])=[O:18]
Reactant: O=C(O)c1cc(Nc2ccccc2)c(C(=O)O)cc1Nc1ccccc1
Agent: Cc1ccc(Nc2cc(C(=O)O)c(Nc3ccc(C)cc3)cc2C(=O)O)cc1
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Temperature: 125 °C

Procedure:
A pressure vessel is charged with 405.7 parts of polyphosphoric acid containing 85.0% P2O5. Then 20.3 parts of 2,5-dianilinoterephthalic acid and 60.9 parts of 2,5-di-(4-toluidino)terephthalic acid are introduced at 80 to 90° C. with stirring, and the mixture is heated at 125° C. and stirred at 125° C. for 1 hour during which ring closure takes place to form the quinacridone. The reaction mixture is then metered over the course of 10 seconds into a second pressure vessel containing 184 parts of water and is hydrolyzed at 150° C. under pressure. Following the hydrolysis, the phosphoric acid strength is 89.7%. During this procedure the temperature rises to 180° C. The mixture is cooled to 150° C. and stirred at 150° C. for 3 hours. It is cooled to 90° C. and the hydrolysis mixture is poured into 6000 parts of water at 25° C. with stirring. Thereafter, the mixed-crystal pigment is filtered off with suction, washed to neutrality with water and dried at 80° C.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][CH:19]=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl.Cl[CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:19]=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)=[CH:24][CH:25]=1
Reactant: O=C(c1ccc2[nH]ccc2c1)N1CCC(Oc2ccc(Cl)cc2)CC1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccc2c(ccn2CCN2CCOCC2)c1)N1CCC(Oc2ccc(Cl)cc2)CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 29.9 %

Procedure:
To a stirred solution of (4-(4-chlorophenoxy)piperidin-1-yl)(1H-indol-5-yl)methanone (30 mg, 0.085 mmol, Step-1) and sodium hydride (60% in oil, 6 mg, 0.25 mmol) in N,N-dimethylformamide (1.5 mL) was added 4-(2-chloroethyl)morpholine hydrochloride (35 mg, 0.19 mmol) at room temperature. Then the mixture was stirred at 70° C. for 2 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with water (20 mL), and dried over sodium sulfate. After removal of the solvent, the residue was purified by silica-gel column chromatography (NH-gel, eluting with ethyl acetate) and then preparative LC-MS to give 11.9 mg (30% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[CH:6][N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[Cl:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[CH2:16][Mg]Cl>>[Cl:1][C:2]1[C:7]([C:8](=[O:9])[CH2:16][C:15]2[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=2[Cl:13])=[CH:6][N:5]=[C:4]([S:11][CH3:12])[N:3]=1
Reactant: Cl[Mg]Cc1ccccc1Cl
Reactant: CSc1ncc(C(=O)Cl)c(Cl)n1
Product: CSc1ncc(C(=O)Cc2ccccc2Cl)c(Cl)n1
Temperature: -78 °C

Procedure:
An oven dried flask, equipped with stir bar and septa, was charged with 4-chloro-2-(methylthio)pyrimidine-5-carbonyl chloride (Aaron Chemistry, 1338 mg, 6 mmol). The flask was capped with septa, evacuated and backfilled with nitrogen (three times). The solid was dissolved in tetrahydrofuran (24.0 mL), cooled to −78° C. and kept under nitrogen. (2-Chlorobenzyl)magnesium chloride (14.40 mL, 7.20 mmol) was then slowly added. After the addition was completed, the dry ice/acetone bath was removed and the mixture was stirred at ambient temperature for 3 hours. The mixture was quenched with aqueous 1 M HCl (50 mL), extracted with ethyl acetate (3×80 mL) and the combined extracts were washed with brine, dried over magnesium sulfate (MgSO4), filtered and concentrated. The crude product obtained was purified by flash chromatography (Isco®, Redi-Sep® column, 0-30% ethyl acetate/hexane, linear gradient) to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 8.72 (s, 1H), 7.47-7.36 (m, 1H), 7.36-7.21 (m, 3H), 4.41 (s, 2H), 2.61 (s, 3H); MS (ESI) m/z 313 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[C:4]([CH3:10])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:30]N1C(=O)CCC1=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:30])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)ccc1CO
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cc(Br)ccc1CBr
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of (4-bromo-2-methyl-phenyl)-methanol (Intermediate 133, 319.0 mg, 1.58 mmol) and triphenylphosphine (466.0 mg, 1.74 mmol) in 5 mL CH2C12 was cooled to 0° C. and N-bromosuccinimide (309.0 mg, 1.74 mmol) was added in 5 portions over 20 minutes. The solution was warmed to 25° C. and stirred for 17 hours. The reaction was quenched by the addition of dilute aqueous NaHCO3. The resulting mixture was extracted with Et2O and the combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (Na2SO4) and concentrated under reduced pressure. The title compound, 350.0 mg (84%), was isolated by column chromatography (2-3% EtOAc-hexanes) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][C@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28](F)[CH:27]=2)[N:3]=1.CCO.CCN(C(C)C)C(C)C.[NH2:47][NH2:48]>CO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][C@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:26]2[CH:27]=[C:28]3[C:29]([C:32]([NH2:33])=[N:47][NH:48]3)=[CH:30][CH:31]=2)[N:3]=1
Reactant: C[C@H](NC(=O)[C@H]1CC[C@@H](C)N(c2cc(-c3ccc(C#N)c(F)c3)nc(N)n2)C1)c1ccccc1
Reactant: NN
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: C[C@H](NC(=O)[C@H]1CC[C@@H](C)N(c2cc(-c3ccc4c(N)n[nH]c4c3)nc(N)n2)C1)c1ccccc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
Into a sealable tube, (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-N-[(1S)-1-phenylethyl]-3-piperidinecarboxamide (186 mg, 0.406 mmol), EtOH (5 mL), Hunig's base (0.071 ml, 0.406 mmol), and hydrazine anhydrous (0.076 mL, 2.434 mmol) were added, and the yellow suspension mixture was heated overnight at 110° C. in an oil bath. When the temperature of the reaction reached to 100° C., the solid in the mixture was all dissolved. After overnight, there was a yellow solution as well as a little amount of black colored solid formed. LCMS showed mainly product. CH3OH (5 mL) was added to the solution. The black solid was filtered from the yellow solution. Water (20 mL) was added to the yellow solution, and a solid was formed. The solid was filtered, washed by water, and dried in vacuum. The solid was recrystallized from CH3CN, and the solid was filtered, washed by CH3CN, and dried in vacuum to afford the title compound (120 mg) as a light yellow solid. LC-MS (ES) m/z=471 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.14 (d, J=6.8 Hz, 3H), 1.36 (d, J=7.1 Hz, 3H), 1.66 (m, 1H), 1.68 (m, 1H), 1.77 (m, 2H), 2.34 (m, 1H), 4.94 (m, 1H), 5.38 (s, 2H), 6.07 (s, 2H), 6.56 (s, 1H), 7.19-7.30 (m, 1H), 7.36 (m, 4H), 7.56 (dd, J=8.6, 1.5 Hz, 1H), 7.70 (d, J=8.34 Hz, 1H), 7.94 (s, 1H), 8.39 (d, J=8.1 Hz, 1H), 11.50 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH3:21])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3/[CH:16]=[CH:17]/[C:18](=[O:20])[CH3:19])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CN(C)C=O.C(O)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH3:21])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3/[CH:16]=[CH:17]/[CH:18]([OH:20])[CH3:19])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)/C=C/c1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(O)/C=C/c1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Reaction time: 2.5 h

Procedure:
2.4 g (7.6 mmol) of 7-chloro-4,5-dihydro-3-[(E)-3-oxo-1-butenyl]-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was dissolved in 50 ml of dimethylformamide while warming. Thereafter, the solution was diluted with 280 ml of ethanol. 0.6 g (15.8 mmol) of sodium borohydride was added to this solution and the mixture was stirred at 20° for 2.5 hours. Thereafter, a further 0.2 g of sodium borohydride was added thereto. After a total reaction period of 4.5 hours the mixture was evaporated in a vacuum. The residue, which still contained dimethylformamide, was poured on to ice/water and stirred at 0° for 1 hour. The crystallizate was filtered off under suction and dried. There was obtained 7-chloro-4,5-dihydro-3-[(E)-3-hydroxy-1-butenyl]-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one as white crystals of melting point 232°-233°.