Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N:20]2[C:25]3=[N:26][C:27](S(C)(=O)=O)=[N:28][CH:29]=[C:24]3[CH2:23][N:22]([C:34]3[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:35]=3[Cl:41])C2=O)[CH:15]=1)([CH2:12][CH3:13])[CH2:10][CH3:11])(C)(C)C.[NH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.[F:51][C:52]([F:57])([F:56])[C:53]([OH:55])=[O:54]>ClCCl>[F:51][C:52]([F:57])([F:56])[C:53]([OH:55])=[O:54].[NH2:7][CH2:8][C:9]([C:14]1[CH:15]=[C:16]([N:20]2[C:25]3=[N:26][C:27]([NH:44][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)=[N:28][CH:29]=[C:24]3[CH2:23][N:22]([C:34]3[C:35]([Cl:41])=[CH:36][CH:37]=[CH:38][C:39]=3[Cl:40])[C:53]2=[O:55])[CH:17]=[CH:18][CH:19]=1)([CH2:12][CH3:13])[CH2:10][CH3:11]
Reactant: CCC(CC)(CNC(=O)OC(C)(C)C)c1cccc(N2C(=O)N(c3c(Cl)cccc3Cl)Cc3cnc(S(C)(=O)=O)nc32)c1
Reactant: Nc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)(CN)c1cccc(N2C(=O)N(c3c(Cl)cccc3Cl)Cc3cnc(Nc4ccccc4)nc32)c1
Temperature: 140 °C
Yield: 19 %

Procedure:
A mixture of 400 mg (0.62 mmol) of (2-[3-[3-(2,6-dichlorophenyl)-7-methanesulfonyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-phenyl]-2-ethyl-butyl)-carbamic acid tert-butyl ester and 600 mg (6.5 mmol) of aniline was heated at 140° C. for 45 minutes and cooled. The residue was dissolved in 20 ml of a 1:1 mixture of dichloromethane and trifluoroacetic acid. After 10 minutes the mixture was evaporated and the product purified by flash chromatography on silica gel using a gradient elution from dichloromethane/methanol 98:2 to dichloromethane/methanol 95:5. Product-containing fractions were evaporated and the residue dissolved in 4 ml of dichloromethane. The product was precipitated by the addition of pentane and subsequently filtered and dried to give 65 mg (19%) of 1-[3-(1-aminomethyl-1-ethyl-propyl)-phenyl]-3-(2,6-dichloro-phenyl)-7-phenylamino-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one trifluoroacetate as a white solid of melting point 232° C.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:50])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:8][C:7]=1[O:31][CH2:32][CH2:33][CH2:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:38][CH:37]=1>>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([C:5]([OH:50])=[O:4])=[C:7]([O:31][CH2:32][CH2:33][CH2:34][O:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)=[CH:38][CH:37]=2)[CH:8]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)OC)c(OCCCOc2ccc(OCc3ccccc3)cc2)c1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)O)c(OCCCOc2ccc(OCc3ccccc3)cc2)c1
Yield: 88 %

Procedure:
Sodium hydroxide hydrolysis of 4-(octadecyloxy)-2-[3-[4-(phenylmethoxy)phenoxy]propoxy]benzoic acid methyl ester gave 4-(octadecyloxy)-2-[3-[4-(phenylmethoxy)phenoxy]propoxy]benzoic acid (88% yield, mp 102°-104°).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[N:25]1[C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=[N:26]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:29]1[N:25]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][O:19]2)[N:26]=[CH:27][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(cc(Br)n2Cc2ccccc2)n1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: Clc1ccc2c(cc(-c3ccnn3C3CCCCO3)n2Cc2ccccc2)n1
Temperature: 25 °C

Procedure:
A mixture of 1-benzyl-2-bromo-5-chloro-1H-pyrrolo[3,2-b]pyridine (0.088 g, 0.27 mmol, from Step 2), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.084 g, 0.30 mmol, Aldrich) and Na2CO3 (0.14 g, 1.4 mmol) in 1,2-dimethoxyethane (3 mL) and water (0.5 mL) was degassed by a stream of nitrogen through the solution for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.032 g, 0.027 mmol, Strem) was added, the vial was capped and heated to reflux for 15 minutes. After cooling to room temperature, the mixture was partitioned between 10% sodium thiosulfate solution and EtOAc. The aqueous layer was extracted three times with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with 25% EtOAc in hexanes afforded product. Yield: (75 mg, 68%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:18]([CH2:19][CH3:20])[N:17]=[C:16]([CH2:21][CH3:22])[C:15]=2[CH3:23])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24]>CO>[ClH:24].[ClH:24].[CH2:19]([N:18]1[C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[C:15]([CH3:23])[C:16]([CH2:21][CH3:22])=[N:17]1)[CH3:20]
Reactant: CCc1nn(CC)c(C2CCN(C(=O)OC(C)(C)C)CC2)c1C
Agent: Cl
Solvent: CO
Product: CCc1nn(CC)c(C2CCNCC2)c1C
Yield: 92 %

Procedure:
A solution of 1-(t-butoxycarbonyl)-4-(1,3-diethyl-4-methyl-(1H)-pyrazol-5-yl)piperidine (348 mg) (from Step E) in 2.5 N HCl in methanol was stirred at rt for 16 h. The solution was concentrated and the resulting solid was suspended in ethyl acetate, filtered and dried to afford 293 mg (92%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[Br:14][C:15]1[CH:16]=[CH:17][C:18]([Cl:25])=[C:19]([S:21](Cl)(=[O:23])=[O:22])[CH:20]=1>C(Cl)Cl>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([Cl:25])=[C:19]([S:21]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)(=[O:23])=[O:22])[CH:20]=1
Reactant: O=S(=O)(Cl)c1cc(Br)ccc1Cl
Reactant: Nc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ccccc1)c1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirring solution of aniline (0.324 ml, 3.55 mmol) in DCM (10 ml) is added pyridine (1.44 ml, 17.76 mmol) followed by a solution of 5-bromo-2-chloro-benzenesulfonyl chloride (1.03 g, 3.55 mmol) in DCM (10 ml). The reaction mixture is stirred at room temperature for 18 hours. DCM (20 ml) is added and the reaction mixture is washed with 2M HCl (50 ml), dried over MgSO4 and concentrated in vacuo to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:11]([Br:12])=[CH:10][C:9]([CH3:13])=[C:8]2[C:3]=1[C:4](=[O:14])[CH2:5][CH2:6][S:7]2.[Cl-].[Na+].[BH4-].[Na+].Cl>ClCCl.CO>[CH3:1][C:2]1[C:11]([Br:12])=[CH:10][C:9]([CH3:13])=[C:8]2[C:3]=1[CH:4]([OH:14])[CH2:5][CH2:6][S:7]2
Reactant: Cc1cc(Br)c(C)c2c1SCCC2=O
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(Br)c(C)c2c1SCCC2O
Yield: 91.3 %

Procedure:
100 ml of methanol and 30 ml of dichloromethane were added to 10 g (36.9 mmol) of 5,8-dimehyl-6-bromothiochroman-4-one. While the mixture was maintained at a temperature not exceeding 0° C. with a sodium chloride aqueous solution and an ice bath, 0.70 g (18.4 mmol) of sodium borohydride as a reducing agent was gradually added. The mixture was allowed to react at room temperature for 3 hours, and then the reaction mixture was poured into a 5% hydrochloric acid aqueous solution and extracted with dichloromethane. The resultant dichloromethane layer was dried over anhydrous sodium sulfate and concentrated to give 9.2 g (yield 91%) of 5,8-dimethyl-4-hydroxy-6-bromothiochroman (corresponding to compound of the formula (VI)).
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:35]3[CH:36]=[CH:37][C:32]([C:31]([F:42])([F:41])[F:30])=[CH:33][CH:34]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2ccc(C(F)(F)F)cc2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and 4-(trifluoromethyl)phenyl boronic acid. The title compound was obtained in 52% yield as yellow foam. MS (m/e): 550.2 (MH+, 100%).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:40]>C(Cl)Cl>[CH2:1]([Br:40])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCBr
Temperature: 25 °C
Yield: 95.5 %

Procedure:
Octadecan-1-ol (1a) (520 mg, 1.92 mmol) and Ph3P (550 mg, 2.10 mmol) were dissolved in CH2Cl2 (25 mL). The mixture was cooled in an ice bath and CBr4 (630 mg, 1.90 mmol) was added with stirring. The mixture was allowed to warm to r.t. and was stirred overnight, then it was concentrated under a stream of N2 and the residue was subjected to flash column chromatography on silica, eluting with hexane, to afford 1-bromooctadecane (2a) (605 mg, 96%) as a waxy solid; mp 26-28° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[C:21]1[CH:25]=[CH:24][N:23]([CH2:26][CH2:27][C:28]([OH:30])=O)[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:31]([N:34](CC)[CH:35](C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.CNC.C1COCC1>CN(C=O)C.CO>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[C:21]1[CH:25]=[CH:24][N:23]([CH2:26][CH2:27][C:28]([N:34]([CH3:35])[CH3:31])=[O:30])[N:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1nnc2ccc3c(cc(-c4ccn(CCC(=O)O)n4)n3Cc3ccccc3)n12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1nnc2ccc3c(cc(-c4ccn(CCC(=O)N(C)C)n4)n3Cc3ccccc3)n12
Reaction time: 0.03 h

Procedure:
To a solution of 3-[3-(6-benzyl-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-7-yl)-1H-pyrazol-1-yl]propanoic acid (7.0 mg, 0.017 mmol, from Step 1) in DMF (0.3 mL) was added N,N-diisopropylethylamine (12 μL, 0.070 mmol, Aldrich) followed by N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (12 mg, 0.031 mmol, Aldrich). After stirring for 2 minutes, 2.0 M dimethylamine in THF (0.070 mL, 0.14 mmol, Aldrich) was added. After 15 minutes, the reaction was diluted with MeOH and purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH). Yield: (4.3 mg, 58%).
Reaction SMILES: [C:1]1([C:7]2[C:11]([CH3:12])=[N:10][N:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]=2[NH2:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C(N=[C:23]=[O:24])C>N1C=CC=CC=1>[CH3:12][C:11]1[C:7]2[C:1]3[CH2:6][CH2:5][CH2:4][CH2:3][C:2]=3[C:23](=[O:24])[NH:19][C:8]=2[N:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:10]=1
Reactant: CCN=C=O
Reactant: Cc1nn(-c2ccccc2)c(N)c1C1=CCCCC1
Solvent: c1ccncc1
Product: Cc1nn(-c2ccccc2)c2[nH]c(=O)c3c(c12)CCCC3
Yield: 35.3 %

Procedure:
To a solution of EXAMPLE 7A (1.26 g, 5 mmol) in pyridine (10 mL) was added ethyl isocyanate (1.18 mL, 15 mmol). The solution was heated at reflux for 7 hours, cooled, concentrated and the residue triturated with methanol. The solid was collected by filtration, washed with methanol and dried to give 493 mg (35%) of the title compound. 1H NMR (DMSO-d6) 1.72-1.83 (m, 4H), 2.49-2.55 (m, 2H), 2.57 (s, 3H), 3.05 (t, J=5.2 Hz, 2H), 7.24 (t, J=7.4 Hz, 1H), 7.43-7.53 (m, 2H), 8.19 (d, J=7.7 Hz, 2H), 11.27 (br s, 1H).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH2:22][C:23](=[O:41])[NH:24][C:25]4[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[C:29]([NH:36][CH2:37][CH:38]([CH3:40])[CH3:39])=[CH:28][C:26]=4[N:27]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH2:37]([NH:36][C:29]1[C:30]([C:32]([F:33])([F:34])[F:35])=[CH:31][C:25]2[NH:24][C:23](=[O:41])[CH2:22][C:21]([C:17]3[CH:16]=[C:15]([C:11]4[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:10]=4)[CH:20]=[CH:19][CH:18]=3)=[N:27][C:26]=2[CH:28]=1)[CH:38]([CH3:40])[CH3:39]
Reactant: CC(C)CNc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c1)=N2
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CNc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cccc(S(N)(=O)=O)c3)c1)=N2

Procedure:
) The title compound was prepared from the above described 3′-(8-isobutylamino-4-oxo-7-trifluoromethyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-biphenyl-3-sulfonic acid tert-butylamide (275 mg) and TFA (6 mL) according to the general procedure I step 2. Obtained as a yellow solid (172 mg, 65%). MS (ISN) 529.4 [(M−H)−]; mp 251° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][N+:10]([O-])=O)=[CH:4][C:3]=1[Cl:13].[Li+].[BH4-].Cl[Si](C)(C)C>C1COCC1>[Cl:13][C:3]1[CH:4]=[C:5]([CH2:8][CH2:9][NH2:10])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: O=[N+]([O-])C=Cc1ccc(Cl)c(Cl)c1
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 75.7 %

Procedure:
Using an analogous procedure and workup as described in Example 15, 1,2-dichloro-4-(2-nitro-vinyl)-benzene (I-41a: 5.1 g, 23.831 mmol) in dry THF (51 mL) was reacted with LiBH4 (2.1 g, 95.327 mmol) and chloro trimethyl silane (20.71 g, 190.64 mmol) at 0° C. The resulting mixture was stirred at room temperature for 72 hours to afford 3.43 g of the crude product which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][O:19][CH3:20])=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.O1CCCC1.[BH4-].[Na+]>O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][O:19][CH3:20])=[CH:13][C:10]=1[CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCOc1ccc(OCc2ccccc2)c(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: COCOc1ccc(OCc2ccccc2)c(CO)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a mixture of 2-benzyloxy-5-methoxymethoxybenzaldehyde (10.03 g), ethanol (50 mL) and tetrahydrofuran (100 mL) was added sodium tetrahydroborate (1.43 g) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give (2-benzyloxy-5-methoxymethoxyphenyl)methanol as a colorless oil (10.08 g, 97%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:4][C:3]=1[N:14]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[N:15]1.[Cl:21]Cl>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:4][C:3]=1[N:14]1[C:18]([CH3:19])=[C:17]([Cl:21])[C:16]([CH3:20])=[N:15]1
Reactant: ClCl
Reactant: Cc1cc(C)n(-c2cc(OS(C)(=O)=O)c(Cl)cc2F)n1
Solvent: ClC(Cl)Cl
Product: Cc1nn(-c2cc(OS(C)(=O)=O)c(Cl)cc2F)c(C)c1Cl
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
Into a solution of 1-(2-fluoro-4-chloro-5-methylsulfonyloxyphenyl)-3,5-dimethylpyrazole (31.9 g) in chloroform (200 ml) was introduced chlorine gas (7.1 g) for 10 minutes under water-cooling, and then the reaction mixture was stirred for further 30 minutes to effect the chlorination reaction. Removal of the solvent from the reaction solution by distillation in vacuo gave the titled compound (35.2 g) as a pale brown oil. Purification of this oil by silica gel column chromatography yielded a colorless oil. nD23 =1.5431.
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[CH:17]=[CH:16][C:11]([C:12](OC)=[O:13])=[CH:10][C:9]=2[C:18]([F:21])([F:20])[F:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Li+].C1COCC1.Cl>O1CCOCC1.O>[CH:1]1([CH2:7][C:8]2[CH:17]=[CH:16][C:11]([CH2:12][OH:13])=[CH:10][C:9]=2[C:18]([F:19])([F:20])[F:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc(CC2CCCCC2)c(C(F)(F)F)c1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: OCc1ccc(CC2CCCCC2)c(C(F)(F)F)c1
Temperature: 80 °C
Yield: 75 %

Procedure:
To a stirred solution of methyl 4-(cyclohexylmethyl)-3-(trifluoromethyl)benzoate (280 mg, 0.93 mmol) in dioxane (8 mL) was added 2 M lithium borohydride in THF solution (0.93 mL, 1.86 mmol). The reaction mixture was heated at 80° C. for 2 h, cooled down, poured into water, acidified with 1 M HCl aqueous solution to pH 4, extracted with ethyl acetate. The combined organics were washed with saturated NaHCO3 solution and water, dried and concentrated. The residue was purified by silica gel column chromatography to give the title compound (190 mg) as colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 0.96-1.06 (m, 2H), 1.14-1.22 (m, 3H), 1.62-1.72 (m, 6H), 2.67 (d, J=6.7 Hz, 2H), 4.71 (d, J=5.7 Hz, 2H), 7.29 (d, J=7.9 Hz, 1H), 7.45 (dd, J=8.0 and 1.6 Hz, 1H), 7.62 (d, J=1.6 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[O:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][NH2:21])[CH2:15][CH2:14]1>CC(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:21][CH2:20][CH2:19][N:16]2[CH2:17][CH2:18][O:13][CH2:14][CH2:15]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: NCCN1CCOCC1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC(C)=O
Product: N#Cc1ccc(S(=O)(=O)NCCN2CCOCC2)cc1
Temperature: 25 °C

Procedure:
A mixture of 4-cyanobenzene sulphonyl chloride (5.15 g) in acetone (70 ml) was stirred at ambient temperature and then a solution of 2-morpholinoethylamine (6.7 ml) in acetone (15 ml) was added dropwise with stirring. The mixture was stirred at ambient temperature for 2 hours and then the acetone was removed by evaporation and the residue was eluted through a silica pad using ethyl acetate to give 4-cyano-N-2-morpholinoethyl-benzenesulphonamide.
Reaction SMILES: [N:1]([CH:4]([CH3:21])[CH2:5][N:6]1[C:10]2=[CH:11][C:12]3[C:17]([C:16]([CH3:19])([CH3:18])[CH:15]=[CH:14][C:13]=3[F:20])=[C:9]2[CH:8]=[N:7]1)=[N+]=[N-].[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26]>C(O)C.C(OCC)C.CO.[Pt]=O>[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26].[F:20][C:13]1[CH:14]=[CH:15][C:16]([CH3:18])([CH3:19])[C:17]2[C:12]=1[CH:11]=[C:10]1[C:9]=2[CH:8]=[N:7][N:6]1[CH2:5][CH:4]([NH2:1])[CH3:21]
Reactant: CC(Cn1ncc2c1=CC1=C(F)C=CC(C)(C)C=21)N=[N+]=[N-]
Agent: O=[Pt]
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOCC
Solvent: CO
Solvent: CCO
Product: CC(N)Cn1ncc2c1=CC1=C(F)C=CC(C)(C)C=21
Temperature: 25 °C
Reaction time: 15 h
Yield: 82.8 %

Procedure:
1.66 g (5.82 mmol) of (RS)-1-(2-azido-propyl)-7-fluoro-4,4-dimethyl-1,4-dihydro-indeno[2,1-c]pyrazole dissolved in 80 ml of anhydrous ethanol were hydrogenated over 160 mg of platinum oxide for 1.5 hours. The catalyst was subsequently filtered off, rinsed with ethanol and the solvent was removed in a vacuum. The yellow oil obtained was dissolved in 80 ml of anhydrous diethyl ether, filtered and treated while stirring with a solution of 676 mg (5.82 mmol) of fumaric acid in 10 ml of methanol. The mixture was stirred at room temperature for 15 hours and the white crystals were subsequently filtered off. 1.81 g (83%) of (RS)-2-(7-fluoro-4,4-dimethyl-1,4-dihydroindeno[2,1-c]pyrazol-1-yl)- 1-methyl-ethylamine fumarate (1:1) with m.p. 144°-146° were obtained.
Reaction SMILES: Cl[C:2]1[C:3]2[C:17]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=3[CH3:26])=[CH:16][N:15]([CH3:27])[C:4]=2[N:5]=[C:6]([N:8]([CH2:12][CH2:13][CH3:14])[CH2:9][CH2:10][CH3:11])[N:7]=1.C(O)(=[O:30])C>[OH-].[Na+].O>[CH2:9]([N:8]([CH2:12][CH2:13][CH3:14])[C:6]1[NH:7][C:2](=[O:30])[C:3]2[C:17]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=3[CH3:26])=[CH:16][N:15]([CH3:27])[C:4]=2[N:5]=1)[CH2:10][CH3:11]
Reactant: CC(=O)O
Reactant: CCCN(CCC)c1nc(Cl)c2c(-c3c(C)cc(C)cc3C)cn(C)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCN(CCC)c1nc2c(c(-c3c(C)cc(C)cc3C)cn2C)c(=O)[nH]1
Yield: 81 %

Procedure:
4-Chloro-5-mesityl-7-methyl-N,N-dipropyl-7H-pyrrolo[2,3-d]pyrimidin-2-amine (50 mg, 0.13 mmol) in aqueous sodium hydroxide (2M, 10 ml) was heated at reflux for 6 hours. The solution was cooled to room temperature and neutralized with acetic acid. The mixture was diluted with water (20 ml) and extracted with ethyl acetate (50 ml×3). The extracts were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (4:1) to give 39 mg (81%) of the title compound.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][O:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2.S(O[CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)(=O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(#N)C>[CH3:35][O:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][CH2:26][CH2:25][N:2]([CH2:3][CH2:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9][O:8][C:7]3[CH:16]=[CH:17][CH:18]=[CH:19][C:6]2=3)[CH3:1])=[CH:29][CH:30]=1
Reactant: CNCCN1c2ccccc2COc2ccccc21
Reactant: COc1ccc(CCCOS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(CCCN(C)CCN2c3ccccc3COc3ccccc32)cc1
Temperature: 90 °C

Procedure:
5,11-Dihydro-5-[2-(N-methylamino]ethyl]dibenzo[b,e][1,4]oxazepine (245 mg, 0.96 mmol), 3-(4-methoxyphenyl)propyl mesylate (353 mg, 1.45 mmol), sodium carbonate (154 mg, 1.45 mmol) and sodium iodide (20 mg, 0.13 mmol) were added to acetonitrile (25 ml), and they were heated under reflux at 90° C. for 6 hours. The solvent was evaporated under reduced pressure. The obtained residue was distributed in ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with water and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography. The product was eluted with dichloromethane and hexane (1:2) and then with dichloromethane. The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain 5,11-dihydro-5-[2-[N-[3-(4-methoxyphenyl)propyl]-N-methylamino]ethyl]dibenzo[b,e][1,4]oxazepine in the form of a light yellow oil (101 mg, 26%).