Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1.Br[CH2:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:20]=1[C:21](OC)=[O:22]>C1C=CC=CC=1.ClCCl>[CH3:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[C:21](=[O:22])[N:1]([C:2]1[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][N:8]3[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1)[CH2:29]2
Reactant: COC(=O)c1c(C)cccc1CBr
Reactant: CCOC(=O)Cn1ccc2ccc(N)cc21
Solvent: c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)Cn1ccc2ccc(N3Cc4cccc(C)c4C3=O)cc21
Yield: 64 %

Procedure:
Ethyl 2-(6-amino-1H-indol-1-yl)acetate (intermediate B) (7.66 mmol, 1 equiv.) was dissolved in benzene (30 ml), and methyl 2-(bromo-methyl)-6-methylbenzoate (8.42 mol, 1.1 equiv.) and TEA (9.19 mmol, 1.2 equiv.) were added at 25° C. and the mixture was refluxed for 12 h. The reaction mixture was reduced under reduced pressure and the residue was taken up in dichloromethane (30 ml), washed with water and sat. NaCl solution (5 ml), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (10% ethyl acetate in hexane). Yield: 64%
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[C:14]3[N:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:16]=[N:17][C:13]=3[CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:28][NH:29][CH3:30]>CN1C(=O)CCC1>[CH3:28][N:29]([CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[C:14]3[N:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:16]=[N:17][C:13]=3[CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1)[CH3:30]
Reactant: FC(F)(F)c1cc(-c2cccc(CCl)c2)c2c(c1)ncn2-c1ccccc1
Reactant: CNC
Solvent: CN1CCCC1=O
Product: CN(C)Cc1cccc(-c2cc(C(F)(F)F)cc3ncn(-c4ccccc4)c23)c1

Procedure:
This was prepared analogeously to the above product from 7-(3-(chloromethyl)phenyl)-1-phenyl-5-trifluoromethylbenzimidazole (0.97 g, 2.5 mmol) and dimethyl amine (2 ml) in NMP (5 ml) to yield 0.54 g (55%), m/z, 396.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[C:27](O)=O)[CH:20]=[CH:19][CH:18]=1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:14][C:27]([C:25]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:26]=2[N:17]=[CH:18][CH:19]=[CH:20]3)=[N:16][N:15]=1
Reactant: O=C(O)c1cccc2cccnc12
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2cccc3cccnc23)o1
Yield: 49 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using quinoline-8-carboxylic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate=80:20 to 50:50, 160 mg, 49%) which was obtained as a white solid. MS: m/e=355.2 [M+H]+.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]#[N:13])(=O)OCC)C.[CH3:14][N:15]1[C:19]([NH:20][C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([CH:40]=O)[CH:17]=[N:16]1>O1CCCC1>[CH3:14][N:15]1[C:19]([NH:20][C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([CH:40]=[CH:11][C:12]#[N:13])[CH:17]=[N:16]1
Reactant: Cn1ncc(C=O)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ncc(C=CC#N)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 60.9 %

Procedure:
To a suspension of sodium hydride (55% dispersion in mineral oil, 26.2 g, 600 mmol) in tetrahydrofuran (1000 ml) was added diethyl(cyanomethyl)phosphonate (106.3 g, 600 mmol) under ice-cooling. The mixture was stirred under ice-cooling for 20 minutes. To the mixture was added 1-methyl-5-triphenylmethylaminopyrazole-4-carbaldehyde (197 g, 530 mmol), and the mixture was stirred for 2 hours. The reaction mixture was poured into ice-cold water. The mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was triturated with diethyl ether to give 3-(1-methyl-5-triphenylmethylaminopyrazol-4-yl)acrylonitrile (E, Z mixture, 126 g) as a solid.
Reaction SMILES: [CH2:1]([C:3](=[CH2:13])[CH2:4][CH2:5][O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)C.[BH4-].[Na+].[CH3:16][OH:17]>[OH-].[Na+].[Hg]>[CH3:16][O:17][C:3]([CH3:1])([CH3:13])[CH2:4][CH2:5][O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1
Reactant: CO
Reactant: C=C(CC)CCOC1CCCCO1
Agent: [BH4-]
Agent: [Hg]
Agent: [Na+]
Product: COC(C)(C)CCOC1CCCCO1
Yield: 93 %

Procedure:
To 2-(3-ethyl-3-butenyloxy)tetrahydropyran (150.0 g, 881.0 mmol) in methanol (600 ml) was added mercuric acetate (309 g, 969 mmol) and the mixture was stirred until it became homogeneous. To this solution was added 0.5N NaOH (500 ml) in one portion followed by dropwise addition of 0.5 N NaBH4 in 0.5 N NaOH (500 ml). The mixture is stirred until mercury metal congeals at the bottom of the flask. The solution is decanted into a separatory funnel and extracted with ether (3×300 ml). The combined ethereal extracts are dried (MgSO4) and concentrated to afford 166 g (93%) of 2-(3-methoxy-3-methylbutyloxy)tetrahydropyran as a colorless liquid.
Reaction SMILES: [CH3:1][N:2]([CH3:44])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([NH:38][CH2:39][CH2:40][N:41]([CH3:43])[CH3:42])=[C:13]3[C:14](=[O:37])[C:15]4[C:20]([C:7]([C:8]=23)=[N:6]1)=[C:19]([O:21]CC1C=CC=CC=1)[CH:18]=[CH:17][C:16]=4[O:29]CC1C=CC=CC=1.ClCCl.B(Cl)(Cl)Cl>CO>[OH:29][C:16]1[CH:17]=[CH:18][C:19]([OH:21])=[C:20]2[C:15]=1[C:14](=[O:37])[C:13]1[C:8]3[C:7]2=[N:6][N:5]([CH2:4][CH2:3][N:2]([CH3:44])[CH3:1])[C:9]=3[CH:10]=[CH:11][C:12]=1[NH:38][CH2:39][CH2:40][N:41]([CH3:43])[CH3:42]
Reactant: CN(C)CCNc1ccc2c3c(nn2CCN(C)C)-c2c(OCc4ccccc4)ccc(OCc4ccccc4)c2C(=O)c13
Agent: ClB(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: CN(C)CCNc1ccc2c3c(nn2CCN(C)C)-c2c(O)ccc(O)c2C(=O)c13
Temperature: 25 °C
Yield: 47.6 %

Procedure:
0.35 g (0.59 mmol) of 2-[2-(dimethylamino)-ethyl]-5-[[2-(dimethylamino)ethyl]amino]-7,10-bis(phenylmethoxy)-anthra[1,9-cd]pyrazol-6(2H)-one is dissolved in cold, dry dichloromethane (4 ml) and boron trichloride (4 ml, 1M solution in dichloromethane) is added dropwise over 30 minutes under argon. The reaction mixture is maintained at 0°-5° C. for 1 hour and then treated dropwise with cold methanol under argon. The mixture is then maintained at room temperature for 2 hours and then evaporated to dryness in vacuo. The resulting crude hydrochloride salt is dissolved in a minimum volume of methanol and then chromatographed on a column of silica gel (60A) using an eluting solvent of dichloromethane:methanol (80:20 v/v) and then dichloromethane:methanol:triethylamine (80:20:1 v/v). The major red band is collected and evaporated in vacuo to yield 0.115 g of the title compound as a red solid, m.p. 101 C; λmax (methanol) (E/cm/M) 580 nm (11200), 334 nm (7463), 290 nm (5667).
Reaction SMILES: [CH:1]1([N:4]([CH2:32][C:33]2[CH:34]=[C:35]([CH:46]=[C:47]([CH2:49][CH2:50][CH2:51][O:52][CH3:53])[CH:48]=2)[O:36][CH2:37][C:38]2([CH2:41][C:42]([O:44]C)=[O:43])[CH2:40][CH2:39]2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][NH:9][CH2:8]2)=[O:6])[CH2:3][CH2:2]1.[Na]>>[CH:1]1([N:4]([CH2:32][C:33]2[CH:34]=[C:35]([CH:46]=[C:47]([CH2:49][CH2:50][CH2:51][O:52][CH3:53])[CH:48]=2)[O:36][CH2:37][C:38]2([CH2:41][C:42]([OH:44])=[O:43])[CH2:40][CH2:39]2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:17][CH:18]=3)[CH2:11][CH2:10][NH:9][CH2:8]2)=[O:6])[CH2:2][CH2:3]1
Reactant: COCCCc1cc(CN(C(=O)[C@H]2CNCC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCC2(CC(=O)OC)CC2)c1
Agent: [Na]
Product: COCCCc1cc(CN(C(=O)[C@H]2CNCC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCC2(CC(=O)O)CC2)c1

Procedure:
Prepared according to the procedure described in Example 2 but using instead methyl (1-{[3-({cyclopropyl[((3R,4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)-ethoxy]phenyl}piperidin-3-yl)carbonyl]amino}methyl)-5-(3-methoxypropyl)phen-oxy]methyl}cyclopropyl)acetate (Example 11) as the starting material. The sodium salt of the title compound was a foam.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH2:16][CH2:15]2.[OH-].[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([F:11])=[CH:20][CH:19]=3)[CH2:15][CH2:16]2)=[O:9])[CH:3]=1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Reactant: Fc1ccc2c(c1)CCN2
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(c1cc(Cl)ncn1)N1CCc2cc(F)ccc21
Reaction time: 1 h

Procedure:
0.92 g (4.9 mmol) 6-chloro-pyrimidine-4-carboxylic acid chloride in 40 mL DCM were cooled in an ice/acetone bath and mixed with 0.67 g (4.9 mmol) 5-fluoro-2,3-dihydro-1H-indole. Another 5 mL (5.0 mmol) of a 1N aqueous sodium hydroxide solution were added dropwise and the mixture was stirred for 1 h with cooling. Then 50 mL of a saturated sodium hydrogen carbonate solution were added and the mixture was stirred for a further 10 min. The organic phase was separated off, extracted with 1N aqueous hydrochloric acid solution and with water, dried and evaporated down.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:30]1[CH2:32][C@@H:31]1[CH2:33][O:34][C:35]1[CH:44]=[CH:43][CH:42]=[C:41]2[C:36]=1[CH:37]=[CH:38][CH:39]=[N:40]2>C(O)(C)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:32][C@@H:31]([OH:30])[CH2:33][O:34][C:35]3[CH:44]=[CH:43][CH:42]=[C:41]4[C:36]=3[CH:37]=[CH:38][CH:39]=[N:40]4)[CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1cc(OC[C@H]2CO2)c2cccnc2c1
Reactant: CN1CCC(C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Solvent: CC(C)O
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCN(CC[C@@H](O)COc2cccc3ncccc23)CC1
Temperature: 70 °C
Yield: 82.6 %

Procedure:
Methylpiperidine-4-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (57) (150 mg; 0.382 mmol) is dissolved in isopropanol (10 mL) at ambient temperature. (R)-5-Oxiranylmethoxy-quinoline (2) (77.5 mg; 0.382 mmol) is added, then the mixture is heated to 70° C. and maintained for 18 hours. After cooling to ambient temperature, the solution is concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (0%→25% methanol in methylene chloride) affording the desired product (187.4 mg) as a solid foam. ESMS:MH+ 594.4 (base).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:14]3[CH2:15][CH2:16][C:17]4[C:18]5[C:23]([S:24][C:25]=4[C:13]=3[CH:12]=[N:11]2)=[N:22][CH:21]=[N:20][C:19]=5[O:26]CCC2C=CC([N+]([O-])=O)=CC=2)[CH2:4][CH2:3]1.CC(C)([O-])C.[K+]>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:14]3[CH2:15][CH2:16][C:17]4[C:18]5[C:19]([OH:26])=[N:20][CH:21]=[N:22][C:23]=5[S:24][C:25]=4[C:13]=3[CH:12]=[N:11]2)[CH2:4][CH2:3]1
Reactant: CN1CCN(CCn2ncc3c2CCc2c-3sc3ncnc(OCCc4ccc([N+](=O)[O-])cc4)c23)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN1CCN(CCn2ncc3c2CCc2c-3sc3ncnc(O)c23)CC1
Reaction time: 0.5 h
Yield: 114.2 %

Procedure:
To a yellow suspension of 3-[2-(4-methyl-piperazin-1-yl)-ethyl]-6-[2-(4-nitro-phenyl)-ethoxy]-4,5-dihydro-3H-10-thia-2,3,7,9-tetraaza-cyclopenta[a]fluorene (2.7 g, 5.2 mmol) in THF (125 ml) was added potassium tert-butoxide (0.92 g, 7.79 mmol) in one portion. The reaction mixture became a solution and then turned into a dark black solution. After stirring for 30 min, analytical HPLC showed no more starting material and two new major peaks. Solvents were evaporated and the dark residue was suspended in EtOAc. To above suspension was added 5 ml of 4M HCl and it turned into a light yellow suspension. The crude HCl salt of the desired product was collected by filtration, washed with EtOAc, and air-dried to afford the crude product (2.2 g, 104%). RT=0.41 min; [M+H]+=371.2.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3](=[O:12])[C:4](=[N:10][OH:11])[C:5](=[N:7][O:8][CH3:9])[CH3:6].[CH3:14][N:15]=[C:16]=[O:17].C1N2CCN(CC2)C1>C(Cl)Cl>[CH3:13][N:2]([CH3:1])[C:3](=[O:12])[C:4](=[N:10][O:11][C:16](=[O:17])[NH:15][CH3:14])[C:5](=[N:7][O:8][CH3:9])[CH3:6]
Reactant: CN=C=O
Reactant: CON=C(C)C(=NO)C(=O)N(C)C
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Product: CNC(=O)ON=C(C(=O)N(C)C)C(C)=NOC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 34 parts of N,N-dimethyl-2-hydroxyimino-3-methoxyiminobutyramide, 350 parts of methylene chloride, 13 parts of methyl isocyanate and one-tenth part triethylenediamine was stirred at 25° C. for 3 hours and then refluxed for 1 hour. The solvent was removed by stripping under reduced pressure (15 mm.) at 50° bath temperature, thereby affording the solid crude product. Recrystallization from a benzene-acetonitrile mixture gave 32 parts of N,N-dimethyl-3-methoxyimino-2-[(methylcarbamoyl)oximino]butyramide, m.p. 172°-173° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[F:16])[C:5]([OH:7])=O)[CH3:2].[NH2:17][CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([Cl:27])[CH:20]=1>>[Cl:27][C:21]1[CH:20]=[C:19]([CH:26]=[CH:25][C:22]=1[C:23]#[N:24])[CH2:18][NH:17][C:5](=[O:7])[CH:4]([O:3][CH2:1][CH3:2])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[F:16]
Reactant: CCOC(C(=O)O)c1ccc(OC)cc1F
Reactant: N#Cc1ccc(CN)cc1Cl
Product: CCOC(C(=O)NCc1ccc(C#N)c(Cl)c1)c1ccc(OC)cc1F

Procedure:
(RS)-Ethoxy-(2-fluoro-4-methoxy-phenyl)-acetic acid, described in example 63.1 was coupled with 4-aminomethyl-2-chlorobenzonitrile (CAS 202522-15-4) according to general procedure C to give (RS)-N-(3-chloro-4-cyano-benzyl)-2-ethoxy-2-(2-fluoro-4-methoxy-phenyl)-acetamide. Yellow oil. MS 377.2 ([M+H]+)
Reaction SMILES: ClCCC1N=CC=CN=1.OCCN1C=CC=NC1.S(Cl)(Cl)=O.[NH2:23][CH2:24][CH2:25][S:26][CH2:27][CH2:28][C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1.[C:35]([NH:37][C:38](=[N:41][CH3:42])SC)#[N:36]>>[C:35]([NH:37][C:38]([NH:41][CH3:42])=[N:23][CH2:24][CH2:25][S:26][CH2:27][CH2:28][C:29]1[N:30]=[CH:31][CH:32]=[CH:33][N:34]=1)#[N:36]
Reactant: NCCSCCc1ncccn1
Reactant: CN=C(NC#N)SC
Agent: ClCCc1ncccn1
Agent: OCCN1C=CC=NC1
Solvent: O=S(Cl)Cl
Product: CNC(=NCCSCCc1ncccn1)NC#N

Procedure:
By the procedure of Example 17 using 2-(2-chloroethyl)pyrimidine, prepared by treating 3-(2-hydroxyethyl)pyrimidine with thionyl chloride, as the starting material, 2-[2-(2-aminoethyl)thioethyl]pyrimidine is prepared, which when treated with N-cyano-N',S-dimethylisothiourea by the procedure of Example 3(a) gives the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:17]4[C:24]5[CH2:25][NH:26][CH2:27][C:23]=5[S:22][C:18]=4[N:19]=[CH:20][N:21]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.Cl.[CH3:32][N:33]([CH3:40])[CH2:34]/[CH:35]=[CH:36]/[C:37](O)=[O:38]>>[CH3:32][N:33]([CH3:40])[CH2:34]/[CH:35]=[CH:36]/[C:37]([N:26]1[CH2:27][C:23]2[S:22][C:18]3[N:19]=[CH:20][N:21]=[C:16]([NH:15][C:11]4[CH:10]=[C:9]5[C:14](=[CH:13][CH:12]=4)[N:6]([CH2:5][C:4]4[CH:28]=[CH:29][CH:30]=[C:2]([F:1])[CH:3]=4)[N:7]=[CH:8]5)[C:17]=3[C:24]=2[CH2:25]1)=[O:38]
Reactant: Fc1cccc(Cn2ncc3cc(Nc4ncnc5sc6c(c45)CNC6)ccc32)c1
Reactant: CN(C)C/C=C/C(=O)O
Agent: Cl
Product: CN(C)C/C=C/C(=O)N1Cc2sc3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c3c2C1

Procedure:
In analogy to Example 89, the title compound was prepared from N-[1-(3-fluorobenzyl)-1H-indazol-5-yl]-6,7-dihydro-5H-pyrrolo[3′,4′:4,5]thieno[2,3-d]pyrimidin-4-amine from Example 33A (51 mg, 0.12 mmol) and (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride from Example 1A (29 mg, 0.17 mmol) to yield 30 mg (44%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[N:22][O:23][CH3:24])[C:7]1[CH:21]=[CH:20][C:10]([O:11][C:12]([CH3:19])([CH3:18])[C:13]([O:15]CC)=[O:14])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[N:22][O:23][CH3:24])[C:7]1[CH:21]=[CH:20][C:10]([O:11][C:12]([CH3:19])([CH3:18])[C:13]([OH:15])=[O:14])=[CH:9][CH:8]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C(=NOC)c2cccs2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CON=C(c1ccc(OC(C)(C)C(=O)O)cc1)c1cccs1
Temperature: 80 °C

Procedure:
2.4 g of ethyl ester obtained in Example 23 and 1.05 g potassium carbonate dissolved in 75% aqueous ethanol (25 ml) are maintained at 80° C. for 5 hours. The alcohol is then evaporated off, the resulting material is made acidic and the acid precipitate is filtered off, to give a mixture of equivalent amounts of both stereoisomers which melts at 168° C.
Reaction SMILES: [NH:1]([C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C@H:2]([C:4]([NH:6][C@H:7]([C:11]([N:13]1[CH2:21][CH2:20][CH2:19][C@H:14]1[C:15]([CH2:17]Cl)=[O:16])=[O:12])[CH:8]([CH3:10])[CH3:9])=[O:5])[CH3:3]>[Zn]>[NH:1]([C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])[C@H:2]([C:4]([NH:6][C@H:7]([C:11]([N:13]1[CH2:21][CH2:20][CH2:19][C@H:14]1[C:15]([CH3:17])=[O:16])=[O:12])[CH:8]([CH3:9])[CH3:10])=[O:5])[CH3:3]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)CCl
Agent: [Zn]
Product: CC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(C)C

Procedure:
14 (1 g, 2.21 mmol) was dissolved in 5.30 ml of warm acidic acid and 1.33 g of zinc-powder was added portion wise to the stirred solution. After 24 h the remaining solid was filtered off and the filtrate was evaporated. The remaining oil was taken up in ethylacetate and washed twice with NaHCO3 and brine. The organic layer was then dried and evaporated and purified by column chromatography using a heptane/chloroform/methanol-gradient.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[CH:6]=1.[Cl:13][C:14]1[CH:19]=[C:18](B(O)O)[CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(Cl)Cl.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]>[Cl:13][C:14]1[CH:19]=[C:18]([C:2]2[CH:3]=[N:4][N:5]([CH:7]3[CH2:12][CH2:11][CH2:10][CH2:9][O:8]3)[CH:6]=2)[CH:17]=[CH:16][N:15]=1
Reactant: Brc1cnn(C2CCCCO2)c1
Reactant: OB(O)c1ccnc(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Clc1cc(-c2cnn(C3CCCCO3)c2)ccn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
4-Bromo-1-(tetrahydro-pyran-2-yl)-1H-pyrazole (0.73 g) and 2-chloropyridine-4-boronic acid (0.20 g) were dissolved in dry DMF (2 mL) under inert atmosphere and 1,1′-bis(diphenylphosphino)ferrocenedichloro palladium(II)(102 mg) was added followed by caesium carbonate (0.84 g). The mixture was heated to 80° C. and stirred for 2 h. After cooling to room temperature the reaction mixture was diluted with DCM and the inorganic salts filtered off. The filtrate was washed with water and brine, dried under Na2SO4, filtered and the solvent was evaporated under reduced pressure. The crude was purified by flash chromatography (20 g Isolute® silica gel cartridge; gradient elution: hexane/EtOAc from 10/0 to 8.5/1.5) affording the title compound (144 mg). HPLC (Rt)=1.39 min (method M)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:6]=2[CH:20]=1.[C:21](Cl)(=O)[CH2:22][CH2:23][CH3:24].C(=O)(O)[O-].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:21]([CH2:22][CH2:23][CH3:24])=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:6]=2[CH:20]=1
Reactant: NNC1=Nc2ccc(Br)cc2C(c2ccccn2)=NC1
Reactant: CCCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2
Reaction time: 4.5 h

Procedure:
A mixture of 1.5 g of 7-bromo-2-hydrazino-5-(2-pyridinyl)-3H-1,4-benzodiazepine in 45 ml of tetrahydrofuran cooled in an ice bath over a nitrogen atmosphere is added 0.57 ml of butyryl chloride dropwise over 90 sec. After stirring for 4.5 hrs, there is added an additional 0.1 ml of butyryl chloride. The resulting mixture is then stirred at ambient temperature for 18 hrs, poured into 300 ml of aqueous sodium bicarbonate and filtered. The filtrate is extracted with dichloromethane, washed with dilute brine, dried over sodium sulphate, and concentrated under reduced pressure. The resulting residue is then heated in an oil bath at 120°-125° C. for 45 min, allowed to cool, and concentrated under reduced pressure. The residue is then dissolved in dichloromethane, washed with aqueous sodium bicarbonate and dilute brine, dried over sodium sulphate, and concentrated under reduced pressure. The resulting residue is then chromatographed on 150 g of silica gel eluting with 2.5% methanol in dichloromethane. Crystallization from ethyl acetate yields 0.27 g of title product. Melting point is 184°-186° C.
Reaction SMILES: COC[O:4][C:5]1[C:6]([CH3:14])=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1.I[C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23]C)=[O:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CO.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>[OH:4][C:5]1[C:6]([CH3:14])=[C:7]([C:16]2[CH:26]=[CH:25][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: COCOc1cccc(B(O)O)c1C
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: CO
Product: COC(=O)c1ccc(-c2cccc(O)c2C)cc1

Procedure:
In a manner similar to that of Example 11(d), by reaction of 3.3 g (16.7 mmol) of 3-methoxymethoxy-2-methylbenzene-1-boronic acid (described in Example 11(c)) with 3 g (13.9 mmol) of ethyl 4-iodobenzoate, 16.7 mL of 2.0M potassium carbonate solution and 800 mg (0.69 mmol) of tetrakis(triphenylphosphine)palladium, followed by deprotection in methanol, the desired product is obtained in the form of a colourless oil (m=3.07 g; Y=77%).
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5]1.Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>O1CCCC1>[C:21]([O:20][C:18](=[O:19])[CH2:17][O:3][C@@H:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5]1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CO[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (704 mg, 60% in mineral oil, 17.6 mmol) was added to an ice-cooled solution of tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (J. Med. Chem. 1998, 41(25), 4983) (5 g, 26.7 mmol) in tetrahydrofuran (100 ml), and the mixture was allowed to warm to room temperature and stirred for 20 minutes. tert-Butyl bromoacetate (5.2 g, 26.7 mmol) was added and the mixture was heated under reflux for 18 hours, then cooled and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water and the phases separated. The organic layer was dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of ethyl acetate:pentane (0:100 to 20:80) to afford the title compound, 1.95 g. 1H-NMR (CDCl3, 400 MHz) δ: 1.42 (s, 9H), 1.44 (s, 9H), 1.85-2.05 (m, 2H), 3.40 (m, 4H), 3.94 (m, 2H), 4.10 (m, 1H). LRMS: m/z (ES+) 324 [MNa+]