Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:28])[C:7]([CH3:27])([CH3:26])[CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([OH:25])[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([CH3:24])([CH3:23])[C:18]([O:20]CC)=[O:19])C>O.C(O)C>[OH:25][CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([CH3:24])([CH3:23])[C:18]([OH:20])=[O:19])[CH2:11][CH2:10][CH2:9][CH2:8][C:7]([CH3:27])([CH3:26])[C:6]([OH:28])=[O:5]
Reactant: CCOC(=O)C(C)(C)CCCCC(O)CCCCC(C)(C)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(CCCCC(O)CCCCC(C)(C)C(=O)O)C(=O)O
Yield: 94.8 %

Procedure:
To a homogeneous solution of potassium hydroxide (3.45 g, 61 mmol) in water (3.3 mL) and ethanol (11.1 mL) was added 7-hydroxy-2,2,12,12-tetramethyltridecanedioic acid diethyl ester (8.2 g, 22 mmol) and the mixture was heated at reflux for 4 h. The mixture was concentrated in vacuo and the residue was extracted with diethyl ether (3×50 mL). The water layer was acidified with concentrated hydrochloric acid (6 mL) to pH 1. The product was extracted with diethyl ether (3′ 100 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica, dichloromethane:methanol=90:10) to give the pure product (6.6 g, 95%) as a colorless oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 8.10 (br., 3 H), 3.58 (br., 1 H), 1.62-1.22 (m, 16 H), 1.18 (s, 12 H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 184.3, 71.8, 42.1, 40.5, 36.9, 25.9, 25.0, 24.9. HRMS (LSIMS, gly): Calcd. for C17H33O5 (MH+): 317.2328; found 317.2330. HPLC: 90.4% purity.
Reaction SMILES: [CH3:1][C:2]([CH3:5])=[C:3]=[O:4].[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[N:18]=[N:19][NH:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[C:31]#[N:32])#[N:7]>C(OCC)(=O)C.CCOCC>[C:3]([N:18]([C:9]1[CH:10]=[C:11]([C:14]([F:15])([F:16])[F:17])[CH:12]=[CH:13][C:8]=1[C:6]#[N:7])[N:19]=[N:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[C:31]#[N:32])(=[O:4])[CH:2]([CH3:5])[CH3:1]
Reactant: N#Cc1ccc(C(F)(F)F)cc1N=NNc1cc(C(F)(F)F)ccc1C#N
Reactant: CC(C)=C=O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)C(=O)N(N=Nc1cc(C(F)(F)F)ccc1C#N)c1cc(C(F)(F)F)ccc1C#N
Reaction time: 12 h

Procedure:
A solution of 3.5 g. (0.05 mol.) of dimethylketene in ethyl acetate is added dropwise under a nitrogen atmosphere to a cooled (0°) solution of 18.6 g. (0.05 mol.) of 1,3-bis(2-cyano-5-trifluoromethylphenyl)triazene in ether. The reaction mixture is stirred for 12 hours then concentrated at reduced pressure. Crystallization of the residue from ether gives 3-isobutyryl-1,3-bis(2-cyano-5-trifluoromethylphenyl)triazene.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]1[N:15]=[N:14][C:13]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][CH:20]=[CH:19]4)=[CH:12][CH:11]=1)[CH2:2]2.CC(O)=O.[Br:29]N1C(=O)CCC1=O>CC#N>[Br:29][C:19]1[C:18]2[C:22](=[CH:23][CH:24]=[C:16]([C:13]3[N:14]=[N:15][C:10]([O:9][C@@H:3]4[CH:4]5[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]5)[CH2:2]4)=[CH:11][CH:12]=3)[CH:17]=2)[NH:21][CH:20]=1
Reactant: c1cc2cc(-c3ccc(O[C@H]4CN5CCC4CC5)nn3)ccc2[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: CC#N
Product: Brc1c[nH]c2ccc(-c3ccc(O[C@H]4CN5CCC4CC5)nn3)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 9B (160 mg, 0.5 mmol) was dissolved in MeCN (10 mL) and treated with HOAc (Sigma, 60 mg, 1 mmol) for 10 min. N-bromosuccinimide (Aldrich, 110 mg, 0.6 mmol) in MeCN (Aldrich, 5 mL) was slowly added over 5 min. The mixture was stirred for 1 hour at ambient temperature and concentrated under vacuum. The title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.15) as a solid (70 mg, yield, 35%). 1H NMR (300 MHz, CD3OD) δ 1.55-1.62 (m, 1H), 1.70-1.96 (m, 2H), 2.05-2.20 (m, 1H), 2.29-2.43 (m, 1H), 2.74-3.13 (m, 5H), 3.42-3.66 (m, 1H, 5.24-5.46 (m, 1H), 7.27 (d, J=9.2 Hz, 1H), 7.38 (s, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.82 (dd, J=8.5, 1.7 Hz, 1H), 8.05 (s, 1H), 8.11 (d, J=9.5 Hz, 1H) ppm. MS (DCI/NH3): 399 (M+H)+, 401 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:3]2[NH:10][CH:9]=[C:8]([CH2:11][NH:12][CH2:13][CH:14]([CH:18]3[CH2:22][O:21]C(C)(C)[O:19]3)[CH2:15][S:16][CH3:17])[C:4]=2[N:5]=[CH:6][N:7]=1.C(Cl)(=O)C>CO>[OH:19][CH:18]([CH2:22][OH:21])[CH:14]([CH2:15][S:16][CH3:17])[CH2:13][NH:12][CH2:11][C:8]1[C:4]2[N:5]=[CH:6][NH:7][C:2](=[O:1])[C:3]=2[NH:10][CH:9]=1
Reactant: CSCC(CNCc1c[nH]c2c(O)ncnc12)C1COC(C)(C)O1
Solvent: CO
Solvent: CC(=O)Cl
Product: CSCC(CNCc1c[nH]c2c(=O)[nH]cnc12)C(O)CO
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred suspension of N-{4-hydroxy-5H-pyrrolo[3,2-d]pyrimidin-7-yl}methyl-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-3-(methylthio)propan-1-amine (0.1 g, 0.28 mmol) in methanol (7 ml) was added a solution of acetyl chloride (0.22 g, 2.8 mmol) in methanol (3 ml) and the solution stirred at ambient temperature for 2.5 hr. Amberlyst A-21 resin was added and the solution made neutral before being filtered free of resin and concentrated to a light yellow gum (0.072 g). This was dissolved in aqueous methanol (1:1) and preabsorbed onto silica for chromatography over silica. Gradient elution with DCM/MeOH/0.88 NH3 cocktails ranging from 9:1:0.1 through to 6:4:0.1 in composition furnished the title compound as a precipitate (free base) in the latter fractions. This was recovered by filtration and dried to give a colourless solid (0.026 g). 1H NMR (CD3OD+DCl) δ 7.93 (s, 1H), 7.42 (s, 1H), 3.94 (s, 2H), 3.82 (q, J=4.8 Hz 1H), 3.58 (m, 2H), 2.89 (m, 2H), 2.66 (dd J=13.2, 6.6 Hz, 1H), 2.55 (dd J=13.2, 7.5 Hz, 1H), 2.13 (s, 3H), 1.94 (m, 1H). 13C NMR (CD3OD+DCl) δ 156.6, 145.2, 143.4, 129.1, 119.7, 115.8, 75.0, 65.9, 50.0, 45.9, 41.5, 36.6, 16.3. HR-ESMS MH+ 313.1332 C13H21N4O3S requires MH+ 313.1334 Δ 0.6 ppm.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH:6]=[CH:7]1)[CH2:4][CH:3]([C:9](O)=O)[CH2:2]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:37][C:38]1[C:39](=[O:52])[N:40]([CH2:49][CH2:50][CH3:51])[C:41](=[O:48])[N:42]([CH2:45][CH2:46][CH3:47])[C:43]=1[NH2:44].CCN(C(C)C)C(C)C>CN(C=O)C>[CH:5]12[O:8][CH:1]([CH:7]=[CH:6]1)[CH2:2][CH:3]([C:9]1[NH:37][C:38]3[C:39](=[O:52])[N:40]([CH2:49][CH2:50][CH3:51])[C:41](=[O:48])[N:42]([CH2:45][CH2:46][CH3:47])[C:43]=3[N:44]=1)[CH2:4]2
Reactant: O=C(O)C1CC2C=CC(C1)O2
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCn1c(=O)c2[nH]c(C3CC4C=CC(C3)O4)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
To a solution of 8-oxa-bicyclo[3.2.1]oct-6-ene-3-carboxylic acid (0.25 mmol, 0.0386 g), HATU (0.25 mmol, 0.0952 g), and 5,6-diamino-1,3-dipropyl-1H-pyrimidine-2,4-dione hydrochloride (Daly, J. W. et al., J. Med. Chem., 1985, 28 (4), 487) (0.25 mmol, 0.0658 g) in DMF (2.5 ml) was added iPr2NEt (0.75 mmol, 0.13 ml). The reaction was stirred overnight at room temperature. It was concentrated at the pump to remove DMF. The residue was dissolved in EtOAc and washed with 1N HCl, 5% NaHCO3, and brine and dried (MgSO4). Filtration and evaporation followed by flash column chromatography, eluting with a THF/CH2Cl2 gradient provided the desired product (0.067 g, 74%) as an oil that solidified on standing. 1H NMR (300 MHz, CDCl3): 0.90 (t, 3H, J=7.4 Hz), 0.97 (t, 3H, J=7.3 Hz), 1.53-1.72 (m, 6H), 1.95-2.03 (m, 2H), 3.0 (br m, 1H), 3.82-3.91 (m, 4H), 4.79 (br s, 2H), 6.18 (s, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][N:18]=[CH:17]2>C(O)(C)C>[F:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:2]([NH:13][C:14]1[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=1)[NH:19][N:18]=[CH:17]3)=[N:3][CH:4]=[N:5]2
Reactant: Fc1cccc2ncnc(Cl)c12
Reactant: Nc1ccc2[nH]ncc2c1
Solvent: CC(C)O
Product: Fc1cccc2ncnc(Nc3ccc4[nH]ncc4c3)c12
Yield: 89 %

Procedure:
A stirred partial solution of 4-chloro-5-fluoroquinazoline (10.95 g, 60 mmol) and 5-aminoindazole (7.98 g, 60 mmol) in isopropanol (300 ml) was heated under reflux for 3 hours. On cooling to ambient temperature the product hydrochloride salt was filtered off and washed with isopropanol and ether. The salt was heated with water (400 ml)/ethanol (100 ml) and the partial solution was basified with aqueous ammonia. The precipitated solid was filtered off and washed with water to provide 5-fluoro-N-1H-indazol-5-ylquinazolin-4-amine (14.91 g, 89%); NMR spectrum (300 MHz) 7.42 (dd, 1H), 7.53 (s, 2H), 7.60 (d, 1H), 7.83 (m, 1H), 8.08 (d, 2H), 8.50 (s, 1H), 9.20 (d, 1H), 13.05 (s, 1H); Mass spectrum MH+ 280.
Reaction SMILES: [CH:1]([NH:3][C@H:4]([CH2:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)[C:5](O)=[O:6])=O.[BH4-].[Na+].II.CO>O1CCCC1>[CH3:1][NH:3][C@H:4]([CH2:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)[CH2:5][OH:6]
Reactant: O=CN[C@H](Cc1cccs1)C(=O)O
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CN[C@@H](CO)Cc1cccs1
Temperature: 9.5 °C
Yield: 105.8 %

Procedure:
A solution of (2R)-2-(formylamino)-3-(2-thienyl)propionic acid (3.58 g, 18.0 mmol) in tetrahydrofuran (50 ml) was added dropwise to a suspension of sodium borohydride in tetrahydrofuran (50 ml), which was cooled to 7-12° C. (inside temperature). After the addition was finished, a solution of iodine (4.57 9, 18.0 mmol) in tetrahydrofuran (100 ml) was added dropwise. The reaction mixture was heated to reflux for 16 h. It was cooled to 0° C. Methanol (200 ml) was added dropwise. The solvent was removed in vacuo. The residue was dissolved in a freshly prepared 20% aqueous sodium hydroxide solution (200 ml). The aqueous phase was extracted with tert-butyl methyl ether (4×150 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo to give 3.26 g of crude (2R)-2-methylamino-3-(2-thienyl)propan-1-ol, which was used for the following step.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[CH2:30][CH3:31])=[CH:11][CH:10]=1)#[N:2].[N-:32]=[N+:33]=[N-:34].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH2:30]([C:17]1[N:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]3[NH:34][N:33]=[N:32][N:2]=3)=[CH:14][CH:13]=2)[C:20]2[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=1)[CH3:31]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1cccc2nc(CC)n(Cc3ccc(-c4ccccc4C#N)cc3)c12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc2nc(CC)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c12
Reaction time: 120 h

Procedure:
A mixture of ethyl 1-[(2'-cyanobiphenyl-4yl)methyl]-2-ethylbenzimidazole-7-carboxylate (1.55 g), sodium azide (2.6 g) and ammonium chloride (2.14 g) in DMF (15 ml) was stirred for 5 days at 110°-120 C. The reaction mixture was worked up according to the procedure described in Working Example 23 to give crystals. Recrystallization from ethanol afforded colorless prisms (0.68 g, 40%), m.p. 188°-189° C.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=[O:12])=[CH:10][C:4]=2[O:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].CCOCC>CN(C=O)C>[Si:24]([O:23][CH2:22][CH2:21][CH2:20][N:6]1[C:5]2[CH:7]=[CH:8][C:9]([CH:11]=[O:12])=[CH:10][C:4]=2[O:3][C:2]1=[O:1])([C:27]([CH3:28])([CH3:29])[CH3:30])([CH3:26])[CH3:25]
Reactant: O=Cc1ccc2[nH]c(=O)oc2c1
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCn1c(=O)oc2cc(C=O)ccc21
Temperature: 75 °C
Reaction time: 0.08 h
Yield: 89.1 %

Procedure:
To a solution of 2-oxo-2,3-dihydro-1,3-benzoxazole-6-carbaldehyde (Intermediate 7, 300 mg, 1.84 mmol) in DMF (10 mL) were added potassium carbonate (633 mg, 4.58 mmol) and (3-bromopropoxy)(tert-butyl)dimethylsilane (0.47 mL, 2.03 mmol), and the resulting mixture was heated to 75° C. Upon complete disappearance of starting material (ca 16 hours), the solvent was removed under reduced pressure and the solid residue was treated with CH2Cl2 and stirred for 5 min. The suspension was filtered through Celite® and the solid residue washed with additional CH2Cl2. The filtrate was concentrated to dryness and the crude was purified by column chromatography over silica gel, eluting with Hexane:Et2O (from 0 to 32% of Et2O) to give the title compound as a white solid (550 mg, 89% yield).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH:6]([CH2:15][CH2:16]Br)[CH:5]1[CH3:18])(=[O:3])[CH3:2].[C:19]1([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH:6]([CH2:15][CH2:16][N:28]2[CH2:29][CH2:30][CH:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:26][CH2:27]2)[CH:5]1[CH3:18])(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)C(CCBr)C(C)N2C(C)=O
Reactant: c1ccc(C2CCNCC2)cc1
Product: COc1ccc2c(c1)C(CCN1CCC(c3ccccc3)CC1)C(C)N2C(C)=O

Procedure:
In the manner described in Example 1, treatment of 1-acetyl-3-(2-bromoethyl)-5-methoxy-2-methylindoline with 4-phenylpiperidine gives the product as an amorphous solid.
Reaction SMILES: I[C:2]1[N:3]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[CH:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH2:14][CH:15]([CH3:17])[CH3:16].[C:29]([OH:35])(=[O:34])[CH2:30][CH2:31][CH:32]=[CH2:33].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(#N)C>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:12][N:8]1[C:9](=[O:11])[C:10]2=[C:2]([CH2:33]/[CH:32]=[CH:31]/[CH2:30][C:29]([OH:35])=[O:34])[N:3]([CH2:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=[CH:21][CH:20]=3)[CH:4]=[C:5]2[N:6]([CH2:14][CH:15]([CH3:16])[CH3:17])[C:7]1=[O:13]
Reactant: C=CCCC(=O)O
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(I)n(Cc3cccc4ccccc34)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(C/C=C/CC(=O)O)n(Cc3cccc4ccccc34)cc21
Temperature: 25 °C

Procedure:
5-Iodo-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo-[3,4-d]pyrimidine-2,4(3H,6H)-dione (100 mg), 4-pentenoic acid (0.042 ml), palladium acetate (5 mg) and tri(o-tolyl)phosphine (13 mg) were dissolved in triethylamine (1 ml) and acetonitrile (5 ml) and heated to 95° C. in a sealed pressure tube for 3 hours. The reaction mixture was allowed to cool to room temperature and was then evaporated to leave a residue which was chromatographed using ethyl acetate containing 1% acetic acid to give an oil (160 mg). Recrystallisation from diethyl ether/isohexane gave the title compound as a pale brown solid (48 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[N:3]=1.[CH3:10][C:11]1[CH:17]=[C:16](B2OC(C)(C)C(C)(C)O2)[CH:15]=[C:14]([CH3:27])[C:12]=1[NH2:13]>>[CH3:9][O:8][C:4]1[N:3]=[C:2]([C:16]2[CH:15]=[C:14]([CH3:27])[C:12]([NH2:13])=[C:11]([CH3:10])[CH:17]=2)[CH:7]=[CH:6][N:5]=1
Reactant: COc1nccc(Cl)n1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1N
Product: COc1nccc(-c2cc(C)c(N)c(C)c2)n1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
The title compound is prepared from 4-chloro-2-methoxypyrimidine and 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline following a procedure analogous to that described in Step 2 of Intermediate 62. The mixture is stirred for 12 hours at 60° C. LC (method 14): tR=0.89 min; Mass spectrum (ESI+): m/z=230 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]#[C:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[S:17][C:10]=12.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:40][CH2:39][CH:38]([C:41](O)=[O:42])[C:37]2=[O:44])=[CH:32][CH:31]=1>>[F:1][C:2]1[CH:3]=[C:4]([NH:28][C:41]([CH:38]2[CH2:39][CH2:40][N:36]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)[C:37]2=[O:44])=[O:42])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]#[C:19][CH2:20][N:21]3[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]3)[S:17][C:10]=12
Reactant: CN1CCN(CC#Cc2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Reactant: O=C(O)C1CCN(c2ccc(F)cc2)C1=O
Product: CN1CCN(CC#Cc2cc3nccc(Oc4ccc(NC(=O)C5CCN(c6ccc(F)cc6)C5=O)cc4F)c3s2)CC1
Yield: 31 %

Procedure:
The title compound was prepared from 3-fluoro-4-(2-(3-(4-methylpiperazin-1-yl)prop-1-ynyl)thieno[3,2-b]pyridin-7-yloxy)aniline (Example 17, Step B) and 1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxylic acid according to the procedure described for Example 89. The crude was purified by silica gel flash column chromatography (5% MeOH in CH2Cl2) to afford 4.7 mg (31%) of the desired product. 1H NMR (400 MHz, CD3OD) δ 8.49 (d, 1H), 7.89 (dd, 1H), 7.63 (m, 2H), 7.60 (s, 1H), 7.45 (m, 1H), 7.37 (t, 1H), 7.14 (t, 2H), 6.69 (d, 1H), 3.97 (m, 2H), 3.68 (s, 2H), 2.75 (m, 4H), 2.58 (m, 3H), 2.47 (m, 3H), 2.30 (s, 3H); 19F NMR (376 MHz, CD3OD) δ −119.2, −129.9. LRMS (ESI pos) m/e 602.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])=[C:12]([F:22])[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH:6]=1)=[O:4].C1C(=O)N([Br:30])C(=O)C1>C1COCC1.CO>[CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:30])=[CH:17][C:16]=2[Cl:21])=[C:12]([F:22])[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccccc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 84.6 %

Procedure:
6-(2-Chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester 7b (55 mg, 0.172 mmol) is dissolved in 1:1 THF/MeOH (2 mL) and cooled to −78° C. under an atmosphere of nitrogen. TsOR.H2O (49 mg, 0.258 mmol) is added followed by NBS (31 mg, 0.174 mmol). After 10 minutes, the reaction mixture is warmed to 0° C. and then 2 hours later warmed to room temperature. After 16 hours, the reaction mixture is quenched by the addition of 10% Na2S2O3 and diluted with ethyl acetate and water. The layers are separated and the aqueous layer is extracted with ethyl acetate. The combined organic extracts are dried (MgSO4) and concentrated under reduced pressure. The crude product is triturated with methylene chloride to give 58 mg (85%) of pure desired product as a tan solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([CH3:14])=[N:11][C:10]=2[C:15]([OH:17])=O)=[CH:5][CH:4]=1)[CH3:2].[NH:18]1[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][C:25]([C:27]2[N:34]3[C:30]([S:31][CH:32]=[CH:33]3)=[N:29][C:28]=2[CH3:35])=[O:26])[CH2:19]1>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:13][C:12]([CH3:14])=[N:11][C:10]=2[C:15]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][C:25]([C:27]3[N:34]4[C:30]([S:31][CH:32]=[CH:33]4)=[N:29][C:28]=3[CH3:35])=[O:26])[CH2:19]2)=[O:17])=[CH:7][CH:8]=1)[CH3:2]
Reactant: Cc1nc2sccn2c1C(=O)N[C@@H]1CCCNC1
Reactant: CCc1ccc(-c2sc(C)nc2C(=O)O)cc1
Product: CCc1ccc(-c2sc(C)nc2C(=O)N2CCC[C@@H](NC(=O)c3c(C)nc4sccn34)C2)cc1

Procedure:
prepared by reaction of 5-(4-ethyl-phenyl)-2-methyl-thiazole-4-carboxylic acid with (R)-6-methyl-imidazo[2,1-b]-thiazole-5-carboxylic acid-piperidin-3-ylamide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1Cl)[CH3:2].[OH:13][C:14]1[CH:15]=[CH:16][C:17]2[C:18]([CH:22]=1)=[N:19][O:20][N:21]=2.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]2=[N:21][O:20][N:19]=[C:18]2[CH:22]=1)[CH3:2]
Reactant: CCOC(=O)c1cccnc1Cl
Reactant: Oc1ccc2nonc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccnc1Oc1ccc2nonc2c1
Temperature: 90 °C
Yield: 26.2 %

Procedure:
A mixture of 5.5 g (29.4 mmol.) 2-chloro nicotinic acid ethyl ester, 4.0 g (29.4 mmol.) 5-hydroxybenzofurazan and 20.1 g (61.7 mmol.) cesium carbonate in 125 ml dry dimethylforamide was heated at 90° C. for five days. The mixture was poured into water and extracted with ethyl acetate. The ethyl acetate extracts were combined, washed successively with sodium bicarbonate solution, water, brine then dried (Na2SO4) and concentrated in vacuo to give a solid. Recrystallization from diethyl ether/pentane gave 2.2 g (26%) solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N+:12]([O-])=O)=[C:4]([F:15])[CH:3]=1.[H][H]>C(O)C.[Pt](=O)=O>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([NH:12][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:4]([F:15])[CH:3]=1
Reactant: CC(C)Oc1cc([N+](=O)[O-])c(F)cc1Cl
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Product: CC(C)Oc1cc(Nc2ccccc2)c(F)cc1Cl
Yield: 69.3 %

Procedure:
A suspension of 4-chloro-2-fluoro-5-isopropoxynitrobenzene (13.5 g) and platinum dioxide (0.4 g) in ethanol (300 ml) was subjected to catalytic reduction with hydrogen under room temperature and atmospheric pressure, whereby a designed amount of hydrogen was absorbed. The resultant mixture was filtered to remove insoluble materials, and the filtrate was concentrated. The residue was subjected to purification by silica gel chromatography to obtain 5.6 g of 4-chloro-2-fluoro-5-isopropoxyphenylaniline. nD24.5 1.5360.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([Cl:11])=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20].C([O-])(O)=O.[Na+]>C1COCC1>[Br:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([Cl:11])=[CH:5][C:3]=1[NH:4][C:19](=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: COc1cc(Br)c(N)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(Br)c(NC(C)=O)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
4.40 g (18.6 mmol) 2-Bromo-5-chloro-4-methoxy-aniline and 3.1 ml (22.0 mmol) triethylamine were dissolved in 50 ml THF. 1.42 ml (20.0 mmol) acetylchloride were added dropwise at room temperature. The reaction mixture was stirred at room temperature for additional 2 hours, saturated NaHCO3 solution was added and the mixture was extracted with ethyl acetate. Removal of the solvent and crystallisation with ether gave 3.6 g (12.9 mmol, 69%) of the title compound.
Reaction SMILES: Br[C:2]1[S:3][C:4]([Cl:7])=[CH:5][CH:6]=1.[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:7][C:4]1[S:3][C:2]([C:9]2[S:8][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=1
Reactant: Clc1ccc(Br)s1
Reactant: OB(O)c1cccs1
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
Product: Clc1ccc(-c2cccs2)s1
Yield: 80.7 %

Procedure:
To a solution of 2-bromo-5-chlorothiophene (4.11 g), thiophene-2-boronic acid (4.00 g), tetrakis(triphenylphosphine)palladium (0) (1.20 g) and 2M aqueous sodium carbonate solution (31.3 ml) in dimethoxyethane (100 ml) was heated under reflux under argon atmosphere for 2.5 hours. The reaction mixture was cooled, and extracted with ethyl acetate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane) to give 2-(5-chloro-2-thienyl)thiophene (3.37 g) as pale yellow oil. (2) The above 2-(5-chloro-2-thienyl)thiophene and 5-bromo-2-methylbenzoic acid obtained in Reference Example 4-(1) were used and treated in a manner similar to Reference Example 5 to give 5-bromo-1-(5-(5-chloro-2-thienyl)-2-thienylmethyl)-2-methylbenzene as a colorless solid. APCI-Mass m/Z 383/385 (M+H).