Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:33])([C:27]2[N:28]([CH3:32])[CH:29]=[N:30][CH:31]=2)[C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH:12]=[C:11]3[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25]C)[CH:20]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br.[CH2:38](Cl)Cl>>[Cl:1][C:2]1[S:6][C:5]([C:7]([OH:33])([C:27]2[N:28]([CH3:32])[CH:29]=[N:30][CH:31]=2)[C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:38])[C:13](=[O:18])[CH:12]=[C:11]3[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=2)=[CH:4][CH:3]=1
Reactant: ClCCl
Reactant: COc1cccc(-c2cc(=O)[nH]c3ccc(C(O)(c4ccc(Cl)s4)c4cncn4C)cc23)c1
Agent: BrB(Br)Br
Product: Cn1cncc1C(O)(c1ccc2c(c1)c(-c1cccc(O)c1)cc(=O)n2C)c1ccc(Cl)s1
Yield: 66 %

Procedure:
Following the same procedure as that described in Example 34A, the title compound of example 31 (100 mg, 0.203 mmol) was treated with BBr3 in CH2Cl2 (1M, 1.02 ml, 1.02 mmol) to give the title compound (64 mg, 67% yield).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=O)[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:7]([OH:20])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]2[N:11]=[C:12]([C:13]3[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=3)[O:20][C:7]=2[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(NC(=O)c2ccncc2)c(O)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc2nc(-c3ccncc3)oc2c1
Temperature: 25 °C
Yield: 26.3 %

Procedure:
A mixture of 1.22 g of N-(4-tert-butyl-2-hydroxyphenyl)isonicotinamide, 15 ml of carbon tetrachloride, 3.55 g of triphenylphosphine and 1.37 g of triethylamine was heated to reflux for three hours. The mixture was cooled to room temperature, and then water was poured into the mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.30 g of 6-tert-butyl-2-(pyridin-4-yl)-benzoxazole (hereinafter, referred to as “active compound 8”).
Reaction SMILES: [I-].[C:2]([C:5]1([P:15]([OH:18])([OH:17])=[O:16])[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH2:10][NH+:11]2[CH3:14])=[CH:6]1)([OH:4])=[O:3]>O.O=[Pt]=O>[CH3:14][N:11]1[CH:12]2[CH:7]([CH2:6][C:5]([P:15]([OH:18])([OH:17])=[O:16])([C:2]([OH:4])=[O:3])[CH2:13]2)[CH2:8][CH2:9][CH2:10]1
Reactant: C[NH+]1CC=CC2=CC(C(=O)O)(P(=O)(O)O)C=C21
Agent: O=[Pt]=O
Agent: [I-]
Solvent: O
Product: CN1CCCC2CC(C(=O)O)(P(=O)(O)O)CC21
Reaction time: 48 h

Procedure:
A suspension of 2.0 g of dihydro-6-carboxy-1-methyl-6-phosphono-1-pyrindinium iodide (Example 32) and 1.0 g of PtO2 in 50 ml of water is hydrogenated at 40 PSI and 50° for 2 days on a Parr apparatus. After the catalyst is removed by filtration, the filtrate is evaporated to dryness. The residue is recrystallized from water/acetone to yield octahydro-1-methyl-6-phosphono-1-pyrindine-6-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16]1.Br[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:31]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:29][C:30](=[O:31])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16]1
Reactant: N#Cc1c(N2CCN(C(=O)c3ccco3)CC2)c2cc(Cl)cnc2[nH]c1=O
Reactant: O=C(CBr)c1ccccc1
Product: N#Cc1c(N2CCN(C(=O)c3ccco3)CC2)c2cc(Cl)cnc2n(CC(=O)c2ccccc2)c1=O

Procedure:
This compound was prepared from 6-chloro-2-oxo-4-[4-(furan-2-carbonyl)-piperazine-1-yl]-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (101) and 2-bromoacetophenone according to General Procedure B. Yield 233 mg (31%), MP 328° C.; 1H-NMR (DMSO-d6): δ 3.81 (m, 4H), 3.97 (m, 4H), 5.86 (s, 2H), 6.66 (dd, J=1.6, 3.2 Hz, 1H), 7.10 (d, J=3.2 Hz, 1H) 7.59 (m, 2H), 7.73 (m, 1H), 7.90 (d, J=1.6 Hz, 1H), 8.14 (m, 2H), 8.37 (d, J=2.0 Hz, 1H), 8.67 (d, J=2.0 Hz, 1H); EIMS: 502 (M+1). Anal. (C26H20ClN5O4) C, H, N.
Reaction SMILES: C[Li].[N:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[CH:4]=1.[C:11]1(C)C=CC=CC=1>CCOCC>[N:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:4]=1[CH3:11]
Reactant: Cc1cncc(C)c1
Reactant: Cc1ccccc1
Agent: [Li]C
Solvent: CCOCC
Product: Cc1cnc(C)c(C)c1
Reaction time: 4 h

Procedure:
To 500 ml of a 5% solution of methyl lithium in ether are added dropwise at room temperature under argon 1200 ml of ether, subsequently 35.6 g of 3,5-lutidine (3,5-dimethylpyridine) and subsequently 400 ml of toluene. The ether is distilled off completely, whereupon the solution is stirred at 100° for 4 hours. Ice is then added portionwise thereto while cooling with methanol/ice until evolution of heat no longer occurs. The toluene phase is separated from precipitated solid and extracted with 66 ml of semi-concentrated hydrochloric acid. The separated aqueous phase is adjusted to a pH of about 10 with 3N sodium hydroxide solution while cooling and extracted twice with 300 ml of ether. The ether extracts are dried over sodium sulphate and evaporated. The residue is distilled in vacuo at 20 mm/72°-74°; there is obtained 2,3,5-collidine (2,3,5-trimethylpyridine) which has a purity of 99.15% according to gas chromatography.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([CH2:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)=[N:2]1.C([N-]C(C)C)(C)C.[Li+].[C:23]1(=[O:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.O>O1CCCC1>[OH:30][C:23]1([CH:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[C:3]2[N:4]=[CH:5][NH:1][N:2]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: N#Cc1ccc(Cc2nc[nH]n2)cc1
Reactant: O=C1CCCCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(C(c2nc[nH]n2)C2(O)CCCCCC2)cc1
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
5 g of 4-[1-(1,2,4-triazolyl)methyl]benzonitrile is dissolved in 100 ml of tetrahydrofuran and combined at -50° with 19.8 ml of 1.5-molar solution of lithium diisopropylamide in tetrahydrofuran, stirred for 0.5 hour, further stirred for 1 hour at -70° with 3.05 g of cycloheptanone, and heated to 25°. Then the mixture is combined with water, extracted twice with ethyl acetate, washed neutral with water, dried over sodium sulfate, and concentrated to dryness under vacuum, thus obtaining 7.9 g of crude 4-[1-hydroxycyclohept-1-yl-1-(1,2,4-triazolyl) methyl]benzonitrile.
Reaction SMILES: O=C1CCC(=O)N1[O:8][C:9](=O)[CH2:10][CH2:11][CH:12]([NH:20][C:21]([CH:23]1[CH2:28][CH2:27][CH:26]([CH2:29][NH:30][C:31](=[O:57])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:25][CH2:24]1)=[O:22])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[NH2:59][C@H:60]([C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])[CH2:61][CH2:62][C:63](=[O:65])[OH:64]>C1COCC1.O>[C:69]([O:68][C:66](=[O:67])[CH:60]([NH:59][C:9](=[O:8])[CH2:10][CH2:11][CH:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[NH:20][C:21]([CH:23]1[CH2:24][CH2:25][CH:26]([CH2:29][NH:30][C:31](=[O:57])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][C:50]([O:52][C:53]([CH3:54])([CH3:55])[CH3:56])=[O:51])[CH2:27][CH2:28]1)=[O:22])[CH2:61][CH2:62][C:63]([OH:64])=[O:65])([CH3:72])([CH3:71])[CH3:70]
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCC(=O)O
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)NCC1CCC(C(=O)NC(CCC(=O)ON2C(=O)CCC2=O)C(=O)OC(C)(C)C)CC1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)NCC1CCC(C(=O)NC(CCC(=O)NC(CCC(=O)O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC1
Yield: 83.6 %

Procedure:
To a solution of 2-({4-[(19-tert-butoxycarbonylnonadecanoylamino)methyl]cyclohexanecarbonyl}-amino)pentanedioic acid 1-tert-butyl ester 5-(2,5-dioxopyrrolidin-1-yl)ester (5.0 g) in THF (100 ml) was added a solution of H-Glu-OtBu (1.36 g) in water (25 ml). After stirring over night the mixture was concentrated in vacuo. The residue was precipitated from water and filtered off and dried in vacuo to give the title compound (4.63 g, 84%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([N:7]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][CH2:9][CH2:10][C:11](=O)[CH3:12])[CH3:6])[CH3:2].[NH2:22][C:23]1[C:28]([CH:29]=O)=[CH:27][CH:26]=[CH:25][N:24]=1.N1CCC[C@H]1C(O)=O>C(O)C>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([N:7]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:29][C:28]2[C:23](=[N:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1)[CH3:6])[CH3:2]
Reactant: Nc1ncccc1C=O
Reactant: CCOC(=O)C(C)N(CCCC(C)=O)C(=O)OC(C)(C)C
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)C(C)N(CCCc1ccc2cccnc2n1)C(=O)OC(C)(C)C

Procedure:
To a solution of 4-6 (12 g, 40 mmol), 2-amino-3-formylpyridine (6.3 g, 52 mmol), proline (4.6 g, 40 mmol) and ethanol (300 mL) was heated at reflux for 15 h. After cooling and evaporation, the residue was chromatographed (silica gel, 1:1 chloroform/ethyl acetate) to give 4-7 as a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:4][NH:5][C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[CH2:41]([N:43]1[CH:47]=[C:46]([S:48](Cl)(=[O:50])=[O:49])[CH:45]=[N:44]1)[CH3:42]>O1CCCC1.O>[CH2:41]([N:43]1[CH:47]=[C:46]([S:48]([N:5]2[C:6]([C:7]3[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=3)=[C:2]([F:1])[C:3]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:4]2)(=[O:50])=[O:49])[CH:45]=[N:44]1)[CH3:42]
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: CCn1cc(S(=O)(=O)Cl)cn1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCn1cc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)cn1
Reaction time: 0.08 h
Yield: 97.4 %

Procedure:
To a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (200 mg) in tetrahydrofuran (10 mL) was added sodium hydride (60% in oil, 50 mg) at room temperature, and the mixture was stirred for 5 min. 15-Crown-5 (273 mg) was added. Then 1-ethyl-1H-pyrazole-4-sulfonyl chloride (181 mg) was added and the mixture was further stirred for 30 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) to give the title compound as a colorless oil (yield 290 mg, 97%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-])=O)[CH:4]=[C:3]1[C:10]([NH:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:11].[CH3:21][N:22]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[C:23]1[C:30](Cl)=[O:31]>CO.C(Cl)Cl.[Pd]>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:30]([C:23]2[N:22]([CH3:21])[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=2)=[O:31])[CH:4]=[C:3]1[C:10]([NH:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:11]
Reactant: Cn1cc([N+](=O)[O-])cc1C(=O)Cl
Reactant: Cn1cc([N+](=O)[O-])cc1C(=O)NCCN1CCOCC1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Cn1cc(NC(=O)c2cc([N+](=O)[O-])cn2C)cc1C(=O)NCCN1CCOCC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1-Methyl-N-[2-(4-morpholinyl)ethyl]-4-nitro-1H-pyrrole-2-carboxamide (1.42 g, 3.41 mmol; see step (iii) above) was dissolved in methanol (10 mL) and cooled to 0° C., Pd/C (0.055 g) was then added in small portions and the solution stirred under H2 for 3 h. The solution was then filtered and the solvent removed under reduced pressure. A solution of 1-methyl-4-nitro-1H-pyrrole-2-carbonyl chloride (0.642 g, 3.42 mmol) in DCM (10 mL) was added and the mixture allowed to stir for 1 h at RT. The solvent was then removed under reduced pressure and the crude product was separated on basified silica using a 1:1 solution of methanol ethyl acetate to yield the sub-title compound.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32]>>[Cl:30][C:19]1[CH:20]=[C:21]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)[C:15]2[O:14][CH:13]([CH2:12][NH:32][CH3:31])[CH2:17][C:16]=2[CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4ccc(F)c(F)c4)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(Cl)cc(-c3ccc(F)c(F)c3)c2O1

Procedure:
The title compound was prepared (0.09 g, 79%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-chloro-7-(3,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.149 g, 0.33 mmol) and methylamine (0.102 g, 3.3 mmol). mp 235-237° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]4[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=4[F:36])=[O:24])=[CH:18][CH:17]=3)[C:9]([CH2:13][O:14][CH3:15])=[C:10]([CH:11]=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1.CC(C[AlH]CC(C)C)C>C1COCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]4[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[CH:28][C:27]=4[F:36])=[O:24])=[CH:18][CH:17]=3)[C:9]([CH2:13][O:14][CH3:15])=[C:10]([CH2:11][OH:12])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c2c(N)ncnn2c1C=O
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c2c(N)ncnn2c1CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.6 %

Procedure:
To a solution of Intermediate AW (N-{4-[4-amino-7-formyl-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoro-methyl)phenyl]urea (50 mg, 0.1 mmol)) in THF at −78° C. under N2 was added DIBAL-H (0.5 ml, 0.5 mmol). The reaction mixture was stirred for 30 min. and was allowed to warm up to 0° C. The reaction was diluted with ethyl acetate (5 mL) and quenched with aqueous saturated Rochelle's salt (5 ml). The reaction mixture was stirred for 10 min at 0° C. and then warmed to rt. The organic layer was collected and washed with aqueous Rochelle's salt (2×), dried (Na2SO4) and concentrated. The crude concentrate was purified via column chromatography (5:95, v/v MeOH—CH2Cl2) to afford 25 mg of the title compound (yield 49%). 1H-NMR (DMSO-d6) δ9.32 (s, 1H), 8.96 (d, J=3 Hz, 1H), 8.63 (d, J=5 Hz, 1H), 7.90 (s, 1H), 7.58 (d, J=7 Hz, 2H), 7.50 to 7.32 (m, 3H), 5.0 (t, J=5 Hz, 1H), 4.79 (d, J=5 Hz, 2H), 4.30 (s, 3H), 3.16 (s, 2H) ppm; MS [M+H]+=505.1; LCMS RT=2.66 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:6](=N)[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[C:4](=[S:20])[N:3]1[CH2:21][CH2:22][CH2:23][CH2:24][OH:25].C(Cl)Cl.C(OCC)(=[O:32])C>>[CH3:1][C:2]1([CH3:26])[C:6](=[O:32])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:18])([F:19])[F:17])[CH:9]=2)[C:4](=[S:20])[N:3]1[CH2:21][CH2:22][CH2:23][CH2:24][OH:25]
Reactant: CCOC(C)=O
Reactant: CC1(C)C(=N)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1CCCCO
Solvent: ClCCl
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1CCCCO

Procedure:
Using the procedure of Example 71, 300 mg of the product of Example 76 were reacted to obtain 236 mg of the expected product melting at 78°-79° C. with a Rf=0.31 (eluant: methylene chloride--acetone (75-25)).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]1([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](O)=[O:20])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.[OH-].[K+]>CCOCC>[C:7]1([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)CCCCCCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: OCCCCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
Under nitrogen atmosphere, at 0° C., to a stirring mixture of LiAlH4 (0.51 g, 13.57 mmol) in dry Et2O (35 mL), 7-phenylheptanoic acid (0.7 g, 3.39 mmol) in dry Et2O (5 mL) was dropwise added. The mixture was left to react at rt for 4 h, then at 0° C. H2O (0.51 mL), 3M KOH solution (0.51 mL) and H2O (1.70 mL) were very slowly added. The mixture was stirred for 1 h at 0° C., filtered to remove the solid residue, and the organic phase dried over Na2SO4. The organic solution was again filtered and concentrated to dryness affording the title compound (0.586 g, 90%) as a colorless oil. 1H NMR (CDCl3): δ 1.17-1.27 (m, 1H), 1.34-1.43 (m, 6H), 1.53-1.71 (m, 4H), 2.59-2.67 (m, 2H), 3.66 (t, J=6.5 Hz, 2H), 7.16-7.23 (m, 3H), 7.26-7.34 (m, 2H).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([F:9])=[CH:4][N:3]=1.[C:10](=[N:23][NH2:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1.C1(B(O)O)C=CC=CC=1>[C:10](=[N:23][NH:24][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([F:9])=[CH:4][N:3]=1)([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cc(F)cnc1Br
Reactant: NN=C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: OB(O)c1ccccc1
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(F)cnc1NN=C(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
A mixture of 2-bromo-5-fluoro-3-methyl-pyridine (190 mg, 1.0 mmol), benzhydrylidene-hydrazine (216 mg, 1.1 mmol), phenylboronic acid (5 mol %, 6 mg) and potassium tert-butoxide (157 mg, 1.4 mmol) in anhydrous toluene (6 mL) was degassed with a stream of argon, treated with Pd(OAc)2 (2 mol %, 5 mg) and racemic (1,1′-binaphthalene-2,2′-diyl)bis(diphenylphosphine) (2 mol %, 12 mg) and stirred at 80° C. for 1 h. After cooling to RT, the reaction mixture was diluted with EtOAc and washed with water followed by a saturated aqueous solution of NaHCO3. The organic layer was dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 1-10% MeOH in DCM followed by 100% DCM, to afford the title compound (196 mg, 64%). LCMS (Method 4): Rt 3.44 min, m/z 306 [MH+].
Reaction SMILES: N1CCCCC1.C(NC(N1C2C(=CC(OC3C=CN=C(NC(=O)OC4C=CC=CC=4)C=3)=CC=2)C=C1)=O)C.[CH2:38]([NH:40][C:41]([N:43]1[C:51]2[C:46](=[CH:47][C:48]([O:52][C:53]3[CH:58]=[CH:57][N:56]=[C:55]([NH:59][C:60]([N:62]4[CH2:67][CH2:66][CH:65](N5CCCC5)[CH2:64][CH2:63]4)=[O:61])[CH:54]=3)=[CH:49][CH:50]=2)[CH:45]=[CH:44]1)=[O:42])[CH3:39]>CN(C)C=O>[CH2:38]([NH:40][C:41]([N:43]1[C:51]2[C:46](=[CH:47][C:48]([O:52][C:53]3[CH:58]=[CH:57][N:56]=[C:55]([NH:59][C:60]([N:62]4[CH2:67][CH2:66][CH2:65][CH2:64][CH2:63]4)=[O:61])[CH:54]=3)=[CH:49][CH:50]=2)[CH:45]=[CH:44]1)=[O:42])[CH3:39]
Reactant: CCNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCC(N5CCCC5)CC4)c3)ccc21
Agent: CCNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)ccc21
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CCNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCCCC4)c3)ccc21
Reaction time: 8 h

Procedure:
N,N-Dimethylformamide (4 ml) and piperidine (0.31 ml, 3.13 mmol) were added to a mixture (0.336 g) of phenyl N-(4-(1-(ethylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate and phenyl N-(4-(1-(ethylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamate obtained in Example 77; the reaction mixture was stirred overnight; the reaction mixture was partitioned between ethyl acetate and water; and the organic layer was concentrated to yield the title compound as crystals (182 mg, 0.45 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1.I[CH2:13][C:14]([CH2:55][O:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH3:74])([CH2:35][O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:15][O: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][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.C(Cl)(Cl)Cl>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([O:1][CH2:13][C:14]([CH2:15][O: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][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])([CH2:55][O:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH3:74])[CH2:35][O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: CCCCCCCCCCCCCCCCCCOCC(CI)(COCCCCCCCCCCCCCCCCCC)COCCCCCCCCCCCCCCCCCC
Reactant: COc1cc(O)ccc1C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOCC(COCCCCCCCCCCCCCCCCCC)(COCCCCCCCCCCCCCCCCCC)COc1ccc(C=O)c(OC)c1
Temperature: 130 °C
Reaction time: 72 h
Yield: 96.3 %

Procedure:
4-Hydroxy-2-methoxybenzaldehyde (136 mg, 894 μmol) was dissolved in DMF (10 ml), 1-[3-iodo-2,2-bis(octadecyloxymethyl)propoxy]octadecane (600 mg, 598 μmol) and potassium carbonate (165 mg, 1.19 mmol) were added, and the mixture was stirred at 130° C. for 3 days. The reaction mixture was cooled to room temperature, 1N hydrochloric acid (10 ml) and chloroform (10 ml) were added, and the mixture was stirred. The aqueous layer was removed, and the organic layer was further washed twice with purified water (10 ml). The organic layer was evaporated under reduced pressure, and the residue was precipitated with methanol to give crude crystals of 2-methoxy-4-[2′,2′,2′-tris(octadecyloxymethyl)ethoxy]benzaldehyde (592 mg, 96%). The obtained crude crystals were purified by silica gel column chromatography (chloroform-hexane=2:1-chloroform→hexane-ethyl acetate=10:1).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>>[C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:28]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[O:29])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CSc1nc(-c2cccc(N)c2)c2c(N)c(C(=O)NC(C)(C)C)sc2n1
Product: CSc1nc(-c2cccc(NC(=O)OCc3ccccc3)c2)c2c(N)c(C(=O)NC(C)(C)C)sc2n1
Reaction time: 0.5 h

Procedure:
The reaction of tert-butyl 5-amino-2-methylthio-4-(3-aminophenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 9e, 100 mg) with benzyl chloroformate (368 μl) was performed using the methods described in example 15. The title compound was purified by HPLC using a Luna C-18 column with the following gradient: CH3CN/10% aq. CH3CN=10/90 to 90/10 (v/v) in 30 min. The title compound was then lyophilized from a mixture of 1,4-dioxane and H2O.