Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=S)(OC1C=CC=CC=1)O[C@@H:3]1[C@@H:7]2[O:8][CH:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[O:10][CH2:11][C@@H:6]2[CH2:5][C@H:4]1[N:20]1[C:24]2[N:25]=[CH:26][N:27]=[C:28]([NH:29][C@@H:30]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH2:32][CH2:31]3)[C:23]=2[CH:22]=[CH:21]1.C([SnH](CCCC)CCCC)CCC.N(C(C)(C)C#N)=NC(C)(C)C#N>C1(C)C=CC=CC=1>[C@@H:30]1([NH:29][C:28]2[C:23]3[CH:22]=[CH:21][N:20]([C@H:4]4[CH2:3][C@@H:7]5[O:8][CH:9]([C:12]6[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=6)[O:10][CH2:11][C@@H:6]5[CH2:5]4)[C:24]=3[N:25]=[CH:26][N:27]=2)[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31]1
Reactant: COc1ccc(C2OC[C@@H]3C[C@@H](n4ccc5c(N[C@H]6CCc7ccccc76)ncnc54)[C@H](OC(=S)Oc4ccccc4)[C@@H]3O2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: COc1ccc(C2OC[C@@H]3C[C@@H](n4ccc5c(N[C@H]6CCc7ccccc76)ncnc54)C[C@@H]3O2)cc1
Yield: 78.9 %

Procedure:
O-[(4aS,6R,7S,7aR)-6-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo-[2,3-d]pyrimidin-7-yl}-2-(4-methoxyphenyl)hexahydrocyclopenta[d][1,3]dioxin-7-yl] O-phenyl thiocarbonate (5.00 g, 7.88 mmol) was dissolved in toluene (150. mL) under an atmosphere of nitrogen and tri-n-butyltin hydride (4.24 mL, 15.8 mmol) was added followed by 2,2′-azo-bis-isobutyronitrile (259 mg, 1.58 mmol). The solution was heated to reflux for 30 min, the mixture was cooled down, the solvent was concentrated to 30 mL and the residue was purified via silica gel chromatography eluting with a gradient of 30 to 100% EtOAc in hexanes to afford the title compound (3.00 g, 79%). LC/MS: Rt=2.12 min, ES+ 483 (AA standard).
Reaction SMILES: C([O:8][C:9]1[CH:51]=[CH:50][C:12]([CH2:13][C@H:14]2[C@@H:18]([CH2:19][N:20]([CH2:33][CH:34]([CH3:36])[CH3:35])[S:21]([C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=3)(=[O:23])=[O:22])[O:17][C:16]([CH3:38])([CH3:37])[N:15]2[C:39]([O:41][C@H:42]2[C@H:49]3[C@H:45]([O:46][CH2:47][CH2:48]3)[O:44][CH2:43]2)=[O:40])=[CH:11][CH:10]=1)C1C=CC=CC=1.N.[H][H]>CO.[Pd]>[NH2:30][C:27]1[CH:28]=[CH:29][C:24]([S:21]([N:20]([CH2:19][C@H:18]2[O:17][C:16]([CH3:37])([CH3:38])[N:15]([C:39]([O:41][C@H:42]3[C@H:49]4[C@H:45]([O:46][CH2:47][CH2:48]4)[O:44][CH2:43]3)=[O:40])[C@H:14]2[CH2:13][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:51][CH:50]=2)[CH2:33][CH:34]([CH3:36])[CH3:35])(=[O:22])=[O:23])=[CH:25][CH:26]=1
Reactant: CC(C)CN(C[C@H]1OC(C)(C)N(C(=O)O[C@@H]2CO[C@H]3OCC[C@H]32)[C@H]1Cc1ccc(OCc2ccccc2)cc1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Agent: N
Solvent: CO
Product: CC(C)CN(C[C@H]1OC(C)(C)N(C(=O)O[C@@H]2CO[C@H]3OCC[C@H]32)[C@H]1Cc1ccc(O)cc1)S(=O)(=O)c1ccc(N)cc1
Yield: 54 %

Procedure:
To a stirred solution of (3S,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (4S,5R)-4-[4-(benzyloxy)benzyl]-5-({isobutyl[(4-nitrophenyl)sulfonyl]amino}methyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate. (0.18 g, 0.25 mmol) in 6 mL of a 2M solution of ammonia in methanol was added 0.18 g of palladium (on charcoal, 10% Pd, Degussa type). The mixture was stirred under an atmospheric pressure of hydrogen for 12 hours. The catalyst was filtered, and the solvent was removed under reduced pressure. The residue was purified on silica gel using ethyl acetate-hexanes (7:3) as eluent to provide 81 mg (54%) of the title compound.
Reaction SMILES: [CH2:1]([NH:4][C@@H:5]1[CH2:14][C:13]2[C:8]3=[C:9]([N:15]([O:18][CH3:19])[C:16](=[O:17])[N:7]3[CH2:6]1)[CH:10]=[CH:11][CH:12]=2)[CH2:2][CH3:3].I[CH2:21][CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([N:4]([CH2:21][CH2:22][CH3:23])[C@@H:5]1[CH2:14][C:13]2[C:8]3=[C:9]([N:15]([O:18][CH3:19])[C:16](=[O:17])[N:7]3[CH2:6]1)[CH:10]=[CH:11][CH:12]=2)[CH2:2][CH3:3]
Reactant: CCCN[C@@H]1Cc2cccc3c2n(c(=O)n3OC)C1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN(CCC)[C@@H]1Cc2cccc3c2n(c(=O)n3OC)C1
Yield: 80.5 %

Procedure:
Following the procedure of Example 3, a mixture of (R)-5-Propylamino-1-methoxy-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (8b, 0.93 g,3.56 mmol), 1-iodopropane (3.05 g, 17.9 mmol), and potassium carbonate (1.97 g, 14.3 mmol) in acetonitrile (25 ml) was heated at reflux under nitrogen for 17 hours. 1-Iodopropane (3.05 g, 17.9 mmol) was again added, and the mixture was refluxed for an additional 5 hours. The solvent was removed under vacuum, and the mixture was diluted with water and extracted twice with diethylether. The organic extract was washed with brine and dried (MgSO4). The solvent was removed under vacuum to leave an amber oil. Purification by flash chromatography (230-400 mesh silica gel; 10-25% ethyl acetate in hexane) gave the title compound (9b) as an amber oil (0.87 g, 90% yield).
Reaction SMILES: [C:1]1([C:7]([NH:10][C:11]2[N:12]=[C:13]([NH2:29])[C:14]3[N:15]=[CH:16][N:17]([C:27]=3[N:28]=2)[C@H:18]2[O:26][C@H:23]([CH2:24][OH:25])[C@@H:21]([OH:22])[C@H:19]2[OH:20])([CH3:9])C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:30]1([C@H](N)CC)C=CC=CC=1>>[C:1]1([CH:7]([NH:10][C:11]2[N:12]=[C:13]([NH2:29])[C:14]3[N:15]=[CH:16][N:17]([C:27]=3[N:28]=2)[C@@H:18]2[O:26][C@H:23]([CH2:24][OH:25])[C@@H:21]([OH:22])[C@H:19]2[OH:20])[CH2:9][CH3:30])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC[C@@H](N)c1ccccc1
Reactant: CC(C)(Nc1nc(N)c2ncn([C@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1)c1ccccc1
Product: CCC(Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1)c1ccccc1
Yield: 34.6 %

Procedure:
Combine the acetonide (2) (3.4 g, 9.95 mmol) with (R)-1-phenylpropylamine (8.62 g) and heat to reflux for 18 hours. Remove some of the excess amine by distillation. After cooling, purify by flash chromatography (3% methanol in dichloromethane). Triturate the product with diethyl ether to provide the secondary amine (3) (1.38 g); 1H NMR (CDCl3) δ 7.41 (1H, s), 7.21-7.34 (4H, m), 7.14-7.22 (1H, m), 5.69 (1H, d), 5.50 (2H, s), 5.25 (1H, d), 5.10 (1H, t), 5.01 (1H, q), 4.90 (1H, q), 4.41 (1H, s), 3.93 (1H, d), 3.80 (1H, d), 1.82 (2H, pent), 1.60 (3H, s), 1.32 (3H, s), 0.94 (3H, t); IR (KBr) 3450-3100, 1633, 1599 cm-1. Anal. Calcd for C22H28N6O4 : C, 59.99; H, 6.41; N, 19.08. Found: C, 59.99; H, 6.38; N, 18.71.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[NH2:11][CH2:12][CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1.CN1CCOCC1.[CH3:30][N:31]([CH3:49])[C:32]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=2)[CH2:37][CH2:36][C:35]([CH2:39][C:40](O)=[O:41])(O)[CH2:34][CH2:33]1.C1(N=C=NC2CCCCC2)CCCCC1.[OH-].[Na+]>O.CN(C)C=O>[CH3:49][N:31]([CH3:30])[C:32]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=2)[CH2:37][CH2:36][C:35](=[CH:39][C:40]([NH:11][CH2:12][CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)=[O:41])[CH2:34][CH2:33]1
Reactant: CN(C)C1(c2ccccn2)CCC(O)(CC(=O)O)CC1
Reactant: NCCc1c[nH]c2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: CN(C)C1(c2ccccn2)CCC(=CC(=O)NCCc2c[nH]c3ccccc23)CC1
Temperature: 0 °C
Reaction time: 168 h
Yield: 25 %

Procedure:
1-Hydroxybenzotriazole (546 mg, 4.0 mmol), tryptamine (320 mg, 2.0 mmol) and N-methylmorpholine (0.444 ml, 4.0 mmol) were added to a solution of (4-dimethylamino-1-hydroxy-4-pyridin-2-yl-cyclohexyl)acetic acid (556 mg, 2.0 mmol) in abs. dimethylformamide (30 ml) under argon. The solution was cooled to 0° C., dicyclohexylcarbodiimide (825 mg, 4.0 mmol) was added and the mixture was stirred at RT for 7 d. Working up of the mixture was carried out by separating off the urea which had precipitated out and introducing the filtrate into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO3 solution (10 ml). Still further urea thereby precipitated out and was separated off. The aqueous phase was diluted with water (400 ml), 5 M sodium hydroxide solution (7 ml, 35 mmol) was added and the mixture was stored at 5° C. for 16 h. The crude product thereby precipitated out as a beige-coloured solid (313 mg, 37%). After chromatography on silica gel (45 g) with EA/methanol (4:1), the product was obtained as a beige-coloured solid in a yield of 25% (210 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)=[CH:9]/[CH2:10][N:11]([CH2:13][C:14]([OH:16])=[O:15])[CH3:12])=[CH:4][CH:3]=1.[CH:22]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)([CH3:24])[CH3:23].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>[CH:22]([C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:7]=[CH:6][C:5](/[C:8](/[C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)=[CH:9]/[CH2:10][N:11]([CH2:13][C:14]([OH:16])=[O:15])[CH3:12])=[CH:4][CH:3]=2)=[CH:27][CH:26]=1)([CH3:24])[CH3:23]
Reactant: CC(C)c1ccc(B(O)O)cc1
Reactant: CN(C/C=C(/c1ccc(Br)cc1)c1ccsc1)CC(=O)O
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: CC(C)c1ccc(-c2ccc(/C(=C/CN(C)CC(=O)O)c3ccsc3)cc2)cc1

Procedure:
To a solution of (Z)-N-(1-(4-bromophenyl)-1-(3-thienyl)prop-1-en-3-yl)sarcosine, tbutyl ester E(i) (21.14 g, 50.05 mmol) in dimethoxyethane (210 mL) was added 4-isopropylbenzeneboronic acid (16.41 g, 100.1 mmol), Pd(PPh3)4 (2.89 g, 2.50 mmol), and 2M Na2CO3 (210 mL). The vigorously stirred mixture was heated to reflux for 2 hours. The mixture was cooled, and partitioned between EtOAc and water. The organic phase was washed with brine, dried (MgSO4), filtered, and concentrated. Column chromatography (2-5% acetone/hexanes) followed by a second chromatography (2-20% EtOAc/hexanes) provided (Z)-N-(1-(4-(4-Isopropylphenyl)phenyl)-1-(3-thienyl)prop-1-en-3-yl)sarcosine, tbutyl ester F(i) (18.65 g, 81%) as a yellow oil. 1H NMR (300 MHz, CDCl3) 1.29 (d, 6H), 1.44 (s, 9H), 2.39 (s, 3H), 2.95 (hept, 1H), 3.16 (s, 2H), 3.30 (d, 2H), 6.26 (t, 1H), 6.93 (d, 1H), 7.18 (d, 1H), 7.26-7.35 (m, 5H), 7.50-7.54 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14]([NH2:15])=[N:13][C:12]([N:16]3[CH2:21][CH2:20][N:19]([C:22]([CH:24]4[O:33][C:32]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[O:26][CH2:25]4)=[O:23])[CH2:18][CH2:17]3)=[N:11][C:6]2=[CH:7][C:8]=1[O:9][CH3:10].O1C(C(N2CCNCC2)=O)COC2C=CC=CC1=2.[Cl:52]C1N=C(N)C2C(=CC(OC)=C(OC)C=2)N=1>C(O)CCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14]([NH2:15])=[N:13][C:12]([N:16]3[CH2:21][CH2:20][N:19]([C:22]([CH:24]4[O:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[O:26][CH2:25]4)=[O:23])[CH2:18][CH2:17]3)=[N:11][C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[ClH:52]
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Agent: COc1cc2nc(N3CCN(C(=O)C4COc5ccccc5O4)CC3)nc(N)c2cc1OC
Agent: O=C(C1COc2ccccc2O1)N1CCNCC1
Solvent: CCCCO
Product: Cl

Procedure:
Organic Preparations and Procedures International (2003); 35; 603-608 describes the procedure for synthesizing doxazosin by treating (2,3-dihydrobenzo[b][1,4]dioxin-2-yl) (piperazin-1-yl)methanone with 2-chloro-6,7-dimethoxy quinazolin-4-amine in presence of n-butanol to obtain doxazosin hydrochloride; which on further treatment with aqueous ammonia solution yields doxazosin base.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[CH2:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.O1CCOC[CH2:14]1>C(OCC)C>[CH:11]1([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:2]([CH3:1])[CH:3]=[CH:4]3)[CH2:14][CH2:12]1
Reactant: C=Cc1ccc2c(ccn2C)c1
Reactant: C1COCCO1
Solvent: CCOCC
Product: Cn1ccc2cc(C3CC3)ccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 96 %

Procedure:
To a solution of 1-Methyl-5-vinyl-1H-indole (290 mg, 1.84 mmol) in dioxane (5 mL) was cooled at 0° C. and solution of CH2N2 in diethyl ether was added. The reaction mixture was allowed to warm to room temperature and stirred for 12 h. The solvents were evaporated and the residue was purified by column chromatography (ethyl acetate:hexane; 5:95) to give a product (305 mg, 96%). 1H NMR (CDCl3, 400 MHz) 0.68 (m, 2H), 0.88 (m, 2H), 2.00 (m, 1H), 3.71 (s, 1H), 6.37 (d, J=2.9 Hz, 1H), 6.97 (m, 2H), 7.18 (d, J=8.4 Hz, 1H), 7.34 (s, 1H); 13C NMR (CDCl3, 100 MHz) 8.5, 13.6, 17.5, 32.8, 100.3, 108.9, 117.5, 120.4, 128.6, 128.9, 134.4, 135.3.
Reaction SMILES: [CH:1]([S:4]([C:7]1[N:8]=[CH:9][C:10](N)=[N:11][CH:12]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].[BrH:14].BrBr.N([O-])=O.[Na+].C([O-])(O)=O.[Na+]>C(O)(=O)C.O>[Br:14][C:10]1[CH:9]=[N:8][C:7]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])=[CH:12][N:11]=1
Reactant: CC(C)S(=O)(=O)c1cnc(N)cn1
Reactant: Br
Agent: BrBr
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)S(=O)(=O)c1cnc(Br)cn1
Yield: 44 %

Procedure:
5-Isopropylsulfonylpyrazin-2-amine was added to a rapidly stirring mixture of hydrobromic acid in acetic acid (2.150 mL of 45% w/v, 11.96 mmol) and acetic acid (649.6 μL) at 0° C. followed by the slow addition of bromine (1.433 g, 462.0 μL, 8.967 mmol) dropwise over a 10 minutes. A solution of sodium nitrite (515.5 mg, 237.8 μL, 7.472 mmol) in water (2.275 mL) was added dropwise over 10 minutes and the reaction mixture was stirred at 0° C. for a further 15 minutes. The reaction mixture was basified with 16 mL of saturated aqueous NaHCO3 at 0° C. and extracted with DCM (×3). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion™, 40 g column, eluting with 0 to 100% EtOAc/Petrol, loaded in DCM) to give the sub-title product as a cream solid (349 mg, 44% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.24 (d, 6H), 3.69 (sept, 1H). 9.04 (s, 1H) and 9.17 (s, 1H); MS (ES+) 267.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3([C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)=[O:23])[CH2:21][CH2:20]3)=[O:18])=[C:11]([F:32])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:33]([CH2:35][C:36](O)=[O:37])#[N:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C.O>[C:33]([CH2:35][C:36]([NH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3([C:22]([NH:24][C:25]4[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=4)=[O:23])[CH2:21][CH2:20]3)=[O:18])=[C:11]([F:32])[CH:10]=2)[CH:5]=[CH:4][N:3]=1)=[O:37])#[N:34]
Reactant: N#CCC(=O)O
Reactant: Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: N#CCC(=O)Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Temperature: 60 °C
Reaction time: 8 h
Yield: 40.4 %

Procedure:
To a solution of N-(4-((2-aminopyridin-4-yl)oxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (150 mg, 0.34 mmol) (as prepared in Example 9) and 2-cyanoacetic acid (44 mg, 0.51 mmol) in DMF (2 mL) was added HATU (258 mg, 0.68 mmol) and DIEA (130 mg, 1 mmol) and the mixture was stirred at 60° C. under nitrogen overnight. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL) and H2O (50 mL) and the organic layer was washed with brine, dried and concentrated under reduced pressure. The residue was purified by prep-TLC to give N-(4-(2-(2-cyanoacetamido)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (70 mg, yield 64.5%). 1H-NMR (400 MHz, DMSO-d6): δ 10.99 (s, 1H), 10.94 (s, 1H), 9.81 (s, 1H), 8.23 (d, J=5.6 Hz, 1H), 8.08 (dd, J=12.4, 6.8 Hz, 1H), 7.59-7.55 (m, 4H), 7.15 (t, J=8.8 Hz, 2H), 6.80 (dd, J=6.0, 2.4 Hz, 1H), 3.92 (s, 2H), 1.61-1.56 (m, 4H); MS (ESI): m/z 510.2 [M+H]+.
Reaction SMILES: I[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.C1([Mg]Br)C=CC=CC=1.C(OCC)C.[F:21][C:22]1[CH:29]=[C:28]([CH:30]=[O:31])[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]>ClCCl>[F:21][C:22]1[CH:29]=[C:28]([CH:30]([OH:31])[C:2]2[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=2)[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]
Reactant: Cn1cncc1I
Reactant: N#Cc1ccc(C=O)cc1F
Agent: Br[Mg]c1ccccc1
Solvent: ClCCl
Solvent: CCOCC
Product: Cn1cncc1C(O)c1ccc(C#N)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-iodo-1-methyl-1H-imidazole (250 mg, 1.2 mmol) in dichloromethane (2 mL) at 0° C. was treated with 3M phenylmagnesium bromide in diethyl ether (0.4 mL, 1.2 mmol), stirred for 30 minutes, warmed to room temperature, stirred for 30 minutes, cooled to 0° C. and treated with a solution of Example 52C (150 mg, 1.0 mmol) in dichloromethane (1 mL). The mixture was warmed to room temperature, stirred for 2 days, and quenched with ethyl acetate and saturated ammonium chloride. The aqueous phase was extracted with ethyl acetate (2×100 mL), and the combined organic layers were dried (MgSO4), filtered, and concentrated. The concentrate was dissolved in 1:1 ethyl acetate/diethyl ether, filtered, rinsed with 1:1 ethyl acetate/diethyl ether and dried to provide the desired product. 1H NMR (400 MHz, CD3OD) δ 7.91 (dd, 1H), 7.56 (s, 1H), 7.51 (d, 1H), 7.42-7.38 (m, 1H), 6.42 (s, 1H), 6.28-6.24 (m, 1H), 5.93-5.91 (m, 1H), 3.52 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]#[C:12][C:13]2[C:21]3[C:20]([NH2:22])=[N:19][CH:18]=[N:17][C:16]=3[N:15]([C@H:23]3[CH2:27][CH2:26][NH:25][CH2:24]3)[CH:14]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[OH:28][C:29]([CH3:36])([CH3:35])[C:30]#[C:31][C:32](O)=[O:33]>>[NH2:22][C:20]1[C:21]2[C:13]([C:12]#[C:11][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=3)=[CH:14][N:15]([C@H:23]3[CH2:27][CH2:26][N:25]([C:32](=[O:33])[C:31]#[C:30][C:29]([OH:28])([CH3:36])[CH3:35])[CH2:24]3)[C:16]=2[N:17]=[CH:18][N:19]=1
Reactant: CC(C)(O)C#CC(=O)O
Reactant: COc1cc(C#Cc2cn([C@H]3CCNC3)c3ncnc(N)c23)cc(OC)c1
Product: COc1cc(C#Cc2cn([C@H]3CCN(C(=O)C#CC(C)(C)O)C3)c3ncnc(N)c23)cc(OC)c1

Procedure:
In accordance with Example 4 (Step 1), except that (S)-5-((3,5-dimethoxyphenyl)ethynyl)-7-(pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (i.e., the intermediate obtained in Example 38 (Step 4)) and 4-hydroxy-4-methylpent-2-ynoic acid were used, the title compound was obtained as a colorless, amorphous substance. Table 1 shows the physical properties thereof.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:32]=[C:31]([F:33])[C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[CH:21]=[CH:20][N:19]=3)=[N:10]2)=[C:6]([F:34])[CH:5]=1)[CH3:2].C(N(CC)CC)C.[C:42](Cl)(=[O:44])[CH3:43]>ClCCl>[CH2:1]([O:3][C:4]1[CH:32]=[C:31]([F:33])[C:7]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[N:23]=[C:22]([N:24]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[C:42](=[O:44])[CH3:43])[CH:21]=[CH:20][N:19]=3)=[N:10]2)=[C:6]([F:34])[CH:5]=1)[CH3:2]
Reactant: CCOc1cc(F)c(Cn2nc(-c3nccc(Nc4ccncc4)n3)c3ccccc32)c(F)c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1cc(F)c(Cn2nc(-c3nccc(N(C(C)=O)c4ccncc4)n3)c3ccccc32)c(F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
100 mg of 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1H-indazol-3-yl]-N-(pyridin-4-yl)-pyrimidin-4-amine (5-1-1, 0.218 mmol, 1. eq.) was dissolved in 2 ml of dry dichloromethane. First 94 μl of dry N,N-diethylethanamine (0.676 mmol, 3.1 eq.) and then 23 μl of acetyl chloride (0.327 mmol, 1.5 eq,) were added under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 18 hours. Then the mixture was partitioned between water and dichloromethane. The phases were separated and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed with brine, dried over a silicon filter and concentrated in vacuo. The residue was purified by flash chromatography and preparative TLC to yield 29.8 mg (0.06 mmol, 26.8%) of the analytically pure target compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Br:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([Br:9])[CH:15]=2)=[N:3][CH:4]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: Brc1ccc(Br)nc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2cccc(Br)c2)nc1
Temperature: 105 °C

Procedure:
A mixture of 2,5-dibromopyridine (4.33 g, 17.7 mmol), 3-bromophenylboronic acid (4.70 g, 21.3 mmol), tetrakis(triphenylphosphine) palladium (0) (800 mg, 0.692 mmol), 2 M Na2CO3(aq) (18 cm3), EtOH (18 cm3) and toluene (50 cm3) was degassed and heated at reflux with a bath temperature of 105° C. under argon for 23 h. The reaction was allowed to cool and the two phases were separated. The aqueous layer was extracted with ether (3×15 cm3). The organic layer and the ether extracts were combined, washed with brine (1×40 cm3) and dried over anhydrous sodium sulfate. The solvents were completely removed to leave an orange oil. The oil was purified by column chromatography over silica gel using DCM-light petroleum (0:1 to 1:10) as eluent to give 2.50 g (45%) of B-1 as a pale yellow solid; δH (200 MHz; CDCl3) 7.26-7.42 (1 H, m, ArH), 7.57 (2 H, m, PyH & ArH), 7.88 (2 H, m, PyH & ArH), 8.14 (1 H, m, ArH), and 8.74 (1 H, m, PyH); m/z [CI(NH3)] 312, 314, 316 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[NH:10][CH:11]([CH3:14])[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:17][O:18][C:19](=[O:25])[C@H:20]([CH2:22][CH2:23][CH3:24])[NH2:21].C(N(C(C)C)CC)(C)C.C([BH3-])#N.[Na+]>CO.C(O)(=O)C.[Cl-].[Cl-].[Zn+2]>[CH3:17][O:18][C:19](=[O:25])[CH:20]([NH:21][CH2:12][CH:11]([NH:10][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:15])[CH3:14])[CH2:22][CH2:23][CH3:24]
Reactant: CCC[C@H](N)C(=O)OC
Reactant: CC(C=O)NC(=O)OCc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Cl-]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(NCC(C)NC(=O)OCc1ccccc1)C(=O)OC
Reaction time: 0.17 h
Yield: 38.6 %

Procedure:
To a solution of [1-methyl-2-oxo-ethyl]-carbamic acid benzyl ester (12.3 g, 69 mmol) and norvaline methylester hydrochloride (11.6 g, 69 mmol) in MeOH (300 mL) is added diisopropyl ethyl amine (9.4 g, 73 mmol) and 2 drops of acetic acid. After 10 min., ZnCl2 (9.46 g, 69 mmol) and sodium cyanoborohydride (8.72 g, 14 mmol) is added. The solution is stirred at ambient for 16 h. The solution is then concentrated. The residue is dissolved in EtOAc and 1N KHSO4. The organic layer is washed with 1N KHSO4, H2O, and sat. NaCl. The organic layer is dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatograghy eluting with a gradient of 20% EtOAc/hexane to 40% EtOAc/hexanes. The title compound (8.6 gm, 26.6 mmol) is obtained as a foam. MS (ion spray) m/z 323, (M+H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]3[O:26][CH2:27][O:28][C:29]=3[C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:39](=[O:40])[CH2:38][O:37][CH3:36])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f3) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.