Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH3:11]
Reactant: O=Cc1c[nH]c2ccc(Br)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c[nH]c2ccc(Br)cc12
Reaction time: 2 h
Yield: 72.6 %

Procedure:
To a solution of 5-bromo-1H-indole-3-carbaldehyde (5.0 g, 22.3 mmol) in THF (80 mL) was added LiAlH4 (1.70 g, 44.6 mmol). The resulting solution was stirred for 2 h under reflux, then poured into 1N NaOH solution (150 mL), extracted with ethyl acetate (3×100 mL), dried over anhydrous sodium sulfate, and then concentrated under vacuum to give a residue, which was purified via silica gel chromatography (3% ethyl acetate in petroleum ether) to afford 5-bromo-3-methyl-1H-indole as a white solid (3.4 g, 73%).
Reaction SMILES: C(OC(=O)[N:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][O:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][CH:22]=[CH:21]3)[N:10]=1)[CH3:8])(C)(C)C.C([O:30][C:31](=[O:44])[C:32]#[C:33][C:34]1[CH:35]=[N:36][C:37]2[C:42]([CH:43]=1)=[CH:41][CH:40]=[CH:39][CH:38]=2)C>>[CH3:8][NH:7][C:9]1[N:10]=[C:11]([CH2:15][CH2:16][O:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[N:23]([CH:33]([C:34]2[CH:35]=[N:36][C:37]4[C:42]([CH:43]=2)=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH2:32][C:31]([OH:44])=[O:30])[CH:22]=[CH:21]3)[CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)C#Cc1cnc2ccccc2c1
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(CCOc2ccc3[nH]ccc3c2)n1
Product: CNc1cccc(CCOc2ccc3c(ccn3C(CC(=O)O)c3cnc4ccccc4c3)c2)n1
Yield: 48 %

Procedure:
The title compound was synthesized from {6-[2-(1H-indol-5-yloxy)-ethyl]-pyridin-2-yl}-methyl-carbamic acid tert-butyl ester and quinolin-3-yl-propynoic acid ethyl ester, using the procedure described in Example 16, step (d1), in 48% yield, as an E/Z isomeric mixture. H1 NMR (Cl3CD), δ: 8.91 (d, 0.3H, J=2.1 Hz), 8.88 (d, 0.3H, J=2.3 Hz), 8.17 (d, 0.7H, J=8.8 Hz), 8.14-8.11 (m, 1H), 7.97 (d, 0.3H, J=2.0 Hz), 7.82-7.74 (m, 2H), 7.60 (m, 1H), 7.53 (m, 1H), 7.49 (m, 1H), 7.17 (m, 1H), 7.11 (m, 1H), 6.92-6.97 (m, 2H), 6.78 (dd, 0.7H, J=2.5, 9.0 Hz), 6.70 (dd, 0.3H, J=2.5, 9.0 Hz), 6.64 (d, 0.3H, J=3.2 Hz), 6.55 (d, 0.7H, J=3.5 Hz), 6.39 (s, 0.3H), 6.32 (s, 0.7H), 4.39 (m, 2H), 4.10 (q, 1.4H, J=7.2 Hz), 4.04 (q, 0.6H, J=7.2 Hz), 1.39 (s, 0.9H), 1.38 (s, 2.1H), 3.21 (m, 2H), 1.51 (s, 9H), 1.14 (t, 2.1H, J=7.2 Hz), 1.05 (t, 0.9H, J=7.2 Hz).
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1.[Li+].CC([N-]C(C)C)C.[CH2:38]([N:40]([CH2:55][CH3:56])[C:41]([N:43]1[C:51]2[C:46](=[CH:47][C:48]([Br:52])=[CH:49][CH:50]=2)[C:45]([CH:53]=O)=[CH:44]1)=[O:42])[CH3:39].Cl>C1COCC1.ClCCl.O=[Pt]=O>[CH2:55]([N:40]([CH2:38][CH3:39])[C:41]([N:43]1[C:51]2[C:46](=[CH:47][C:48]([Br:52])=[CH:49][CH:50]=2)[C:45]([CH2:53][CH2:8][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:29][CH:28]=2)=[CH:44]1)=[O:42])[CH3:56]
Reactant: COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCN(CC)C(=O)n1cc(C=O)c2cc(Br)ccc21
Agent: O=[Pt]=O
Agent: CC(C)[N-]C(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCN(CC)C(=O)n1cc(CCc2ccc(OC)cc2)c2cc(Br)ccc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a solution of 4-methoxybenzyl triphenyphosphonium chloride (7.5 g, 18 mmol) in anhydrous THF (75 mL) at −78° C. was added LDA (9.0 mL, 18 mmol) and the resulting reaction mixture was allowed to stir at −78° C. for 1 h. Thereafter, 5-bromo-3-formyl-indole-1-carboxylic acid diethylamide (1.9 g, 6 mmol, Example 1, Part A) was added and the resulting reaction mixture was allowed to stir at −78° C. for 1 h and then warmed to room temperature to stir overnight. The reaction mixture was poured onto 1N HCl solution and extracted with ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by chromatography on silica gel eluting with ethyl acetate/hexane (1:4) to provide the mixture of alkenes (2.3 g, 90%, E:Z ˜1:1) as a brown oil. A solution of the above alkenes (2.3 g, 5.4 mmol) in dichloromethane (100 mL) was hydrogenated over Adam's catalyst (300 mg) under H2 (15 psi) for 2 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The crude product was purified by chromatography on silica gel eluting with ethyl acetate/hexane (1:4) to provide the title compound (1.43 g, 62%) as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[NH2:11][OH:12]>CCO>[OH:12][N:11]=[C:7]([C:6]1[CH:9]=[CH:10][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=1)[NH2:8]
Reactant: N#Cc1ccc(CO)cc1
Reactant: NO
Solvent: CCO
Product: NC(=NO)c1ccc(CO)cc1
Temperature: 74 °C
Yield: 94.9 %

Procedure:
To a solution of 4-(hydroxymethyl)benzonitrile (11.05 g; 83.08 mmol) in EtOH (100 mL) was added hydroxylamine (27.4 mL; 415 mmol) (50% in water) and the mixture was heated to 74° C. for 16 hours. The mixture was poured into a crystallizing dish and the solvent were evaporated. The residue was washed with copious amounts of EtOAc, dry MeOH and dry MeCN which was filtered through a hydrophobic frit and the solvent removed in vacuo to give the title compound as a white solid (13.1 g, 95%). 1H NMR (DMSO-d6, 400 MHz) δ 9.58 (s, 1H), 7.70-7.62 (m, 2H), 7.34 (d, J=8.1 Hz, 2H), 5.79 (s, 2H), 5.23 (t, J=5.6 Hz, 1H), 4.54 (d, J=5.6 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[N:19]3[CH2:20][CH2:21][CH2:22][CH:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:18]3=[N:17][N:16]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][C:12]([CH3:14])=[N:11][CH:10]=1.[H-].[Na+].[Cl:31]N1C(=O)CCC1=O.[Cl-].[NH4+]>CN(C=O)C.C(OCC)(=O)C>[Cl:31][C:23]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:22][CH2:21][CH2:20][N:19]2[C:15]([C:5]3[CH:6]=[CH:7][C:8]([C:9]4[O:13][C:12]([CH3:14])=[N:11][CH:10]=4)=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:16][N:17]=[C:18]12
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)C1CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(Cl)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Reaction time: 0.33 h
Yield: 68.8 %

Procedure:
Under an argon atmosphere, ethyl 3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (1.00 g) was added to a suspension of sodium hydride (60%, 115 mg) in DMF (10 mL) under ice-cooling. The reaction mixture was stirred for 20 min under ice-cooling, N-chlorosuccinimide (383 mg) was added under ice-cooling, and the mixture was stirred for 20 min under ice-cooling. The reaction mixture was diluted with ethyl acetate, the mixture was poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (750 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]([O:15]C(C)(C)C)=[O:14])[N:10]([C:20](=[O:33])[C@H:21]([CH3:32])[CH2:22][S:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:9]1=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]([OH:15])=[O:14])[N:10]([C:20](=[O:33])[C@H:21]([CH3:32])[CH2:22][S:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:9]1=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](CSC(=O)c1ccccc1)C(=O)N1C(=O)N(Cc2ccccc2)C[C@H]1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](CSC(=O)c1ccccc1)C(=O)N1C(=O)N(Cc2ccccc2)C[C@H]1C(=O)O
Yield: 90.9 %

Procedure:
30 g of tert.-butyl (4S)-1-benzyl-3-[(2S)-3-benzoylthio-2-methylpropionyl]-2-oxo-imidazolidine-4-carboxylate and 120 ml of trifluoroacetic acid are treated in the same manner as described in Example 2-(3). 24.1 g of (4S)-1-benzyl-3-[(2S)-3-benzoylthio-2-methylpropionyl]-2-oxo-imidazolidine-4-carboxylic acid are obtained as colorless crystals. Yield: 90.9% The physico-chemical properties of this product are identical with those of the sample obtained in Example 8-(4).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:17][C:16]3[C:11](=[N:12][CH:13]=[CH:14][C:15]=3[O:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=3[F:28])[CH:10]=2)=[CH:5][CH:4]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>CN(C=O)C>[F:28][C:20]1[CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=[CH:24][C:19]=1[O:18][C:15]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[CH:4][CH:5]=3)[S:17][C:16]=12
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(CCl)cc4)sc23)c(F)c1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(CN5CCOCC5)cc4)sc23)c(F)c1
Temperature: 60 °C
Yield: 94.4 %

Procedure:
To a suspension of 52 (823 mg, 1.82 mmol) in DMF (10 ml) was added morpholine (317 mg, 3.65 mmol) and the reaction mixture was heated for 4 hours at 60° C., the solvent was removed under reduced pressure and the residual solid was triturated with EtOAc and collected by filtration. It was further washed with EtOAc until no color was observed in the filtrate, to form the title compound 53 (800 mg, 94% yield), which was used without additional purification 1HNMR (DMSO) δ (ppm): 8.57 (d, J=4.7 Hz, 1H), 8.46 (dd, J=2.7 and 10.4 Hz, 1H), 8.18 (m, 1H), 8.07 (s, 1H), 7.83 (d, J=12.2 Hz, 1H), 7.71 (t, J=8.02 Hz, 1H), 7.42 (d, J=8.2 Hz, 1H), 6.91 (d, J=5.3 Hz, 1H), 3.56 (m, 4H), 3.51 (m, 2H), 3.33 (m, 2H), 2.50 (m, 2H).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])=[CH:3][CH:2]=1.[NH:16]1[CH2:21][CH2:20][CH:19]([O:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:18][CH2:17]1.CN1CCOCC1>ClCCl>[C:27]([O:26][C:24]([CH2:23][O:22][CH:19]1[CH2:18][CH2:17][N:16]([C:13]([CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:7][C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)=[O:15])[CH2:21][CH2:20]1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)COC1CCNCC1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)COC1CCN(C(=O)CNC(=O)OCc2ccccc2)CC1
Yield: 88.7 %

Procedure:
5.8 g of Z-glycine are first activated with 5.4 g of CDMT and then coupled with 6.0 g of t-butyl 4-piperidinyloxyacetate and 6.3 ml of N-methylmorpholine in dichloromethane there are obtained 10 g of benzyl [[[4-[(t-butoxycarbonyl)methoxy]piperidinyl]carbonyl]methyl]carbamate. MS (EI): 406 (M+).
Reaction SMILES: [CH:1]1([S:4]([N:7]2[CH2:17][CH2:16][C:10]3([C:14](=[O:15])[NH:13][CH2:12][CH2:11]3)[CH2:9][CH2:8]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[F:18][C:19]([F:30])([F:29])[CH:20]([C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1)[OH:21]>>[CH:1]1([S:4]([N:7]2[CH2:17][CH2:16][C:10]3([C:14](=[O:15])[N:13]([C:25]4[CH:26]=[CH:27][C:22]([CH:20]([OH:21])[C:19]([F:29])([F:30])[F:18])=[CH:23][CH:24]=4)[CH2:12][CH2:11]3)[CH2:9][CH2:8]2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: OC(c1ccc(I)cc1)C(F)(F)F
Reactant: O=C1NCCC12CCN(S(=O)(=O)C1CC1)CC2
Product: O=C1N(c2ccc(C(O)C(F)(F)F)cc2)CCC12CCN(S(=O)(=O)C1CC1)CC2

Procedure:
This material was prepared In analogy to example 162 step B) from 8-(cyclopropylsulfonyl)-2,8-diazaspiro[4.5]decan-1-one and 2,2,2-trifluoro-1-(4-iodo-phenyl)-ethanol. White solid. MS (ESI): 433.14 MH+).
Reaction SMILES: [O:1]1[CH2:17][CH:2]1[CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH2:11][N:10]([CH:15]=[O:16])[CH2:9][CH2:8]2.[CH:18]([NH2:21])([CH3:20])[CH3:19]>C(O)(C)C>[CH:15]([N:10]1[CH2:9][CH2:8][C:7]2[C:12](=[CH:13][CH:14]=[C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:17][NH:21][CH:18]([CH3:20])[CH3:19])[CH:6]=2)[CH2:11]1)=[O:16]
Reactant: CC(C)N
Reactant: O=CN1CCc2cc(OCC3CO3)ccc2C1
Solvent: CC(C)O
Product: CC(C)NCC(O)COc1ccc2c(c1)CCN(C=O)C2

Procedure:
23.3 g. of 6-(2,3-epoxy-propoxy)-2-formyl-1,2,3,4-tetrahydroisoquinoline are held at the boiling point under reflux with 59.1 g of isopropylamine in 100 ml of isopropanol for 5 hours. The mixture is evaporated and the residue is rubbed with 150 ml of diethyl ether. 27.5 g of 2-formyl-1,2,3,4-tetrahydro-6-(2-hydroxy-3-isopropylamino-propoxy)-isoquinoline are obtained. m.p. = 56.6° - 58° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH3:10])[CH:5]=[C:4]([F:11])[C:3]=1[OH:12].[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([F:22])[CH:21]=1)[CH2:17]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O.C1COCC1>[F:13][C:14]1[CH:15]=[C:16]([CH2:17][O:12][C:3]2[C:2]([F:1])=[CH:7][C:6]([CH2:8][CH2:9][CH3:10])=[CH:5][C:4]=2[F:11])[CH:19]=[C:20]([F:22])[CH:21]=1
Reactant: OCc1cc(F)cc(F)c1
Reactant: CCCc1cc(F)c(O)c(F)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCc1cc(F)c(OCc2cc(F)cc(F)c2)c(F)c1
Temperature: -10 °C
Reaction time: 3 h

Procedure:
Into THF (85 mL), 2,6-difluoro-4-propylphenol obtained in (1-2) in Example 1 (17.2 g), 3,5-difluorobenzyl alcohol (17.2 g), triphenylphosphine (28.9 g) were dissolved, and the product was cooled to −10° C. DIAD (21.2 g) was added thereto at a rate which did not allow the internal temperature to exceed 15° C., and the product was stirred for 3 hours at room temperature. Then, 5 mL of water was added thereto, the solvent was distilled off under reduced pressure, hexane (300 mL) was added thereto, and the product was stirred. The precipitate was removed by filtration, the filtrate was washed with an aqueous solution of 50% methanol (200 mL) and a saturated salt solution in sequence, and sodium sulfate was added thereto for dehydration. The solvent was distilled off under reduced pressure, and the product was purified by silica gel column chromatography, thereby yielding a slightly yellow liquid that what 1,3-difluoro-5-[(2,6-difluoro-4-propylphenyloxy)methyl]benzene (19.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:12][C:13]1[N:14]=[CH:15][C:16]2[C:21]([C:22]([C:24]3[CH:25]=[N:26][CH:27]=[C:28]([NH2:30])[CH:29]=3)=[O:23])=[CH:20][N:19]([CH:31]([CH3:34])[CH2:32][OH:33])[C:17]=2[N:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[NH2:12][C:13]1[N:14]=[CH:15][C:16]2[C:21]([C:22]([C:24]3[CH:29]=[C:28]([NH:30][C:9](=[O:11])[CH2:8][C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH:27]=[N:26][CH:25]=3)=[O:23])=[CH:20][N:19]([CH:31]([CH3:34])[CH2:32][OH:33])[C:17]=2[N:18]=1
Reactant: CC(CO)n1cc(C(=O)c2cncc(N)c2)c2cnc(N)nc21
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: c1ccncc1
Product: CC(CO)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cc3)c2)c2cnc(N)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 48 %

Procedure:
4-Chlorophenylacetic acid (25 mg, 0.14 mmol) was added to [2-amino-7-(2-hydroxy-1-methylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl](5-aminopyridin-3-yl)methanone (50 mg, 0.16 mmol) (see Preparation 57) and HATU (91 mg, 0.24 mmol) in pyridine (2 mL). The mixture was stirred at room temperature for 16 hours. Saturated aqueous sodium bicarbonate (5 mL) was added then extracted with ethyl acetate (3×5 mL). The combined organic phases were washed with brine (5 mL) then dried over sodium sulfate and evaporated in vacuo. The residue was purified by preparative TLC (95:5 DCM:MeOH) to afford the title compound as a yellow solid in 48% yield, 32 mg.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH:24]([NH:26][CH2:27][C@@H:28]([C:30]2[CH:31]=[C:32]([OH:36])[CH:33]=[CH:34][CH:35]=2)[OH:29])[CH3:25])=[CH:17][CH:16]=1.I.[NH2:38][C:39]1[C:40]([C:47]([NH:49][C:50](=[NH:53])SC)=[O:48])=[N:41][C:42]([Cl:46])=[C:43]([NH2:45])[N:44]=1>C(O)C>[NH2:38][C:39]1[C:40]([C:47]([NH:49][C:50](=[NH:53])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][CH:24]([NH:26][CH2:27][C@H:28]([OH:29])[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=3)[CH3:25])=[CH:19][CH:20]=2)=[O:48])=[N:41][C:42]([Cl:46])=[C:43]([NH2:45])[N:44]=1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: CC(CCCc1ccc(CCCCN)cc1)NC[C@H](O)c1cccc(O)c1
Agent: I
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(CCCc1ccc(CCCCNC(=N)NC(=O)c2nc(Cl)c(N)nc2N)cc1)NC[C@H](O)c1cccc(O)c1
Temperature: 75 °C
Reaction time: 4.5 h
Yield: 30.4 %

Procedure:
Diisopropylethylamine (0.45 mL, 2.58 mmol) was added to a mixture of amino alcohol 142 (0.63 g, 1.69 mmol) and 1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methylisothiourea hydriodide (0.66 g, 2.58 mmol) in absolute ethanol (10 mL). The mixture was stirred at 75° C. (oil bath) for 4.5 h. After this time the mixture was cooled to rt and the solvent was removed by rotary evaporation. Purification by column chromatography (silica gel, a gradient of 5:95 to 10:90 methanol/dichloromethane, followed by a gradient of 5:95 to 10:90 (10% concentrated aqueous ammonium hydroxide/methanol)/dichloromethane) and subsequent drying in a 40° C. vacuum oven for 88 h afforded the phenol derivative 143 (0.30 g, 30% yield) as a yellow solid: mp 82-86° C.; 1H NMR (500 MHz, DMSO-d6) δ 0.93 (dd, 3H, J=6.0, 3.5 Hz), 1.21-1.28 (m, 1H), 1.32-1.40 (m, 1H), 1.49-1.60 (m, 6H), 1.75 (s, 1H), 2.49-2.66 (m, 5H), 3.11-3.19 (m, 2H), 4.44-4.48 (m, 1H), 5.17 (br s, 1H), 6.59-6.72 (m, 6H), 7.06-7.11 (m, 5H), 9.09 (br s, 1H); m/z (ESI) 583 [C29H39ClN8O3+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1.[I:9]N1C(=O)CCC1=O>CC(O)=O>[I:9][C:7]1[C:3]([O:2][CH3:1])=[N:4][O:5][C:6]=1[CH3:8]
Reactant: O=C1CCC(=O)N1I
Reactant: COc1cc(C)on1
Solvent: CC(=O)O
Product: COc1noc(C)c1I
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 3-Methoxy-5-methyl-isoxazole (0.60 g, 5.0 mmol) in AcOH (15 mL) is added N-iodosuccinimide (1.10 g, 5.00 mmol) at 60° C. under nitrogen. Then the reaction mixture is stirred at 60° C. for 2 h. The mixture is concentrated in vacuo to give an oil. This oil is purified by column chromatography on silica gel to give the desired compound.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([F:11])=[CH:6][N:5]=1.BrCC1CCCCO1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]2([C:40]3[C:31](=[CH:32][C:33]4[O:38][CH2:37][CH2:36][O:35][C:34]=4[CH:39]=3)[O:30][CH2:29]2)[C:21]1=[O:41]>>[F:10][C:9]1[C:4]([CH2:3][N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]3([C:40]4[C:31](=[CH:32][C:33]5[O:38][CH2:37][CH2:36][O:35][C:34]=5[CH:39]=4)[O:30][CH2:29]3)[C:21]2=[O:41])=[N:5][CH:6]=[C:7]([F:11])[CH:8]=1
Reactant: Fc1cnc(CCl)c(F)c1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: BrCC1CCCCO1
Agent: Cl
Product: O=C1N(Cc2ncc(F)cc2F)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(chloromethyl)-3,5-difluoropyridine hydrochloride to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-[(3,5-difluoropyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (64%) as a colorless solid: mp 220-222° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.27 (d, J=1.7 Hz, 1H), 7.26-7.11 (m, 3H), 7.04-6.96 (m, 1H), 6.77 (d, J=7.7 Hz, 1H), 6.49-6.46 (m, 1H), 6.39-6.36 (m, 1H), 5.27 (d, J=16.1 Hz, 1H), 5.00 (d, J=16.1 Hz, 1H), 4.95-4.90 (m, 1H), 4.68-4.63 (m, 1H), 4.20-4.06 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.5, 159.7, 156.2, 155.3, 144.6, 142.0, 139.0, 138.9, 138.3, 133.8, 133.6, 132.5, 123.9, 123.4, 121.2, 112.0, 111.6, 108.9, 99.2, 80.1, 64.5, 63.9, 58.1, 40.3; MS (ES+) m/z 422.8 (M+1).
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[CH2:15]([O:17][C:18](=[O:44])[CH2:19][O:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C:28](=O)[NH:29][CH2:30][C:31]1[S:32][C:33]2[C:39]([F:40])=[CH:38][C:37]([F:41])=[C:36]([F:42])[C:34]=2[N:35]=1)[CH3:16]>N1C=CC=CC=1.O.C(OCC)(=O)C>[CH2:15]([O:17][C:18](=[O:44])[CH2:19][O:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C:28](=[S:2])[NH:29][CH2:30][C:31]1[S:32][C:33]2[C:39]([F:40])=[CH:38][C:37]([F:41])=[C:36]([F:42])[C:34]=2[N:35]=1)[CH3:16]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCOC(=O)COc1cc(F)ccc1C(=O)NCc1nc2c(F)c(F)cc(F)c2s1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)COc1cc(F)ccc1C(=S)NCc1nc2c(F)c(F)cc(F)c2s1
Temperature: 115 °C
Yield: 68.2 %

Procedure:
In a flame dried flask under a nitrogen atmosphere, a suspension of phosphorus pentasulfide (2.9 g, 6.4 mmol) in pyridine (26 mL) was treated with {5-Fluoro-2[(4,5,7-trifluoro-benzothiazol-2-ylmethyl)carbamoyl]-phenoxy}-acetic acid ethyl ester (Example 54, 5.7 g, 13 mmol) and heated to 115° C. for 4 h. After cooling to room temperature, the mixture was diluted with water and ethyl acetate. The organic layer was washed successively with 2 N HCl (2×) and saturated NaCl, dried over MgSO4, and concentrated. The resulting brown oil was chromatographed by MPLC (10-100% ethyl acetate in heptane, 23 mL/min, 75 min) to give {5-fluoro-2-[(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-thiocarbamoyl]-phenoxy}-acetic acid ethyl ester (2.0 g, 34%): 1H NMR (DMSO-d6 300 MHz) δ 10.98 (br s, 1H), 7.79 (br t, J=6.0 Hz, 2H), 7.06 (br d, J=11.1 Hz, 1H), 6.90 (br t, J=9 Hz, 1H), 5.38 (br s, 2H), 4.89 (s, 2H), 4.12 (q, J=7.2 Hz, 2H), 1.16 (t, J=7.1 3H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5](=[CH2:8])[C:6]#[N:7])[CH3:3].[C:9]1([NH:15][NH2:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[O-]CC.[Na+].O=O.S(=O)(=O)(O)O>C(O)C>[CH3:1][N:2]([CH2:4][CH:5]1[CH2:8][N:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:16][C:6]1=[NH:7])[CH3:3]
Reactant: NNc1ccccc1
Reactant: C=C(C#N)CN(C)C
Agent: CC[O-]
Agent: O=O
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CN(C)CC1CN(c2ccccc2)NC1=N
Yield: 81.7 %

Procedure:
2-Dimethylaminomethylacrylonitrile (11.0g) was added in one portion to a solution of phenylhydrazine (10.8g) and sodium ethoxide (2.3g sodium) in ethanol (100 ml). The product was rapidly oxidised in alkaline solution to a deep purple material; contact with oxygen was prevented by vigorous boiling of the solvent during 11/2 hours reflux. After cooling, the sodium ethoxide was neutralised with sulphuric acid (50 ml 2N) and the mixture was extracted with chloroform (3 × 100 ml). Evaporation of the solvent gave a brown solid (17.8g) which was recrystallised from petroleum ether (boiling point 80°-100° C; 300 ml) to yield colourless plates (16.4g, 75%, melting point 117°-8° C).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:4]([OH:5])[C:3]=1[OH:11].Br[CH2:13]Br.[F-].[K+].O>CN(C=O)C>[Br:1][C:2]1[C:3]2[O:11][CH2:13][O:5][C:4]=2[C:6]([O:9][CH3:10])=[CH:7][CH:8]=1
Reactant: BrCBr
Reactant: COc1ccc(Br)c(O)c1O
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Br)c2c1OCO2
Temperature: 110 °C

Procedure:
3-Bromo-6-methoxycatechol (23.4 g) was dissolved in DMF (150 ml), and dibromomethane (15.4 ml) and potassium fluoride (31.1 g) were added thereto, followed by heating at 110° C. for 6 hours with stirring. After being allowed to stand for cooling, water was added to the mixture followed by extraction with ether. The organic layer was washed with an aqueous solution of sodium hydroxide, with water, and with a saturated saline, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/1) to give Compound IIbj-a (5.6 g, 40%) as a white solid.