Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:36])=[C:5]([C:20]([O:22][CH2:23][CH2:24][N:25]2C(=O)C3=CC=CC=C3C2=O)=[O:21])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])[C:7]=1[C:8]([O:10][CH3:11])=[O:9].O.NN>C(OC)(C)(C)C>[CH3:1][C:2]1[NH:3][C:4]([CH3:36])=[C:5]([C:20]([O:22][CH2:23][CH2:24][NH2:25])=[O:21])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2C(=O)c3ccccc3C2=O)C1c1cccc(Cl)c1Cl
Agent: NN
Solvent: COC(C)(C)C
Solvent: O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN)C1c1cccc(Cl)c1Cl
Yield: 50.8 %

Procedure:
Prepared by a method analogous to that of Example 1(b) from 10.0 g (19 mmol) of 1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(2,3-dichlorophenyl)-5-(2-phthalimidoethoxy)carbonyl-pyridine and 2.84 ml (57 mmol) of hydrazine hydrate. 3.85 g (51%) of pale yellow crystals melting at 166°-167° C. obtained from tert.-butylmethyl ether.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[C:5]([CH3:7])[N:6]=1.[C:15](#[N:17])[CH3:16]>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:4]2[O:3][C:2]([NH:17][C:15]3[CH:13]=[CH:12][CH:11]=[C:10]4[C:16]=3[CH2:5][CH:4]([OH:3])[CH2:8][CH2:9]4)=[N:6][C:5]=2[CH3:7])=[CH:9][CH:10]=1
Reactant: CC#N
Reactant: Cc1nc(Cl)oc1-c1ccc(Cl)cc1
Product: Cc1nc(Nc2cccc3c2CC(O)CC3)oc1-c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 17 %

Procedure:
A mixture of Example 13D (540 mg, 2.37 mmol) and Example 1A (657 mg, 2.37 mmol) in acetonitrile (6 mL) was heated in a microwave reactor at 150° C. for 20 minutes. The reaction was cooled and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (20 mL) and 10 mL 6N HCl and the mixture was stirred several hours at ambient temperature. The mixture was then diluted with ethyl acetate, and the organic phase was washed with water, brine, dried over Na2SO4, filtered, and evaporated. The crude product was chromatographed on silica gel using methanol/CH2Cl2 as eluent (2% to 20%) that gave a solid that was further purified by trituration to afford 143 mg (17% yield) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.05 (s, 1H) 7.56 (d, J=7.12 Hz, 1H), 7.48 (s, 4H), 7.10 (t, J=7.80 Hz, 1H), 6.84 (d, J=7.12 Hz, 1H), 4.79 (d, J=3.73 Hz, 1H), 3.92 (bs, 1H), 2.97 (m, 2H), 2.68 (m, 1H), 2.26 (s, 3H), 1.87 (bs, 1H), 1.61 (bs, 1H). MS (ESI+) m/z 354 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=[O:6].CO>O1CCCC1>[F:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([CH2:5][OH:6])[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: COc1c(F)cc(F)cc1C=O
Solvent: CO
Solvent: C1CCOC1
Product: COc1c(F)cc(F)cc1CO
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.6 %

Procedure:
To an ice-cold solution of 1.7 g (9.03 mmol) of 3,5-difluoro-2-methoxy-benzaldehyde in 10 ml of dry tetrahydrofuran was added under an argon atmosphere 1 ml of borane dimethylsulfide complex. The reaction mixture was warmed up and stirred for 24 hours at room temperature. Thereupon, the mixture was again cooled to 0° C. and 5 ml of methanol were added dropwise within 30 minutes. Subsequently, the solvent was distilled and the crude product was purified by chromatography on silica gel with a 1:1 mixture of diethylether and dichloromethane as the eluent. There were obtained 0.89 g (56% of theory) of (3,5-difluoro-2-methoxy-phenyl)-methanol as a colorless liquid; MS: 174 (M)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[NH:7]1[CH:11]=[CH:10][C:9]([C:12]([OH:14])=O)=[CH:8]1.[NH:15]1[CH2:18][CH2:17][CH2:16]1>CN(C)C=O.ClCCl>[N:15]1([C:12]([C:9]2[CH:10]=[CH:11][NH:7][CH:8]=2)=[O:14])[CH2:18][CH2:17][CH2:16]1
Reactant: O=C(O)c1cc[nH]c1
Reactant: C1CNC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(c1cc[nH]c1)N1CCC1
Temperature: 2.5 °C
Reaction time: 15 h
Yield: 39.3 %

Procedure:
Oxalyl chloride (0.13 mL, 1.5 mmol) was added to a mixture of 1H-pyrrole-3-carboxylic acid (0.111 g, 1.00 mmol) and 1 drop of N,N-dimethylformamide in 5 mL of dichloromethane. The mixture was stirred for 15 h, then concentrated, then redissolved in 5 mL of dichloromethane and cooled to 0-5° C. Azetidine (0.21 mL, 2.5 mmol) was added, and the mixture was stirred for 1 h at 0-5° C. then absorbed onto silica gel and concentrated. Column chromatography (2->10% MeOH/CH2Cl2) afforded 0.059 g (39%) of azetidin-1-yl-(1H-pyrrol-3-yl)-methanone as an off-white solid.
Reaction SMILES: Cl.[P:2]([C:6]1[C:7]([C:12]([OH:14])=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1)([OH:5])([OH:4])=[O:3]>O=[Pt]=O.C(O)(=O)C>[P:2]([CH:6]1[CH2:11][CH2:10][CH2:9][NH:8][CH:7]1[C:12]([OH:14])=[O:13])([OH:4])([OH:5])=[O:3]
Reactant: O=C(O)c1ncccc1P(=O)(O)O
Agent: O=[Pt]=O
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)C1NCCCC1P(=O)(O)O

Procedure:
A mixture of 348 g mg of 3-phosphonopyridine-2-carboxylic acid hydrochloride and 100 mg of Adams catalyst in dilute aqueous acetic acid is hydrogenated at 3 atmospheres pressure and room temperature to yield 3-phosphonopiperidine-2-carboxylic acid, mp 150° dec.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH3:34][O:35][C:36]1[CH:42]=[C:41]([N:43]2[CH2:48][CH2:47][CH:46]([N:49]3[CH2:54][CH2:53][N:52]([CH2:55][CH2:56][S:57]([CH3:60])(=[O:59])=[O:58])[CH2:51][CH2:50]3)[CH2:45][CH2:44]2)[CH:40]=[CH:39][C:37]=1[NH2:38].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:38][C:37]3[CH:39]=[CH:40][C:41]([N:43]4[CH2:44][CH2:45][CH:46]([N:49]5[CH2:50][CH2:51][N:52]([CH2:55][CH2:56][S:57]([CH3:60])(=[O:59])=[O:58])[CH2:53][CH2:54]5)[CH2:47][CH2:48]4)=[CH:42][C:36]=3[O:35][CH3:34])[N:7]=2)[CH:18]=1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Reactant: COc1cc(N2CCC(N3CCN(CCS(C)(=O)=O)CC3)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: COc1cc(N2CCC(N3CCN(CCS(C)(=O)=O)CC3)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 175 °C
Yield: 64 %

Procedure:
A mixture of 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (0.70 g, 1.52 mmol), 2-(methyloxy)-4-(4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}-1-piperidinyl)aniline (0.60 g, 1.52 mmol), p-toluenesulfonic acid (0.69 g, 3.64 mmol) and iPrOH (15 mL) were heated in the microwave at 175° C. for 25 min. LCMS indicated the reaction had proceeded to completion and the reaction mixture was concentrated onto silica gel. Flash chromatography afforded the title compound (0.80 g, 64%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 9.40 (bs, 1H), 8.45 (s, 1H), 8.33-8.31 (m, 1H), 8.19 (d, J=5.5 Hz, 1H), 8.07-8.03 (m, 1H), 7.83-7.79 (m, 1H), 7.74-7.70 (m, 1H), 7.60 (at, J=7.9 Hz, 1H), 7.48-7.35 (m, 3H), 7.24-7.16 (m, 2H), 7.00-6.94 (m, 1H), 6.67 (d, J=2.2 Hz, 1H), 6.50-6.44 (m, 2H), 3.79 (s, 3H), 3.75-3.68 (m, 2H), 3.25 (t, J=6.6 Hz, 2H), 3.01 (s, 3H), 2.70-2.60 (m, 5H), 2.45-2.24 (m, 5H), 1.86-1.79 (m, 2H), 1.55-1.44 (m, 2H). MS (ES+, m/z) 822 (M+1).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][NH:8][C:7]=12.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:17]1([C:21]([NH2:23])=[O:22])[CH2:20][CH2:19]C1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[NH:8]1[C:7]2=[C:2]([NH:23][C:21]([CH:17]3[CH2:20][CH2:19]3)=[O:22])[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9]1
Reactant: NC(=O)C1CCC1
Reactant: Brc1nccc2cc[nH]c12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(Nc1nccc2cc[nH]c12)C1CC1
Temperature: 120 °C
Reaction time: 8 h
Yield: 39.3 %

Procedure:
To a solution of 7-bromo-1H-pyrrolo[2,3-c]pyridine (500 mg, 2.53 mmol) in toluene were added tris (dibenzylidene acetone)dipalladium (116.20 mg, 0.126 mmol), Xantphos (32.98 mg, 0.057 mmol), cesium carbonate (896 mg, 2.75 mmol), and cyclobutanecarboxamide (251 mg, 2.96 mmol, Intermediate 4). The resulting reaction mixture was heated to 120° C. and stirred for 8 hours. After cooling to room temperature a saturated aqueous sodium bicarbonate solution (20 mL) was added to the reaction mixture and extracted with ethyl acetate (3×50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel (100-200) column chromatography to afford N-(1H-pyrrolo[2,3-c]pyridin-7-yl)cyclopropane carboxamide (200 mg, 36% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=O)[CH2:15][C:16]2[N:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:18]=[C:19]3[C:28]=2[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:21]=[C:20]3[Cl:29])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2[N:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:18]=[C:19]3[C:28]=2[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:21]=[C:20]3[Cl:29])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cc1c2c(nn1-c1ccccc1)c(Cl)nc1ccccc12)N1CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Clc1nc2ccccc2c2c(CCN3CCN(Cc4ccccc4)CC3)n(-c3ccccc3)nc12
Temperature: 0 °C
Reaction time: 48 h
Yield: 15.6 %

Procedure:
1-[2-(4-Benzylpiperazin-1-yl)-2-oxoethyl]-4-chloro-2-phenyl-2H-pyrazolo[3,4-c]quinoline (3.05 g, 6.1 mmol) was dissolved in 90 mL of tetrahydrofuran and cooled to 0° C. Lithium aluminum hydride (0.41 g, 10.75 mmol) was added. The mixture was allowed to stir at ambient temperature for 48 hours. A second portion of lithium aluminum hydride (0.17 g, 4.5 mmol) was added, and the mixture was stirred for 24 hours at ambient temperature. 0.6 mL of water, followed by 0.6 mL of 2 N aqueous sodium hydroxide and 1.8 mL of water was added. After stirring at ambient temperature for 30 minutes, the mixture was dried over magnesium sulfate, filtered through a layer of CELITE filter aid, and concentrated under reduced pressure. The residue was purified by automated flash chromatography eluting with a gradient of 4-18% CMA in chloroform, followed by automated flash chromatography eluting with a gradient of 10-67% ethyl acetate in hexanes to provide 0.46 g of 1-[2-(4-benzylpiperazin-1-yl)ethyl]-4-chloro-2-phenyl-2H-pyrazolo[3,4-c]quinoline as a yellow solid, mp 75-77° C. MS (ESI) m/z 482 (M+H)+; Anal. calcd for C29H28ClN5: C, 72.26; H, 5.85; N, 14.53. Found: C, 72.00; H, 5.67; N, 14.37.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][C@H:8]([CH3:11])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].[Cl-].[NH4+]>ClCCl>[C:1]([O:5][C:6]([NH:7][C@H:8]([CH3:11])[CH2:9][O:10][S:23]([CH3:22])(=[O:25])=[O:24])=[O:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 101.1 %

Procedure:
((R)-2-Hydroxy-1-methyl-ethyl)-carbamic acid tert-butyl ester (0.5 g, 2.85 mmol) was dissolved in dichloromethane (14 ml) and stirred in an ice bath. N,N-diisopropylethylamine (0.75 ml, 4.28 mmol) and then methanesulfonyl chloride (0.27 ml, 3.4 mmol) were slowly added and the reaction was warmed to room temperature over 16 h. Ammonium chloride solution was added to the reaction and it was extracted two times with ethyl acetate. The combined organics were washed with sodium chloride solution and dried over sodium sulfate. Evaporation gave 0.73 g of methanesulfonic acid (R)-2-tert-butoxycarbonylamino-propyl ester as a waxy white solid. 1H NMR (CDCl3) δ: 4.51-4.68 (m, 1H), 4.19-4.28 (m, 1H), 4.11-4.18 (m, 1H), 3.90-4.04 (m, 1H), 3.03 (s, 3H), 1.24 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([O:23][CH3:24])=[CH:6][C:7]2[O:12][C:11](=[O:13])[C:10]([CH2:14][CH2:15]OS(C)(=O)=O)=[C:9]([CH3:21])[C:8]=2[CH:22]=1)[CH3:2].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>C(O)C.C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]1[C:5]([O:23][CH3:24])=[CH:6][C:7]2[O:12][C:11](=[O:13])[C:10]([CH2:14][CH2:15][N:36]3[CH2:35][CH2:34][N:33]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[O:26][CH3:25])[CH2:38][CH2:37]3)=[C:9]([CH3:21])[C:8]=2[CH:22]=1)[CH3:2]
Reactant: COc1ccccc1N1CCNCC1
Reactant: CCOc1cc2c(C)c(CCOS(C)(=O)=O)c(=O)oc2cc1OC
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCOc1cc2c(C)c(CCN3CCN(c4ccccc4OC)CC3)c(=O)oc2cc1OC
Yield: 54 %

Procedure:
Process A; starting materials: 6-ethoxy-3-[2-(methanesulphonyloxy)ethyl]-7-methoxy-4-methyl-2H-1-benzopyran-2-one (Example 29) and 1-(2-methoxyphenyl)piperazine; yield 54%; m.p. 143°-145° C. (from ethanol/chloroform).
Reaction SMILES: CN(C)CCCOC1C=CC(C2S[C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=NC=2)=CC=1.[S:26]1[CH:30]=[CH:29][C:28]([C:31]2[S:35][C:34]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=3)=[N:33][CH:32]=2)=[CH:27]1.Cl.ClCCC1CCCN1C>>[CH3:16][N:18]1[CH2:22][CH2:23][CH2:24][CH:19]1[CH2:20][CH2:21][O:43][C:40]1[CH:41]=[CH:42][C:37]([NH:36][C:34]2[S:35][C:31]([C:28]3[CH:29]=[CH:30][S:26][CH:27]=3)=[CH:32][N:33]=2)=[CH:38][CH:39]=1
Reactant: Oc1ccc(Nc2ncc(-c3ccsc3)s2)cc1
Reactant: CN(C)CCCOc1ccc(-c2cnc(Nc3ccccc3)s2)cc1
Agent: CN1CCCC1CCCl
Agent: Cl
Product: CN1CCCC1CCOc1ccc(Nc2ncc(-c3ccsc3)s2)cc1

Procedure:
The title compound is prepared as described in Example 8 for {5-[4-(3-dimethylamino-propoxy)-phenyl]-thiazol-2-yl}-phenyl-amine but starting from 4-(5-thiophen-3-yl-thiazol-2-yl-amino)-phenol (Example 12) and using 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride. MPLC (CH3CN/H2O/TFA) purification affords the title compound: ES-MS: 386.0 [M+H]+; single peak at tR=3.09 min (System 2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]3[NH:25][C:24](=[O:26])[O:23][C:22]([CH2:29][CH3:30])([CH2:27][CH3:28])[C:21]=3[CH:31]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH:32]O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]3[NH:25][C:24](=[O:26])[O:23][C:22]([CH2:27][CH3:28])([CH2:29][CH3:30])[C:21]=3[CH:31]=2)=[O:32])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCC1(CC)OC(=O)Nc2ccc(OCCCCSc3ccc(OC)c(OC)c3)cc21
Reactant: OO
Product: CCC1(CC)OC(=O)Nc2ccc(OCCCCS(=O)c3ccc(OC)c(OC)c3)cc21

Procedure:
Prepared analogously to Example 2 from 6-[4-(3,4-dimethoxy-phenylmercapto)-butoxy]-4,4-diethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: S[C:2]1[NH:6][C:5]2[CH:7]=[C:8]3[C:12](=[CH:13][C:4]=2[N:3]=1)[C:11]([CH3:15])([CH3:14])[C:10](=[O:16])[C:9]3([CH3:18])[CH3:17].Cl.ClCC1C(C)=C(OC)C(C)=CN=1.[OH-].[Na+]>O>[CH3:14][C:11]1([CH3:15])[C:12]2[C:8](=[CH:7][C:5]3[NH:6][CH:2]=[N:3][C:4]=3[CH:13]=2)[C:9]([CH3:18])([CH3:17])[C:10]1=[O:16]
Reactant: CC1(C)C(=O)C(C)(C)c2cc3[nH]c(S)nc3cc21
Agent: COc1c(C)cnc(CCl)c1C
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC1(C)C(=O)C(C)(C)c2cc3[nH]cnc3cc21

Procedure:
18.0 g (69.2 mmol) of 5,7-dihydro-2 -mercapto-5,5,7,7-tetramethylindeno[5,6-d]imidazol-6(1H)-one are suspended in 400 ml of alcohol and treated with 15.6 g (70.2 mmol) of 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine hydrochloride while cooling with ice. Thereafter, a solution of 5.6 g of sodium hydroxide in 150 ml of water is added dropwise thereto, the mixture is left to boil at reflux overnight and subseguently evaporated to dryness in vacuo. The residue is dissolved in 1000 ml of methylene chloride; the solution is washed firstly with 500 ml of 1.5N sodium hydroxide solution and then with 3×500 ml of water, dried over sodium sulphate and evaporated in vacuo. The crude product is purified on 300 g of silica gel with ethyl acetate/methylene chloride (1:1) as the elution agent. Crystallization from methylene chloride/petroleum ether gives 5,7-dihydro-2-[[(4-methoxy-3,5 -dimethyl-2ether -pyridyl)methyl]thio]-5,5,7,7 -tetramethylindeno[5,6-d)-imidazol-6(1H)-one of melting point 166°-168°.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1([F:44])[CH2:31][NH:30][CH2:29][C:28]2([CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]2)[O:27]1.[CH3:45][C:46]1[S:50][C:49]([C:51](O)=[O:52])=[CH:48][CH:47]=1.C(N(CC)CC)C>CN(C=O)C>[F:44][C:26]1([F:25])[CH2:31][N:30]([C:51]([C:49]2[S:50][C:46]([CH3:45])=[CH:47][CH:48]=2)=[O:52])[CH2:29][C:28]2([CH2:32][CH2:33][N:34]([C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])[CH2:35][CH2:36]2)[O:27]1
Reactant: Cc1ccc(C(=O)O)s1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCC(F)(F)O2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)N2CC(F)(F)OC3(CCN(C(=O)OC(C)(C)C)CC3)C2)s1
Temperature: 20 °C
Reaction time: 7 h

Procedure:
HATU (0.541 g) was added in one portion to a stirred solution at 0° C. of tert-butyl 2,2-difluoro-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (example 37, step c) (0.32 g) and 5-methylthiophene-2-carboxylic acid (0.171 g) and triethylamine (0.458 mL) in DMF (20 mL). The mixture was then stirred at 20° C. for 7 hours. The mixture was partitioned between ethyl acetate and brine, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography, elution gradient 0.5 to 5% methanol in dichloromethane. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.4 g.
Reaction SMILES: C1(C2OC3=C(N)N=CC=C3C=2)C=CC=CC=1.[I:17][C:18]1[CH:23]=[N:22][C:21]([NH2:24])=[C:20]2[O:25][C:26]([C:28]3[CH:37]=[CH:36][CH:35]=[C:34]4[C:29]=3C=CN=C4)=[CH:27][C:19]=12>>[I:17][C:18]1[CH:23]=[N:22][C:21]([NH2:24])=[C:20]2[O:25][C:26]([C:28]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:29]=3)=[CH:27][C:19]=12
Reactant: Nc1ncc(I)c2cc(-c3cccc4cnccc34)oc12
Agent: Nc1nccc2cc(-c3ccccc3)oc12
Product: Nc1ncc(I)c2cc(-c3ccccc3)oc12
Yield: 65 %

Procedure:
The title compound was prepared in 65% yield from 2-phenylfuro[2,3-c]pyridin-7-amine by a procedure analogous to Intermediate 10, Step B. 1H NMR (300 MHz, CDCl3): δ ppm 4.84 (brs, 2H), 6.87 (s, 1H), 7.40-7.55 (m, 3H), 7.85-7.88 (m, 2H), 8.08 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([OH:20])=O)=[C:13]([C:15](=[O:17])[NH2:16])[N:14]=[C:7]3[C:6]=2[CH:21]=1.Cl.[CH3:23][NH2:24]>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:24][CH3:23])=[O:20])=[C:13]([C:15]([NH2:16])=[O:17])[N:14]=[C:7]3[C:6]=2[CH:21]=1
Reactant: CN
Reactant: NC(=O)c1nc2n(c1C(=O)O)CCOc1ccc(Br)cc1-2
Agent: Cl
Solvent: O
Product: CNC(=O)c1c(C(N)=O)nc2n1CCOc1ccc(Br)cc1-2

Procedure:
10-Bromo-3-iodo-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide (5 g) was subjected similar to as described in Example 6 to yield 4.2 g of methyl 10-bromo-2-carbamoyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylate. Methyl 10-bromo-2-carbamoyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylate (0.52 g) was subjected to lithium hydroxide water/THF to give 0.44 g of 10-bromo-2-carbamoyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylic acid. 10-bromo-2-carbamoyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylic acid (0.44 g) was reacted with Methylamine hydrochloride similar to as described in Example 2 to afford 314 mg 10-bromo-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following triteration from water. 10-bromo-9-fluoro-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide (0.1 g) was then reacted with (2R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol similar to as described in Procedure G to afford 43.9 mg of 10-[(3R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl]-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following reverse phase hplc purification. MS (Q1) 436 (M)+. 1H NMR (400 MHz, DMSO) δ 11.06 (q, J=4.3 Hz, 1H), 8.55 (d, J=2.0 Hz, 1H), 8.33 (s, 1H), 7.88 (s, 1H), 7.40 (dd, J=8.5, 2.0 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H), 6.47 (s, 1H), 6.36 (s, 1H), 5.04-4.91 (m, 2H), 4.57-4.44 (m, 2H), 2.81 (d, J=4.5 Hz, 3H), 2.41 (s, 3H), 1.81 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[N:10](COCC[Si](C)(C)C)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]21[CH2:26][C:25]1[C:20](=[CH:21][CH:22]=[C:23]([C:27]([O:29][CH3:30])=[O:28])[CH:24]=1)[CH2:19]2.C(C(O)=O)(F)(F)F.C(N)CN>C(Cl)Cl.C([O-])(O)=O.[Na+]>[O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]21[CH2:26][C:25]1[C:20](=[CH:21][CH:22]=[C:23]([C:27]([O:29][CH3:30])=[O:28])[CH:24]=1)[CH2:19]2
Reactant: COC(=O)c1ccc2c(c1)CC1(C2)C(=O)N(COCC[Si](C)(C)C)c2ncccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (±)-methyl 2′-oxo-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridine]-5-carboxylate (3.65 g, 8.60 mmol) in CH2Cl2 (80 mL) was added CF3CO2H (40 mL, 52 mmol) and the resulting mixture was stirred at ambient temperature for 18 h, then concentrated in vacuo. The residue was dissolved in CH2Cl2 (100 mL) and treated with ethylene diamine (2.3 mL, 34.4 mmol). The reaction mixture was stirred at ambient temperature for 18 h, then diluted with saturated aqueous NaHCO3 (50 mL). The organic layer was removed and the aqueous layer was extracted further with CH2Cl2 (2×100 mL). The combined organic layers were washed with brine (50 mL), then dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with CH2Cl2:MeOH—97:3, to give methyl 2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridine]-5-carboxylate as a tan solid. This solid was dissolved in MeOH (22 mL) and 1 N sodium hydroxide (25.4 mL, 25.4 mmol) was added. The reaction mixture was heated at 60° C. for 18 h then allowed to cool. The mixture was acidified by addition of 6 N HCl, and the resulting precipitate was isolated by filtration, washed with H2O, and dried in vacuo to give the title compound as an off-white solid. MS: m/z=281 (M+1).
Reaction SMILES: C([N:9]1[C:14](=[O:15])[C:13]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([CH3:22])[CH:17]=2)=[CH:12][N:11]([CH2:23][CH2:24][CH2:25][CH2:26][Cl:27])[C:10]1=[O:28])(=O)C1C=CC=CC=1>N.CO>[Cl:27][CH2:26][CH2:25][CH2:24][CH2:23][N:11]1[CH:12]=[C:13]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([CH3:22])[CH:17]=2)[C:14](=[O:15])[NH:9][C:10]1=[O:28]
Reactant: Cc1cc(-c2cn(CCCCCl)c(=O)n(C(=O)c3ccccc3)c2=O)ccn1
Agent: N
Solvent: CO
Product: Cc1cc(-c2cn(CCCCCl)c(=O)[nH]c2=O)ccn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-Benzoyl-1-(4-chloro-butyl)-5-(2-methyl-pyridin-4-yl)-1H-pyrimidine-2,4-dione (Prep 45, 100 mg, 0.25 mmol) was dissolved in a solution of 3% NH3 in MeOH (5 mL). The mixture was stirred at room temperature for 3 hours, the solvent was then evaporated under vacuum to give the title compound that was used in the next step without further purification.