Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17](CCC(O)=O)=[CH:16][CH:15]=3)[C:11]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=3[N:9]=2)=[C:4](OCC2CCCC2)[CH:3]=1.[Br:38]C1C=C(Cl)C=CC=1C1NC2C=C(F)C(F)=CC=2N=1.BrCC1CCCCC1>>[Br:38][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[C:8]1[N:12]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]2[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=2[N:9]=1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3Br)[nH]c2cc1F
Reactant: O=C(O)CCc1ccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)cc1
Agent: BrCC1CCCCC1
Product: Fc1cc2nc(-c3ccc(Cl)cc3Br)n(CC3CCCCC3)c2cc1F

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 2-(2-bromo-4-chloro-phenyl)-5,6-difluoro-1H-benzoimidazole and bromomethyl-cyclohexane (CAS Reg. No. 2550-36-9). Off-white solid (60%). MS (Turbo Spray): m/z=440.2 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][CH:11]=[N:10][C:9]=2[C:13]2[CH:14]=[C:15]([NH:19][S:20]([C:23]3[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=3[F:30])(=[O:22])=[O:21])[CH:16]=[CH:17][CH:18]=2)[CH:5]=[CH:4][N:3]=1>C(N)C(C)C>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[S:20]([NH:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:9]2[N:10]=[CH:11][S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:10][CH2:9][CH:13]([CH3:14])[CH3:18])[N:7]=2)[CH:14]=1)(=[O:22])=[O:21]
Reactant: O=S(=O)(Nc1cccc(-c2ncsc2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Solvent: CC(C)CN
Product: CC(C)CNc1nccc(-c2scnc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)n1
Temperature: 35 °C
Yield: 130 %

Procedure:
N-{3-[5-(2-Chloro-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide (0.1 g, 0.2 mmol) was taken up in 2 mL isobutylamine and heated to 35° C. overnight. The solvent was removed in vacuo and the residue taken up in EtOAc and washed with 2 mL of 0.1N HCl (aq). The organic layer was dried over Na2SO4 and evaporated to afford the title compound (65 mg, 0.130 mmol), 60.2% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.00 (s, 1H), 9.15 (s, 1H), 7.98 (d, J=5.1 Hz, 1H), 7.60-7.69 (m, 1H), 7.37 (t, J=5.9 Hz, 1H), 7.31 (t, J=7.9 Hz, 1H), 7.26 (s, 1H), 7.15-7.24 (m, 4H), 5.93-6.05 (m, 1H), 2.95-3.06 (m, 2H), 0.82 (d, J=6.6 Hz, 6H). MS (ESI): 501 [M+H]+.
Reaction SMILES: [ClH:1].Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[N:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[Cl:15][CH:16]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26](=[O:28])[CH3:27])=[CH:20][CH:19]=1)[CH3:17]>>[ClH:15].[ClH:1].[N:3]1[CH:8]=[CH:7][CH:6]=[N:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26](=[O:28])[CH3:27])=[CH:20][CH:19]=2)[CH3:17])[CH2:11][CH2:10]1
Reactant: CC(=O)NCc1ccc(C(C)Cl)cc1
Reactant: c1cnc(N2CCNCC2)nc1
Agent: Cl
Product: CC(=O)NCc1ccc(C(C)N2CCN(c3ncccn3)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using 1-(2-pyrimidyl) piperazine dihydrochloride instead of phenylpiperazine and N-(4-(1-chloroethyl)phenylmethyl)acetamide instead of N-(4-chloromethylphenylmethyl) acetamide, the title compound was obtained as a yellow amorphous solid.
Reaction SMILES: CS[C:3]1[CH2:4][C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(O)(=O)C>C(Cl)(Cl)Cl>[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:3]2[CH2:4][C:5]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[N:9]=2)[CH2:23][CH2:22]1
Reactant: CN1CCNCC1
Reactant: CSC1=Nc2ccccc2N=C(c2ccccc2)C1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CN1CCN(C2=Nc3ccccc3N=C(c3ccccc3)C2)CC1

Procedure:
A solution of 13.3 parts of 2-methylthio-4-phenyl-3H-1,5-benzodiazepine, 26 parts by volume of 1-methylpiperazine and 1.5 part of glacial acetic acid in 150 parts by volume of chloroform is stirred at reflux temperature overnight. The solvent is then removed under reduced pressure and the residue partititoned between water and benzene. The benzene portion is washed with water and then extracted with 10% acetic acid. The acidic extract is washed with benzene and then made alkaline with concentrated ammonia. The alkaline mixture is extracted with benzene, the benzene extract washed with water and then dried over anhydrous magnesium sulfate. After the solvent is removed a crude yellow solid is obtained. The crude solid is recrystallized from a mixture of chloroform and n-hexane to yield 4-(4-methyl-1-piperazinyl)-2-phenyl-3H-1,5-benzodiazepine, melting at about 155°-157° C. This compound has the following formula ##STR16##
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]1(=O)[CH2:11][CH2:10][CH2:9][CH2:8]1>C1C=CC=CC=1>[C:7]1([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:11][CH2:10][CH2:9][CH:8]=1
Reactant: O=C1CCCC1
Reactant: C1CCNCC1
Solvent: c1ccccc1
Product: C1=C(N2CCCCC2)CCC1
Temperature: 80 °C

Procedure:
Piperidine (4.0 g, 46.98 mmol) was added to a solution of cyclopentanone Compound 1a (4.0 g, 46.50 mmol) in benzene (100 mL) at ambient temperature under a N2 atmosphere. The mixture was refluxed at 80° C. for 5 hrs using a Dean Stark apparatus, then concentrated to dryness to provide 1-cyclopent-1-enyl-piperidine Compound 1b (7.0 g) as a crude oil which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=4)=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:23][OH:24])=[CH:4][CH:3]=1.[C:27](Cl)(=[O:29])[CH3:28]>>[C:27]([O:24][CH2:23][C:8]1[N:7]([CH2:6][C:5]2[CH:25]=[CH:26][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:15]2[C:10]([CH:9]=1)=[CH:11][C:12]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1)=[CH:13][CH:14]=2)(=[O:29])[CH3:28]
Reactant: Cc1ccc(Cn2c(CO)cc3cc(-c4cccc(C)c4)ccc32)cc1
Reactant: CC(=O)Cl
Product: CC(=O)OCc1cc2cc(-c3cccc(C)c3)ccc2n1Cc1ccc(C)cc1

Procedure:
The title compound was prepared from [1-(4-methylbenzyl)-5-(3-methylphenyl)-1H-indol-2-yl)methanol and acetyl chloride in substantially the same manner, as described in step 4 of Example 1. The product was obtained as a brown oil. Mass spectrum (ESI, [M+H]+) m/z 384. 1H NMR (400 MHz, DMSO-d6) δ 7.82 (s, 1H), 7.47 (s, 1H), 7.45-7.40 (m, 3H), 7.31 (t, 1H, J=7.74 Hz), 7.13-7.08 (m, 3H), 6.90 (d, 2H, J=8.09 Hz), 6.68 (s, 1H), 5.43 (s, 2H), 5.22 (s, 2H), 2.36 (s, 3H), 2.23 (s, 3H), and 1.85 ppm (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:6][C:5]2[CH:7]=[C:8]([CH:11]3[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)[CH:9]=[CH:10][C:4]=2[O:3]1.[C:19]([NH:21][C:22]([NH2:24])=[NH:23])#[N:20]>C(OCCOCCO)C>[NH2:24][C:22]1[N:21]=[C:19]([NH2:20])[C:15]2[CH2:16][CH:11]([C:8]3[CH:9]=[CH:10][C:4]4[O:3][C:2]([CH3:18])([CH3:1])[CH2:6][C:5]=4[CH:7]=3)[CH2:12][CH2:13][C:14]=2[N:23]=1
Reactant: N#CNC(=N)N
Reactant: CC1(C)Cc2cc(C3CCC(=O)CC3)ccc2O1
Solvent: CCOCCOCCO
Product: CC1(C)Cc2cc(C3CCc4nc(N)nc(N)c4C3)ccc2O1

Procedure:
This compound is prepared in a manner analogous to that of Example 1, using 3.2 grams (0.013 mole) of 4-(2,3-dihydro-2,2-dimethylbenzofuran-5-yl)-1-cyclohexanone and 1.2 grams (0.014 mole) of cyanoguanidine in 2-(2-ethoxyethoxy)ethanol, yielding 2,4-diamino-6-(2,3-dihydro-2,2-dimethylbenzofuran-5-yl)-5,6,7,8-tetrahydroquinazoline.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11](=[O:24])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:5]=1.[I-].[Li+]>N1C=CC=CC=1>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:11]([NH:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][N:7]=2)[C:3]([OH:25])=[O:2])=[O:24])=[CH:15][CH:16]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: COC(=O)c1ccnc(NC(=O)COc2ccc(C(C)(C)C)cc2)c1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(OCC(=O)Nc2cc(C(=O)O)ccn2)cc1
Temperature: 125 °C
Yield: 799.9 %

Procedure:
To solution of 2-[2-(4-tert-butyl-phenoxy)-acetylamino]-isonicotinic acid methyl ester (51.8 mg, 0.15 mmol) in pyridine 6 ml was added lithium Iodide (12.6 mg, 0.30 mmol), and stirred at 125° C. Reaction mixture was concentrated, and purified by Prep-TLC(CH2Cl2:MeOH=10:1) to give as a colorless solid (394 mg, 77.94% yield).
Reaction SMILES: B.[C:2]([C:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24]([O:26][CH3:27])=[O:25])=[CH:21][CH:22]=2)[NH:17][CH:16]=1)(=O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C(OCC)(=O)C.CO>O1CCCC1.O>[CH2:2]([C:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24]([O:26][CH3:27])=[O:25])=[CH:21][CH:22]=2)[NH:17][CH:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCC(=O)c1c[nH]c2cc(C(=O)OC)ccc12
Agent: B
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCCCCCCc1c[nH]c2cc(C(=O)OC)ccc12
Temperature: 50 °C
Yield: 52.3 %

Procedure:
A solution of borane in tetrahydrofuran (134 ml, of strength 1M) in portions (13×10 ml) was added during 20 minutes to a stirred solution of methyl 3-(n-dodecanoyl)indole-6-carboxylate (19.9 g) in a mixture of dry tetrahydrofuran (330 ml) and dry ethyl acetate (330 ml), the temperature of the reaction being maintained at 50° C. by external warming. The mixture was stirred and refluxed for 1.5 hours and then methanol (330 ml) was added to the refluxing mixture during 10 minutes. The mixture was refluxed for a further 30 minutes and water (50 ml) was added. The mixture was distilled at atmospheric pressure to remove the organic solvents to give a yellow residue. The residue was triturated with water (50 ml) to give a solid, which was collected and washed with water (100 ml). The solid was recrystallised from methanol (100 ml) (with treatment with charcoal) and then from toluene to give methyl 3-(n-dodecyl)-indole-6-carboxylate (10 g), in the form of a white solid, m.p. 85°-89° C.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][C:11]([NH2:13])=[CH:12][C:7]=2[N:6]=[CH:5]1)([CH3:3])[CH3:2].[I:14]I.N.CO.C(Cl)Cl>CC(O)=O.[Hg](OC(C)=O)OC(C)=O>[CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][C:11]([NH2:13])=[C:12]([I:14])[C:7]=2[N:6]=[CH:5]1)([CH3:3])[CH3:2]
Reactant: II
Reactant: CC(C)n1cnc2cc(N)ccc21
Agent: CC(=O)O[Hg]OC(C)=O
Agent: N
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)n1cnc2c(I)c(N)ccc21
Yield: 35 %

Procedure:
To a solution of 1-isopropyl-5-aminobenzimidazole (0.70 g, 3.7 mmol) and Hg(OAc)2 (2.1 g, 5.6 mmol) in 10 ml of AcOH was added solution of I2 in ACOH until it produces a precipitation; The reaction mixture was concentrated in vacuo to provide a brown solid which was subjected to column chromatography (5% NH3 sat'd MeOH/CH2Cl2) to provide 0.40 g (1.3 mmol, 35%) of the product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[CH3:54][O:55][C:56]1[CH:61]=[CH:60][C:59]([S:62](Cl)(=[O:64])=[O:63])=[C:58]([N+:66]([O-:68])=[O:67])[CH:57]=1>>[CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:62]([C:59]1[CH:60]=[CH:61][C:56]([O:55][CH3:54])=[CH:57][C:58]=1[N+:66]([O-:68])=[O:67])(=[O:63])=[O:64])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: COc1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1S(=O)(=O)c1ccc(OC)cc1[N+](=O)[O-])O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester (20 mg) was reacted with 4-methoxy-2-nitro-benzenesulfonyl chloride to give (S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-(4-methoxy-2-nitro-benzenesulfonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-propionic acid methyl ester according to General Procedure E. This product (5 mg) was hydrolyzed according to General Procedure B to give the title compound (4 mg). LCMS (m/z): 951.
Reaction SMILES: C(O[C:4]([CH:6]1[C:11](=O)[CH2:10][CH2:9][N:8]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7]1)=[O:5])C.Cl.[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([Cl:31])[CH:30]=1)[C:25]([NH2:27])=[NH:26]>>[CH2:13]([N:8]1[CH2:9][CH2:10][C:11]2[N:27]=[C:25]([C:24]3[CH:28]=[C:29]([Cl:31])[CH:30]=[C:22]([Cl:21])[CH:23]=3)[N:26]=[C:4]([OH:5])[C:6]=2[CH2:7]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCC1=O
Reactant: N=C(N)c1cc(Cl)cc(Cl)c1
Agent: Cl
Product: Oc1nc(-c2cc(Cl)cc(Cl)c2)nc2c1CN(Cc1ccccc1)CC2

Procedure:
The title compound was prepared from 1-benzyl-4-oxo-piperidine-3-carboxylic acid ethyl ester and 3,5-dichloro-benzamidine hydrochloride according to general procedure 1. 1H NMR (DMSO-d6, 400 MHz) δ 2.70-2.90 (m, 4H), 3.20-3.50 (m, 4H), 3.70-3.90 (m, 2H), 7.10-7.50 (m, 6H), 7.83 (s, 1H), 8.12 (s, 2H), 12.70 (br s, 1H); MS: m/z (ESI) 386 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([F:12])[C:3]=1[CH:4]=O.[CH2:13]([NH2:17])[CH2:14][CH2:15][CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:13](/[N:17]=[CH:4]/[C:3]1[C:2]([F:1])=[CH:9][C:8]([O:10][CH3:11])=[CH:7][C:6]=1[F:12])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCN
Reactant: COc1cc(F)c(C=O)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCC/N=C/c1c(F)cc(OC)cc1F

Procedure:
Butyl-[1-(2,6-difluoro-4-methoxy-phenyl)-meth-(E)-ylidene]-amine was prepared from 2,6-difluoro-4-methoxybenzaldehyde, N-butylamine and p-toluenesulphonic acid in analogy to Example 186a): yellow oil; MS (ISP): 228.4 ([M+H]+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[CH:3]=1.[Cl:13][S:14](O)(=[O:16])=[O:15]>>[Cl:1][C:2]1[C:11]([S:14]([Cl:13])(=[O:16])=[O:15])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[CH:3]=1
Reactant: COC(=O)c1ccc(Cl)cc1C
Reactant: O=S(=O)(O)Cl
Product: COC(=O)c1cc(S(=O)(=O)Cl)c(Cl)cc1C
Temperature: 0 °C
Reaction time: 3 h
Yield: 75.6 %

Procedure:
A mixture of 15.8 g (0.086 mol) of methyl 4-chloro-2-methylbenzoate (2) and 25.8 ml (45.2 g, 0.39 mol) of chlorosulfonic acid was heated to a gentle reflux under nitrogen. After 3 hrs., the mixture was cooled and poured slowly into an ice-water mixture. After stirring for 1 hr., the mixture was filtered and rinsed well with ice cold water. Drying in a vacuum oven (60° C.) gave 17.4 g (0.065 mol, 75% yield) of the sulfonylated acid (off-white crystals). A mixture of 14.5 g of the acid and 2 drops of dimethylformamide in 50 ml of thionyl chloride was heated to reflux under nitrogen. After 11/2 hrs., the solvent was removed under reduced pressure. Methanol (125 ml) was added to residue material and the solution was cooled to 10° C. After 5 hrs., the solid was filtered and airdried, giving 12.8 g of off-white crystals (3); m.p. 94.5° -96° C.
Reaction SMILES: [O:1]1[C:6]2=[CH:7][N:8]=[C:9]([CH2:11][OH:12])[CH:10]=[C:5]2[CH2:4][CH2:3][CH2:2]1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[O:1]1[C:6]2=[CH:7][N:8]=[C:9]([CH:11]=[O:12])[CH:10]=[C:5]2[CH2:4][CH2:3][CH2:2]1
Reactant: OCc1cc2c(cn1)OCCC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1cc2c(cn1)OCCC2
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 97.2 %

Procedure:
To a solution of 0.25 g of (3,4-dihydro-2H-pyrano(2,3-c)pyridin-6-yl)methanol in 7.5 mL of chloroform, 0.66 g of manganese dioxide was added, and the mixture was heated under reflux while stirring for 4 hours 50 minutes. The reaction mixture was cooled to room temperature, the insoluble substance was then filtered off, and the solvent was distilled off under reduced pressure to obtain 0.24 g of 3,4-dihydro-2H-pyrano(2,3-c)pyridine-6-carbaldehyde as a light yellow oily substance.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16](OC)=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:4](=[O:34])[CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[CH2:46][C:47]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[N:49]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[N:48]=1.O>CN(C=O)C.C1(C)C=CC=CC=1>[C:59]([O:58][C:56]([N:49]1[C:50]2[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:47]([CH2:46][CH:3]2[C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:11])[C:7]3[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=3[N:5]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:4]2=[O:34])=[N:48]1)=[O:57])([CH3:62])([CH3:61])[CH3:60]
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)N(C(=O)CN1C(=O)C(Cc2nn(C(=O)OC(C)(C)C)c3ccccc23)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
To a solution of 427 mg of 2-(2,4-Dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl) acetamide in 5 mL of dry DMF at 0° C. is added 2.2 mL of a 0.5M solution of potassium bis(trimethylsilyl)amide in toluene. The reaction mixture is stirred for 30 min at 0° C. and a solution of 311 mg of 3-Bromomethyl-1-tert-butoxycarbonyl indazole, prepared as in Intermediate 1, in 2 mL of dry DMF is added dropwise. The reaction mixture is stirred overnight at rt, poured into water and the product extracted with ethyl acetate (2×15 mL). The solvent is removed in vacuo and the residue is purified by silica gel flash column chromatography (MeOH 1% CHCl3 99%) to afford 420 mg of the title compound: 1H NMR (400 MHz, CDCl3) δ8.03 (d, 1H, J=8.3), 7.86 (d, 1H, J=8.0), 7.51-7.18 (m, 14H), 7.10 (m, 1H), 6.94 (m, 1H), 5.02 (m, 1H,J=6.8), 4.32 (dd, 1H, J=8.9, 4.7), 4.24 (d, 1H, J=16.4), 4.22 (d, 1H, J=16.4), 3.85 (dd, 1H, J=16.5, 8.9), 3.53 (dd, 1H, J=16.5, 4.7), 1.64 (s, 9H), 1.07 (d, 6H, J=6.8).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])=[O:2].Br[CH2:15][CH3:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl.CCOCC>[CH2:15]([O:13][C:12]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH:1]=[O:2])[CH3:16]
Reactant: CCBr
Reactant: COC(=O)c1ccc(O)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1ccc(C(=O)OC)cc1C=O
Temperature: 40 °C
Reaction time: 16 h
Yield: 101.2 %

Procedure:
A suspension of methyl 3-formyl-4-hydroxy-benzoate (3.0 g, 16.7 mmol), bromoethane (2.7 g, 1.85 mL, 24.9 mmol) and powdered K2CO3 (6.9 g, 49.9 mmol) in DMF (15 mL) was heated at 40° C. for 16 hours. After 16 hours, a further aliquot of bromoethane (1 mL) was added and the reaction mixture was heated for a further 2 hours. The reaction mixture was diluted with DCM (50 mL), filtered and concentrated in vacuo to give a yellow solid, which was diluted with ether (200 mL), washed sequentially with water (50 mL), sat. aq. NaHCO3 (50 mL) and brine solution (50 mL). The organics were separated, dried over MgSO4 and concentrated in vacuo to give methyl 4-ethoxy-3-formylbenzoate (3.52 g, 100%) as a white solid. ESI-MS m/z calc. 208.0. Found 209.3 (M+1)+; Retention time: 1.34 minutes (3 min run). Methyl 4-ethoxy-3-formylbenzoate (1.73 g, 8.91 mmol) was dissolved in THF (20 mL) and cooled to 0° C. LiBH4 (100 mg, 4.59 mmol) was added and the reaction mixture was stirred for 1 hour, then slowly quenched with dropwise addition of acetic acid. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate (50 mL), washed sequentially with sat. aq. NaHCO3 (20 mL) and brine (20 mL). The organics were separated, dried over MgSO4 and purified by silica gel column chromatography using 0-100% EtOAc/DCM as eluent to give methyl 4-ethoxy-3-(hydroxymethyl)benzoate (1.6 g, 46%) as a white solid. ESI-MS m/z calc. 210.0. Found 211.3 (M+1)+; Retention time: 1.11 minutes (3 min run); 1H NMR (400 MHz, CDCl3) δ 8.05-7.86 (m, 2H), 6.99-6.79 (m, 1H), 4.72 (s, 2H), 4.16 (q, J=7.0 Hz, 2H), 3.89 (s, 3H), 1.64 (d, J=7.0 Hz, 2H), 1.47 (t, J=7.0 Hz, 3H).
Reaction SMILES: [ClH:1].CO.[Cl:4][C:5]1[C:6]([C:52]([F:55])([F:54])[F:53])=[CH:7][C:8]2[N:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]([CH2:19][C@@H:20]3[C@H:24]4[O:25]C(C)(C)[O:27][C@H:23]4[C@H:22]([N:30]4[C:34]5[N:35]=[CH:36][N:37]=[C:38]([NH:39][CH:40]6[CH2:42][CH2:41]6)[C:33]=5[CH:32]=[CH:31]4)[CH2:21]3)[CH3:18])[N:10](COCC[Si](C)(C)C)[C:9]=2[CH:51]=1.Cl>>[ClH:4].[ClH:1].[ClH:4].[Cl:4][C:5]1[C:6]([C:52]([F:55])([F:53])[F:54])=[CH:7][C:8]2[N:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]([CH2:19][C@H:20]3[CH2:21][C@@H:22]([N:30]4[C:34]5[N:35]=[CH:36][N:37]=[C:38]([NH:39][CH:40]6[CH2:42][CH2:41]6)[C:33]=5[CH:32]=[CH:31]4)[C@H:23]([OH:27])[C@@H:24]3[OH:25])[CH3:18])[NH:10][C:9]=2[CH:51]=1
Reactant: CN(CCCCc1nc2cc(C(F)(F)F)c(Cl)cc2n1COCC[Si](C)(C)C)C[C@H]1C[C@@H](n2ccc3c(NC4CC4)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Agent: Cl
Solvent: CO
Product: CN(CCCCc1nc2cc(C(F)(F)F)c(Cl)cc2[nH]1)C[C@H]1C[C@@H](n2ccc3c(NC4CC4)ncnc32)[C@H](O)[C@@H]1O
Temperature: 40 °C
Reaction time: 5 h

Procedure:
A solution of 12N HCl:MeOH (1:1, 6 ml) was added to 7-[(3aS,4R,6R,6aR)-6-[({4-[6-chloro-5-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl]butyl}(methyl)amino)methyl]-2,2-dimethyl-hexahydrocyclopenta[d][1,3]dioxol-4-yl]-N-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine at 0° C. The mixture was stirred at 40° C. for 5 hrs, a further aliquot of HCl (12N, 1 ml) was added to the reaction mixture and continued at 40° C. for a further 1 h. This was then evaporated in vacuo. The residue was dissolved in DCM (100 ml) and MeOH (1 ml), washed with sat. NaHCO3 (2×50 ml), dried over Na2SO4, filtered and evaporated. Purification by prep.TLC, eluting with 7N NH3 in MeOH:DCM (5:95, then 2×1:9) gave the desired product. AcCl(5 eq) was added slowly to MeOH (1 ml) at 0° C., this was then added to a solution of the above product in MeOH and stirred for 5 mins before concentrating. Water (1 ml) was added and then lyophilized to give a white solid (129 mg, 81%); MS (ESI+) for C28H33ClF3N7O2 m/z 592.20 [M+H]+; HPLC purity 99% (ret. time, 2.61 min); 1H NMR (500 MHz, MeOD) δ ppm 8.33 (1H, s), 8.21 (1H, s), 8.07 (1H, s), 7.62 (1H, d, J=3.47 Hz), 6.91 (1H, br. s.), 5.04-5.14 (1H, m), 4.33 (1H, t, J=6.38 Hz), 4.10-4.21 (1H, m), 3.38-3.65 (3H, m), 3.31-3.37 (3H, m), 2.98 (3H, d, J=4.89 Hz), 2.85 (1H, br. s.), 2.44-2.63 (2H, m), 1.94-2.11 (4H, m), 1.88 (1H, q, J=11.24 Hz), 1.07-1.15 (2H, m), 0.81-0.89 (2H, m).