Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:19][CH2:20][CH3:21])[C@@H:5]([NH:7][CH2:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[N:11]=[CH:12][CH:13]=[N:14]2)[CH3:6])[CH3:2].[CH:22]1[C:34]2[CH:33]([CH2:35][O:36][C:37]([NH:39][C@@H:40]([CH2:44][C:45]3[CH:50]=[CH:49][C:48]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:47][CH:46]=3)[C:41](O)=[O:42])=[O:38])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1>>[C:52]([O:51][C:48]1[CH:47]=[CH:46][C:45]([CH2:44][C@H:40]([NH:39][C:37](=[O:38])[O:36][CH2:35][CH:33]2[C:34]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=3[C:27]3[C:32]2=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:41]([N:7]([C@@H:5]([CH3:6])[CH:4]([O:19][CH2:20][CH3:21])[O:3][CH2:1][CH3:2])[CH2:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[N:11]=[CH:12][CH:13]=[N:14]3)=[O:42])=[CH:50][CH:49]=1)([CH3:55])([CH3:53])[CH3:54]
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Reactant: CCOC(OCC)[C@H](C)NCc1cccc2nccnc12
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2nccnc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Yield: 48.3 %

Procedure:
According to the procedure described in the synthesis method of Compound III-1, (S)-1,1-diethoxy-N-(quinoxalin-5-ylmethyl)propan-2-amine (Compound IX-8) 1.93 g (6.65 mmol) was coupled with (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tert-butoxyphenyl)propanoic acid 3.36 g (7.31 mmol) and purified on Buch silica gel column chromatography (chloroform:methanol=100:0 to 98:2) to obtain the title compound 2.35 g (48%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1I)[O:5][CH2:6][CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[CH:31])=[N:28][CH:29]=2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[C:31][C:15]3[CH:14]=[CH:13][C:4]([O:5][CH2:6][CH2:7][N:8]4[CH2:12][CH2:11][CH2:10][CH2:9]4)=[CH:3][C:2]=3[F:1])=[N:28][CH:29]=2)=[CH:22][CH:23]=1
Reactant: Fc1cc(OCCN2CCCC2)ccc1I
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: Fc1cc(OCCN2CCCC2)ccc1C#Cc1ccc(-c2ccc(Cl)cc2)cn1

Procedure:
Prepared according to general working method I from 1-[2-(3-fluoro-4-iodo-phenoxy)-ethyl]-pyrrolidine (500 mg, 0.75 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (159 mg, 0.75 mmol).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][C:11]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][C:24]2[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:26]2[CH:25]=[C:24]([CH2:23][CH:20]3[CH2:19][CH2:18][N:17]([C:15]([O:14][C:11]([CH3:13])([CH3:12])[CH3:10])=[O:16])[CH2:22][CH2:21]3)[CH:29]=[CH:28][CH:27]=2)[CH:7]=1)#[N:9]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc(B(O)O)c2)CC1
Reactant: N#Cc1ccnc(Cl)c1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(Cc2cccc(-c3cc(C#N)ccn3)c2)CC1
Temperature: 140 °C
Yield: 56.5 %

Procedure:
To 2-chloro-4-pyridinecarbonitrile (416 mg, 3 mmol) was added {3-[(1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-piperidinyl)methyl]phenyl}boronic acid (958 mg, 3.00 mmol) followed by K2CO3 (1,244 mg, 9.00 mmol) and Pd(Ph3P)4 (139 mg, 0.120 mmol) in 1,4-dioxane (15 mL) and water (5 mL). The mixture was heated in a microwave oven for 30 min at 140° C. The organic layer was collected and the aqueous layer was extracted with EtOAc (3 mL). The combined organic layers were filtered, concentrated on Glas-Col, redissolved in hexane/DCM (3:1, 4 mL), loaded onto Redisep silica gel column (40 g) and purified with Combiflash chromatograph to afford 640 mg (57%) of the title compound. LC-MS m/z 378 (M+H)+.
Reaction SMILES: B1([O-])OO1.[OH2:5].[OH2:6].O.O.[Na+].[CH3:10][N:11]([C:18]1[S:19][C:20]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[N:21][N:22]=1)[C:12](=[O:17])[CH2:13][CH2:14][S:15][CH3:16]>C(O)(=O)C.C(=O)(O)[O-].[Na+]>[CH3:10][N:11]([C:18]1[S:19][C:20]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[N:21][N:22]=1)[C:12](=[O:17])[CH2:13][CH2:14][S:15]([CH3:16])(=[O:6])=[O:5]
Reactant: CSCCC(=O)N(C)c1nnc(-c2cccnc2)s1
Reactant: O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)O
Product: CN(C(=O)CCS(C)(=O)=O)c1nnc(-c2cccnc2)s1
Temperature: 60 °C
Yield: 81.1 %

Procedure:
Sodium perborate tetrahydrate (130 mg, 0.84 mmol, 2.4 equiv) was added to a stirred solution of N-methyl-3-(methylthio)-N-(5-(pyridin-3-yl)-1,3,4-thiadiazol-2-yl)propanamide (100 mg, 0.34 mmol, 1.0 equiv) in glacial acetic acid (1.8 mL) at 23° C. The resulting yellow suspension was heated to 60° C. for 15 h. The cooled reaction mixture was diluted with a saturated solution of sodium bicarbonate (50 mL) and extracted with dichloromethane (3×30 mL). The combined organic layers were dried (sodium sulfate), gravity filtered, and concentrated by rotary evaporation. The residue was rinsed with cold ethyl acetate and vacuum-filtered to afford the title compound as an off-white powder (90 mg, 82% yield): mp 199-201° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.15 (d, J=2 Hz, 1H), 8.73 (dd, J=6, 2 Hz, 1H), 8.32 (dt, J=8, 2 Hz, 1H), 7.46 (dd, J=8, 5 Hz, 1H), 3.94 (s, 3H), 3.59 (t, J=7 Hz, 2H), 3.33 (t, J=7 Hz, 2H), 3.09 (s, 3H); ESIMS m/z 327 ([M+H]+). Compounds 33, 36, 37, 40, 43, 46, 52, 76 were prepared as described in Example 11.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)=[CH:23][C:12]=1[C:13]([O:15]CC1C=CC=CC=1)=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCOCC1.CO>[CH2:3]([O:10][C:11]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=2)=[CH:23][C:12]=1[C:13]([OH:15])=[O:14])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(OCc1ccccc1)c1cc(-c2ccncc2)ccc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(O)c1cc(-c2ccncc2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
An 2 mol/L aqueous solution of sodium hydroxide (1.1 mL) was added to a solution mixture of the obtained benzyl 2-(benzyloxy)-5-(pyridin-4-yl)benzoate (0.29 g) in dioxane (2.9 mL) and methanol (2.9 mL), followed by stirring at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and water was added to the residue. After adjusting the pH to 4 with 6 mol/L hydrochloric acid, ethyl acetate was added thereto. The reaction mixture was filtrated to collect the solid substance to obtain 0.19 g of 2-(benzyloxy)-5-(pyridin-4-yl)benzoic acid as a white solid.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([O:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=3[CH3:27])[CH:14]=[N:13]2)[C:9](O)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:28][C:29]1[CH:33]=[CH:32][N:31]([CH2:34][C:35]([CH3:38])([OH:37])[CH3:36])[N:30]=1>>[CH:1]1([CH2:7][CH:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([O:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=3[CH3:27])[CH:14]=[N:13]2)[C:9]([NH:28][C:29]2[CH:33]=[CH:32][N:31]([CH2:34][C:35]([OH:37])([CH3:38])[CH3:36])[N:30]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: Cc1ccc(Oc2cnn(C(CC3CCCCC3)C(=O)O)c(=O)c2)c(C)c1
Product: Cc1ccc(Oc2cnn(C(CC3CCCCC3)C(=O)Nc3ccn(CC(C)(C)O)n3)c(=O)c2)c(C)c1
Yield: 75 %

Procedure:
Using the method described in Example 49, 3-cyclohexyl-2-[4-(2,4-dimethyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 89) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclohexyl-2-[4-(2,4-dimethyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide as a light yellow solid (202 mg, 75%); ES+-HRMS m/e calcd for C28H37N5O4 [M+H+] 508.2919 found 508.2920. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.85-1.29 (m, 6H), 1.04 (s, 3H), 1.06 (s, 3H), 1.52-1.73 (m, 5H), 1.73-1.90 (m, 1H), 2.11 (s, 3H), 2.11-2.22 (m, 1H), 2.31 (s, 3H), 3.89 (s, 2H), 4.67 (s, 1H), 5.47-5.58 (m, 2H), 6.39 (d, J=2.1 Hz, 1H), 7.08 (d, J=8.2 Hz, 1H), 7.10-7.15 (m, 1H), 7.21 (s, 1H), 7.52 (d, J=2.1 Hz, 1H), 8.14 (d, J=2.7 Hz, 1H), 10.79 (s, 1H).
Reaction SMILES: [CH2:1]([C:8]1([N:15]([CH3:17])[CH3:16])[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Cl>CN(C)C=O>[CH2:1]([C:8]1([N:15]([CH3:16])[CH3:17])[CH2:13][CH2:12][CH:11]([O:14][CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([F:24])[CH:26]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cccc(CCl)c1
Reactant: CN(C)C1(Cc2ccccc2)CCC(O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C1(Cc2ccccc2)CCC(OCc2cccc(F)c2)CC1
Temperature: 0 °C
Yield: 50.5 %

Procedure:
2.65 g of 4-benzyl-4-dimethylaminocyclohexanol were dissolved in 20 ml of dimethylformamide; 1.40 g of potassium tert.-butoxide were added and stirring was carried out for 45 minutes, before 2.0 g of 3-fluorobenzyl chloride were added dropwise in the course of 30 minutes. After stirring overnight, the mixture was added to 25 ml of ice-water and extracted repeatedly with ethyl acetate. The combined extracts were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The resulting crude product (3.69 g) was separated on silica gel with hexane/ethyl acetate (V:V=1:1). 1.96 g of [1-benzyl-4-(3-fluoro-benzyloxy)-cyclohexyl]dimethylamine were obtained and, as described for Example 1, were converted into 1.13 g of the corresponding hydrochloride using chlorotrimethylsilane and water in 2-butanone (white solid).
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](I)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:19]=1.[CH3:20][N:21]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[N:22]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:24]4[CH:23]=[N:22][N:21]([CH3:20])[CH:25]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:19]=1
Reactant: NC(=O)c1nc2n(c1I)CCOc1ccc(Br)cc1-2
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: Cn1cc(-c2c(C(N)=O)nc3n2CCOc2ccc(Br)cc2-3)cn1

Procedure:
10-Bromo-3-iodo-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide (0.1 g) was reacted with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole similar to as described in Example 4 and triturated from water to give 90 mg of 10-bromo-3-(1-methylpyrazol-4-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide. This intermediate was reacted with 2-Methyl-3-butyne-ol similar to as described in Procedure E to afford 13.2 mg of 10-(3-hydroxy-3-methyl-but-1-ynyl)-3-(1-methylpyrazol-4-yl)-5,6-dihydroimidazo[1,2-d][1,4]benz oxazepine-2-carboxamide following reverse phase hplc purification. MS (Q1) 392 (M)+. 1H NMR (400 MHz, DMSO) δ 8.56 (d, J=2.0 Hz, 1H), 8.07 (s, 1H), 7.74 (s, 1H), 7.54 (s, 1H), 7.29 (dd, J=8.5, 2.1 Hz, 1H), 7.05-7.00 (m, 2H), 5.43 (s, 1H), 4.46-4.40 (m, 2H), 4.31 (d, J=4.0 Hz, 2H), 3.90 (s, 3H), 1.48 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[NH2:15][C:16]1[C:25]2[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=2[CH:19]=[CH:18][CH:17]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]([NH2:14])=[O:13])=[CH:7][C:8]=1[C:9]([NH:15][C:16]1[C:25]2[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=2[CH:19]=[CH:18][CH:17]=1)=[O:11]
Reactant: Nc1cccc2c1CCCC2
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1cccc2c1CCCC2

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 1-amino-5,6,7,8-tetrahydronaphthalene by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:17])=[C:4]2[O:8][C:7]([CH:9]3[CH2:11][CH2:10]3)=[N:6][C:5]2=[C:12]([C:15]#[N:16])[C:13]=1[CH3:14].CO[CH:20]1[CH2:24][CH2:23][CH:22](OC)O1>C(O)(=O)C>[CH:9]1([C:7]2[O:8][C:4]3[C:5](=[C:12]([C:15]#[N:16])[C:13]([CH3:14])=[C:2]([N:1]4[CH:20]=[CH:24][CH:23]=[CH:22]4)[C:3]=3[F:17])[N:6]=2)[CH2:10][CH2:11]1
Reactant: COC1CCC(OC)O1
Reactant: Cc1c(N)c(F)c2oc(C3CC3)nc2c1C#N
Solvent: CC(=O)O
Product: Cc1c(-n2cccc2)c(F)c2oc(C3CC3)nc2c1C#N
Temperature: 100 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
6-Amino-2-cyclopropyl-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-319) (29 mg, 0.13 mmol) was dissolved in acetic acid (2 ml), then at room temperature, 2,5-dimethoxytetrahydrofuran (49 μl, 0.38 mml) was added. The solution was stirred at 100° C. for 3 hours, then cooled to room temperature. The solvent was evaporated away under reduced pressure, the resulting residue was fractionated with ethyl acetate and an aqueous saturated sodium hydrogencarbonate solution. The aqueous layer was further extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was purified by middle-pressure liquid chromatography (eluent, n-hexane:ethyl acetate=9:1, v/v) to obtain the entitled compound (28.5 mg, 81%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH:35]1[C:43]2[C:38](=[C:39]([C:44]3[CH:45]=[C:46]([NH2:59])[C:47]4[C:51]([CH:52]=3)=[N:50][N:49](C3CCCCO3)[CH:48]=4)[CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36]1>CN(C=O)C.CCN(C(C)C)C(C)C>[NH:35]1[C:43]2[C:38](=[C:39]([C:44]3[CH:52]=[C:51]4[C:47]([CH:48]=[N:49][NH:50]4)=[C:46]([NH:59][C:8]([C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=4)=[O:10])[CH:45]=3)[CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2nn(C3CCCCO3)cc12
Reactant: Cc1cccc(C(=O)O)n1
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: CN(C)C=O
Product: Cc1cccc(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)n1
Reaction time: 0.08 h
Yield: 29.9 %

Procedure:
6-Methyl-2-pyridinecarboxylic acid (8 mg, 0.06 mmol) in DMF (0.20 ml) was treated with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (27 mg, 0.07 mmol) in DMF (0.20 ml) and DIPEA (0.030 ml). The reaction mixture was shaken for five minutes then treated with 6-(1H-Indol-4-yl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (20 mg, 0.06 mmol) in DMF (0.20 ml). The reaction mixture was shaken for 5 mins then left to stand at room temperature overnight. Solvent was removed, and the product re-dissolved in methanol (1 ml) then applied to an SCX cartridge (1 g) which had been pre-rinsed with methanol. After 1 h, the cartridge was eluted with ammonia in methanol (2M, 2×3 ml). Fractions containing product were combined, dried and then further purified by Mass Directed Automated Preparative HPLC (Method D). Fractions containing product were combined and dried to give the title compound (6.6 mg) as a pale brown gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:48]=[C:47]([O:49][CH3:50])[CH:46]=[CH:45][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH:42]([CH3:44])[CH3:43])[CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34]CC4C=CC=CC=4)=[O:33])[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.C1CC=CCC=1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:48]=[C:47]([O:49][CH3:50])[CH:46]=[CH:45][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:24])([CH3:25])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH:42]([CH3:44])[CH3:43])[CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(CCCCC(=O)OCc3ccccc3)C(C)C)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCC=CC1
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(CCCCC(=O)O)C(C)C)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 85 °C
Reaction time: 1 h
Yield: 103.4 %

Procedure:
A solution of benzyl 5-((((3aR,4R,6R,6aR)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(isopropyl)amino)pentanoate (151 mg, 0.220 mmol) in ethanol (4.1 mL) was treated with 10% palladium on carbon (51 mg, 0.048 mmol) and 1,4-cyclohexadiene (0.23 mL, 2.4 mmol). The mixture was heated at 85° C. until the starting material was consumed as indicated by HPLC. After about 1 h, the starting material was consumed as indicated by HPLC and the reaction mixture was cooled to room temperature. The mixture was filtered through a pad of celite and the pad was washed with 40 mL EtOH. The solution was concentrated to yield the title compound (136 mg, 104%) as a nearly colorless glass, which was taken up in toluene, concentrated and placed under high vac. The material was determined to be of sufficient purity to be used in the next step without purification: MS (ESI+) for C31H43N5O7 m/z 598.7 (M+H)+; HPLC purity>95% (ret. time, 2.84 min).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.[CH2:10](O)[CH2:11][OH:12].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>O.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)=[CH:6][N:7]=1
Reactant: O=Cc1ccc(Br)nc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1ccc(C2OCCO2)cn1
Yield: 96.6 %

Procedure:
To a toluene (100 mL) solution of 6-bromo-pyridine-3-carbaldehyde (5.0 g, 27 mmol) described in Manufacturing Example 154-1-1 were added ethylene glycol (3.0 mL, 54 mmol) and p-toluenesulfonic acid monohydrate (512 mg, 2.7 mmol), which was refluxed for 3 hours and 40 minutes under nitrogen atmosphere. Sodium hydrogencarbonate and water were added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (6.0 g, 97%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:24])[C:8]=2[C:12]2[C:13]([OH:23])=[CH:14][CH:15]=[C:16]3[C:21]=2[CH:20]=[CH:19][C:18](Br)=[CH:17]3)[CH:3]=1.[Cl-].O.NN.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O.C1COCC1>[C:29]1([C:18]2[CH:19]=[CH:20][C:21]3[C:16](=[CH:15][CH:14]=[C:13]([OH:23])[C:12]=3[C:8]3[C:7]([OH:24])=[CH:6][CH:5]=[C:4]4[C:9]=3[CH:10]=[CH:11][C:2]([C:2]3[CH:11]=[CH:10][CH:9]=[CH:4][CH:3]=3)=[CH:3]4)[CH:17]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: OB(O)c1ccccc1
Reactant: Oc1ccc2cc(Br)ccc2c1-c1c(O)ccc2cc(Br)ccc12
Agent: NN
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: Oc1ccc2cc(-c3ccccc3)ccc2c1-c1c(O)ccc2cc(-c3ccccc3)ccc12

Procedure:
12.0 g (25.7 mmol) of (±)-6,6′-dibromo[1,1′]binaphthalinyl-2,2′-diol, 11.5 g (41 mmol) of sodium metaborate octahydrate and 800 mg of bistriphenylphosphinepalladium(II) chloride are initially introduced in 100 ml of water and 20 ml of THF, 0.13 ml of hydrazine hydrate is added, and a solution of 7.0 g (57 mmol) of benzeneboronic acid in 80 ml of THF is added dropwise. The batch is subsequently heated under reflux overnight, added to water and extracted three times with MTB ether. The combined org. phases are washed with water and dried over sodium sulfate. The solvent is removed in vacuo, and the residue is filtered through silica gel with toluene/ethyl acetate (19:1) and evaporated, and the product is recrystallized once each from toluene/cyclohexane (1:1) and isopropanol, giving (±)-6,6′-diphenyl[1,1′]binaphthalinyl-2,2′-diol as colorless crystals.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[Cl-].[CH3:14][O:15][C:16]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:17]=1[CH:18]=[N+:19]([CH3:21])[CH3:20].COC1C(OC)=CC=CC=1C=O.CNC>>[CH3:14][O:15][C:16]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:17]=1[CH:18]([N:19]([CH3:21])[CH3:20])[C:3]1[C:4]2[CH2:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH2:8][C:9]=2[NH:1][CH:2]=1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: COc1cccc(C=[N+](C)C)c1OC
Agent: CNC
Agent: COc1cccc(C=O)c1OC
Agent: [Cl-]
Product: COc1cccc(C(c2c[nH]c3c2CC=C(C(=O)O)C3)N(C)C)c1OC

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1H-indole-6-carboxylic acid and (2,3-dimethoxy-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 2,3-dimethoxy-benzaldehyde and dimethylamine.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1.Cl[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([O:12][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:15]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CSc1nc2ccc(O)cc2s1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)ccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc2ccc(Oc3ccnc(C(=O)OC(C)(C)C)c3)cc2s1
Temperature: 75 °C
Reaction time: 6 h
Yield: 61.4 %

Procedure:
To a solution of 2-(methylthio)benzo[d]thiazol-6-ol (5.0 g, 25.38 mmol, 1.0 eq) in 25 mL of N,N-dimethylformamide was added tert-butyl 4-chloropicolinate (8.13 g, 38.07 mmol, 1.5 eq) and cesium carbonate (20.67 g, 63.45 mmol, 2.5 eq). The reaction mixture was stirred at 75° C. for 6 hours. After the mixture was cooled to room temperature, the mixture was added 120 mL of water and aqueous phase extracted with ethyl acetate (3×150 mL), combined organic layers were dried over sodium sulfate. After filtration, the solid was purified by silica gel column eluted with ethyl acetate-hexane 0%-50% mixture to give 5.84 g of the titled compound as brown powder (62%). MH+=375.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[C:8]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:7][C:6]=1[NH:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29]Cl)[CH:24]=1)[CH3:2].C(N(CC)CC)C.[SH:40][CH2:41][CH:42]([OH:45])[CH2:43][OH:44].ClCC1C=C(C=CC=1)C(O)=O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:32])[C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[C:8]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:7][C:6]=1[NH:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][S:40][CH2:41][CH:42]([OH:45])[CH2:43][OH:44])[CH:24]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(OCCOC)c(OCCOC)cc1NC(=O)c1cccc(CCl)c1
Reactant: OCC(O)CS
Agent: O=C(O)c1cccc(CCl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cc(OCCOC)c(OCCOC)cc1NC(=O)c1cccc(CSCC(O)CO)c1
Reaction time: 36 h
Yield: 77 %

Procedure:
Subsequently, 2-(3-chloromethyl-benzoylamino)-4,5-bis-(2-methoxy-ethoxy)-benzoic acid ethyl ester (1.1 g) was dissolved in anhydrous methylene chloride (20 ml). Triethylamine (800 μl) and 3-mercapto-1,2-propanediol (compound B′) (600 μl) were added dropwise to the solution at room temperature, and the mixture was stirred at that temperature for 36 hr. After the completion of the reaction, distilled water was added thereto at room temperature, and the mixture was then subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated under the reduced pressure. The residue was purified by column chromatography eluted with a chloroform-methanol system to give 2-[3-(2,3-dihydroxy-propylsulfanylmethyl)-benzoylamino]-4,5-bis-(2-methoxy-ethoxy)-benzoic acid ethyl ester (970 mg, yield 77%).