Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1.CO[CH:27]1[CH2:31][CH2:30][CH:29](OC)O1>C(O)(=O)C>[N:1]1([C:2]2[CH:3]=[C:4]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:5]=[CH:6][C:7]=2[O:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:27]=[CH:31][CH:30]=[CH:29]1
Reactant: COC1CCC(OC)O1
Reactant: COC(=O)Cc1ccc(OCc2ccc3ccccc3n2)c(N)c1
Solvent: CC(=O)O
Product: COC(=O)Cc1ccc(OCc2ccc3ccccc3n2)c(-n2cccc2)c1
Reaction time: 2 h

Procedure:
5 g (0.016 mmol) of the compound from Example XXIX are dissolved in 70 ml of acetic acid, 2.78 g (0.02 mol) of 2,5-dimethoxytetrahydrofuran are added and the mixture is heated to boiling for 2 hours. After distilling off the acetic acid in vacuo, taking up the residue in 200 ml of dichloromethane, extracting with water, drying with sodium sulphate and concentrating in vacuo to a small volume, the brown oil which remains (6 g) is separated by column chromatography (silica gel 60, eluent: toluene/ethyl acetate=4:1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13]CC)=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:16]1[CH2:20][CH2:19][S:18](=[O:22])(=[O:21])[CH2:17]1.[OH-].[Na+]>O.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:16]1[CH2:20][CH2:19][S:18](=[O:21])(=[O:22])[CH2:17]1
Reactant: CCOC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)C3)c[nH]c12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(Br)cc2c(C3CCS(=O)(=O)C3)c[nH]c12
Temperature: 85 °C
Yield: 91.2 %

Procedure:
Ethyl 5-bromo-3-(1,1-dioxidotetrahydro-3-thienyl)-1H-indole-7-carboxylate (0.596 g, 1.54 mmol) was dissolved in water (8.2 mL) and methanol (13.8 mL). A 6M NaOH solution (2.55 mL) was added and heated to 85° C. for 1.5 hours. The methanol was then concentrated and the solution was acidified with 6M HCl. The resulting white solid was filtered and dried to give 0.503 g (91%) of product.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:35]=[CH:34][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C(=O)C>O>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:4]=[N:3][C:2]([N:15]3[CH2:16][CH2:17][CH:18]([CH2:21][CH2:22][CH2:23][O:24][C:25]4[CH:26]=[CH:27][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:34][CH:35]=4)[CH2:19][CH2:20]3)=[CH:7][CH:6]=2)=[CH:9][CH:10]=1
Reactant: Fc1ccc(-c2ccc(Cl)nn2)cc1
Reactant: CCOC(=O)c1ccc(OCCCC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1ccc(OCCCC2CCN(c3ccc(-c4ccc(F)cc4)nn3)CC2)cc1
Temperature: 140 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
A mixture of 2.1 parts of 3-chloro-6-(4-fluorophenyl)pyridazine, 2.9 parts of ethyl 4-[3-(4-piperidinyl)propoxy]benzoate, 1.1 parts of sodium carbonate and 2 parts of N,N-dimethylacetamide was stirred for 2 hours in an oil bath at 140° C. The reaction mixture was diluted with water while cooling. The precipitated product was filtered off, washed with water and dissolved in trichloromethane. The organic layer was dried, filtered and evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 3.4 parts (73.3%) of ethyl 4-[3-[1-[6-(4-fluorophenyl)-3-pyridazinyl ]-4-piperidinyl]propoxy]benzoate; mp. 160.4° C. (comp. 81).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:10][N:11]([CH3:14])[CH:12]=O>>[CH3:10][N:11]([CH3:14])[CH:12]=[CH:1][C:2]1[CH:3]=[CH:4][N:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1ccncc1C#N
Reactant: CN(C)C=O
Product: CN(C)C=Cc1ccncc1C#N
Reaction time: 16 h
Yield: 63 %

Procedure:
A solution of 4-methylnicotinonitrile (13.8 g, 0.12 m), dimethylformamide (DMF) (100 mL) and DMF acetal (14.0 g, 0.12 m) was heated at reflux under N2. After 16 hours, the reaction mixture was concentrated at atmospheric pressure until the internal temperature reached 150°. The mixture was then cooled, poured into H2O (1 L) and extracted with C6H6 (6×200 mL). The combined organic extracts were washed with H2O (2×200 mL), dried, filtered and evaporated to dryness. The residue was distilled at 150°-160° (0.2 mm) to yield 12.6 g (63%) of N,N-dimethyl-2-(3-cyano-4-pyridyl)ethenamine. An analytical sample was prepared by crystallization from C6H6 --C6H14, mp 88°-90°.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[NH:19]1[C:27]2[C:22](=[CH:23][C:24](B(O)O)=[CH:25][CH:26]=2)[CH:21]=[CH:20]1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[CH:23]=[C:22]4[C:27](=[CH:26][CH:25]=3)[NH:19][CH:20]=[CH:21]4)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: OB(O)c1ccc2[nH]ccc2c1
Product: CCCNC(=O)c1nnc2c(-c3ccc4[nH]ccc4c3)cccc2c1N
Yield: 92.1 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (100 mg, 0.33 mmol) and 5-indolyl boronic acid (156 mg, 0.97 mmol) were reacted to afford the title compound (105 mg, 95.1% yield) as a pale-yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.60 (br, 1H), 8.34 (s, 1H), 7.94 (s, 1H), 7.86 (d, J=7.1 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.69 (t, J=7,7 Hz, 1H), 7.57 (d, J=8.5 Hz, 1H), 7.47 (d, J=8.5 Hz, 1H), 7.22 (s, 1H), 6.61 (s, 1H), 3.46 (q, J=6.7 Hz, 2H), 1.66 (m, J=7.2 Hz, 2H), 0.99 (t, J=7.4 Hz, 3H) MS APCI, m/z=346 (M+H) HPLC 1.88 min.
Reaction SMILES: N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:28]([C:29](=[O:41])[C:30]3[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=3)=[C:27]([CH:42]([CH3:44])[CH3:43])[CH:26]=[C:25]3[C:20]=2[C:21](=[O:47])[CH2:22][C:23]([CH3:46])([CH3:45])[O:24]3)=[CH:15][CH:14]=1.CO>O1CCCC1>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[C:28]([C:29]([C:30]3[CH:35]=[CH:34][C:33]([O:36][C:37]([F:38])([F:39])[F:40])=[CH:32][CH:31]=3)=[O:41])=[C:27]([CH:42]([CH3:43])[CH3:44])[CH:26]=[C:25]3[C:20]=2[C@@H:21]([OH:47])[CH2:22][C:23]([CH3:45])([CH3:46])[O:24]3)=[CH:17][CH:18]=1
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(=O)c1ccc(OC(F)(F)F)cc1)C(=O)CC(C)(C)O2
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(=O)c1ccc(OC(F)(F)F)cc1)[C@@H](O)CC(C)(C)O2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
97 μl (540 μmol) of borane/N,N-diethylaniline complex are added slowly to a solution of 3.04 mg (20 μmol) of (1R,2S)-1-aminoindan-2-ol in 2.5 ml of tetrahydrofuran. The mixture is then cooled to 0° C., and a solution of 68 mg (140 μmol) of 5-(4-fluorophenyl)-7-isopropyl-2,2-dimethyl-6-[4-(trifluoromethoxy)benzoyl]-2,3-dihydro-4H-chromen-4-one (Example 26A) in 4 ml of tetrahydrofuran is then slowly added dropwise. The mixture is allowed to thaw slowly and stirred at room temperature overnight. To bring the reaction to completion, the reaction mixture is again cooled to 0° C., and a further 97 μl (540 μmol) of borane/N,N-diethylaniline complex are added. The mixture is then thawed slowly to room temperature and stirred at this temperature overnight. Methanol is then added, and the solvent is removed under reduced pressure. The residue is taken up in ethyl acetate and washed in each case twice with 1 M hydrochloric acid and saturated sodium bicarbonate solution and once with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure. Purification of the residue by preparative HPLC (method 1) and subsequent chiral HPLC (method 2) gives the target compound.
Reaction SMILES: [Br-].[F:2][CH2:3][CH2:4][CH2:5][CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[F:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH:36]=O.CCCCCC>O1CCCC1>[F:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH:36][C:35]1[CH:34]=[C:33]([F:32])[CH:40]=[CH:39][CH:38]=1
Reactant: O=Cc1cccc(F)c1
Reactant: FCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: FCCCC=Cc1cccc(F)c1
Reaction time: 1 h
Yield: 79.2 %

Procedure:
To a mixture of 4-fluorobutyltriphenylphosphonium bromide 273 g (660 mmol) and tetrahydrofuran (abbreviated THF hereinafter) 1000 ml, potasium-tert-butoxide 88 g (684 mmol) was added under ice cooling and stirred for one hour. Then, under ice cooling, a solution of 3-fluorobenzaldehyde 74 g (596 mmol) in THF 200 ml was added dropwise, and the mixture was stirred for one hour at room temperature. The reaction mixture was poured into hexane 1000 ml, and the crystals deposited were filtered off. The filtrate was concentrated, and distilled (93° C./6 mmHg) to obtain 3-(5-fluoro-1-pentenyl)fluorobenzene 86 g. (Yield:79.6%).
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=1>C1COCC1>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2([CH3:8])[CH2:21][O:22]2)=[CH:16][CH:15]=1
Reactant: C[S+](C)C
Reactant: COc1ccc(C(C)=O)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C2(C)CO2)cc1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 1-(4-methoxyphenyl)ethanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][C@H:9]([NH:12][S:13]([C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=4)[CH:17]=3)(=[O:15])=[O:14])[C:8]2=[O:28])=[CH:4][C:3]=1[N+:31]([O-])=O.[H][H]>[Pd].CO.C(Cl)(Cl)Cl>[NH2:31][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:2]=1[NH2:1])[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([NH:12][S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28]
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4ccc(N)c([N+](=O)[O-])c4)C3=O)cc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4ccc(N)c(N)c4)C3=O)cc2c1

Procedure:
10% Palladium on carbon (0.08 g) is added to a solution of 7-methoxy-naphthalene-2-sulfonic acid [1-(4-amino-3-nitrobenzyl)-2-oxopyrrolidin-3-(S)-yl]-amide (0.22 g, 0.5 mmol) (prepared as described in EXAMPLE 25, Part F) in MeOH (40 mL) and CHCl3, (3 mL) under nitrogen atmosphere. The heterogeneous mixture is hydrogenated at room temperature on a Parr apparatus under 47 p.s.i. of hydrogen for 5 hours. The catalyst is filtered and the filtrate checked by the shows no starting material. The filtrate is concentrated in vacuo and used in the subsequent step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:16]=[C:15]3[NH:40][C:41](=[O:64])[C:42]2[CH:47]=[CH:46][C:45]([N+:48]([O-])=O)=[CH:44][C:43]=2[N:51]([CH:58]2[CH2:63][CH2:62][O:61][CH2:60][CH2:59]2)[C:52](=[O:57])[C:53]([F:56])([F:55])[F:54])(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.C1CCCCC=1>O1CCOCC1.[Pd]>[NH2:48][C:45]1[CH:46]=[CH:47][C:42]([C:41]([NH:40][C:15]2[C:14]3[C:18](=[CH:19][CH:20]=[C:12]([S:9]([C:4]4[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=4)(=[O:10])=[O:11])[CH:13]=3)[N:17]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:16]=2)=[O:64])=[C:43]([N:51]([CH:58]2[CH2:59][CH2:60][O:61][CH2:62][CH2:63]2)[C:52](=[O:57])[C:53]([F:56])([F:54])[F:55])[CH:44]=1
Reactant: O=C(Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(S(=O)(=O)c3cc(F)cc(F)c3)cc12)c1ccc([N+](=O)[O-])cc1N(C(=O)C(F)(F)F)C1CCOCC1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: C1=CCCCC1
Product: Nc1ccc(C(=O)Nc2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(S(=O)(=O)c4cc(F)cc(F)c4)cc23)c(N(C(=O)C(F)(F)F)C2CCOCC2)c1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
To a solution of N-[5-(3,5-difluoro-benzenesulfonyl)-1-trityl-1H-indazol-3-yl]-4-nitro-2-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-benzamide (4.05 g, 4.5 mmol) in 1,4-dioxane (100 mL) was added cyclohexene (10 mL) and 10% Pd/C (405 mg). The mixture was stirred at 90° C. for 5 hours, filtered and evaporated to dryness. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/n-hexane 2:1 affording the title compound as white solid (2.9 g).
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[C:11]([CH3:12])=[N:10][N:9]=[N:8]1.[Br:13][C:14]1[CH:25]=[CH:24][C:17]2[C:18](=O)[O:19]C(=O)[NH:21][C:16]=2[CH:15]=1>CCCCCC.O1CCCC1>[NH2:21][C:16]1[CH:15]=[C:14]([Br:13])[CH:25]=[CH:24][C:17]=1[C:18](=[O:19])[CH2:12][C:11]1[N:7]([CH3:6])[N:8]=[N:9][N:10]=1
Reactant: Cc1nnnn1C
Reactant: O=c1[nH]c2cc(Br)ccc2c(=O)o1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cn1nnnc1CC(=O)c1ccc(Br)cc1N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of butyl lithium in hexane (2.7M, 104 ml) was added slowly to a stirred solution of 1,5-dimethyltetrazole (27.5 g) in dry tetrahydrofuran (500 ml) at -5° to 0° under nitrogen. After stirring for 1.5 hours, 7-bromo-1H-3,1-benzoxazine-2,4-dione (22.6 g) was added and stirring continued for 18 hours at room temperature and for 3.5 hours at 40° to 50°. The mixture was cooled to room temperature, industrial methylated spirit (15 ml) added and most of the solvents distilled off. The residue was added to water (200 ml) and acidified with 5N hydrochloric acid to pH 1. The resulting solid was collected by filtration and crystallised from ethyl acetate to give the novel compound 1-(2-amino-4-bromophenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethanone, m.p. 159°-160°.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][S:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[N:5][C:6]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:7]([Cl:18])[N:8]=2)[N:3]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[Cl:18][C:7]1[N:8]=[C:9]2[C:4](=[N:5][C:6]=1[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[N:3]=[C:2]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[N:11]=[C:10]2[N:12]1[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1
Reactant: C1CNCCN1
Reactant: Clc1nc(N2CCSCC2)c2nc(Cl)c(NCc3ccccc3)nc2n1
Product: Clc1nc2c(N3CCSCC3)nc(N3CCNCC3)nc2nc1NCc1ccccc1

Procedure:
This compound was prepared analogous to Example 1 from 2,6-dichloro-4-thiomorpholino-7-benzylamino-pteridine and piperazine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Cl[C:28]1[N:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:28]5[N:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Fc1cnc(Cl)nc1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ncc(F)cn5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-chloro-5-fluoro-pyrimidine following a procedure analogous to that described for Intermediate 12. LC (method 2): tR=1.03 min; Mass spectrum (ESI+): m/z=455 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[S:9]2(=[O:11])=[O:10])[CH:6]=[CH:5]C=CC=1.S1(C2C(=CC=CC=2)C(=O)N1)(=O)=O.[H-].[Na+].[O:34](CCCCBr)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C=O)C>[O:34]([CH2:5][CH2:6][CH2:1][CH2:7][N:8]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[S:9]1(=[O:10])=[O:11])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: BrCCCCOc1ccccc1
Reactant: O=C1c2ccccc2S(=O)(=O)N1Cc1ccccc1
Agent: O=C1NS(=O)(=O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2S(=O)(=O)N1CCCCOc1ccccc1
Yield: 67 %

Procedure:
The synthesis was carried out analogous to the preparation of 83.1 using 82 (0.23 g, 1.25 mmol), NaH (0.030 g, 1.25 mmol) and 4-phenoxy-butyl bromide (0.115 g, 0.5 mmol) in DMF (5 mL). Purification by flash column chromatography on silica gel gave 83.2 (0.1 g, 67% yield) as a white solid (m p 92-94° C.).
Reaction SMILES: N[C@@H]1CCN(C2N=C3C(N=CN3[C@@H]3C[C@H](N4N=NC(CC)=N4)[C@@H](O)[C@H]3O)=C(NCC(C3C=CC=CC=3)C3C=CC=CC=3)N=2)C1.[ClH:45].[C:46]1([CH:52]([C:94]2[CH:99]=[CH:98][CH:97]=[CH:96][CH:95]=2)[CH2:53][NH:54][C:55]2[N:63]=[C:62]([N:64]3[CH2:68][CH2:67][C@@H:66]([NH:69][C:70](NCC4C=CC=CN=4)=[O:71])[CH2:65]3)[N:61]=[C:60]3[C:56]=2[N:57]=[CH:58][N:59]3[C@@H:80]2[CH2:84][C@H:83]([N:85]3[N:89]=[N:88][C:87]([CH2:90][CH3:91])=[N:86]3)[C@@H:82]([OH:92])[C@H:81]2[OH:93])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[NH2:100][CH2:101][CH2:102][C:103]1[CH:111]=[CH:110][C:106]([C:107]([OH:109])=[O:108])=[CH:105][CH:104]=1>>[ClH:45].[C:94]1([CH:52]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH2:53][NH:54][C:55]2[N:63]=[C:62]([N:64]3[CH2:68][CH2:67][C@@H:66]([NH:69][C:70](=[O:71])[NH:100][CH2:101][CH2:102][C:103]4[CH:111]=[CH:110][C:106]([C:107]([OH:109])=[O:108])=[CH:105][CH:104]=4)[CH2:65]3)[N:61]=[C:60]3[C:56]=2[N:57]=[CH:58][N:59]3[C@@H:80]2[CH2:84][C@H:83]([N:85]3[N:89]=[N:88][C:87]([CH2:90][CH3:91])=[N:86]3)[C@@H:82]([OH:92])[C@H:81]2[OH:93])[CH:99]=[CH:98][CH:97]=[CH:96][CH:95]=1
Reactant: NCCc1ccc(C(=O)O)cc1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCc6ccccn6)C5)nc43)[C@H](O)[C@@H]2O)n1
Agent: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](N)C5)nc43)[C@H](O)[C@@H]2O)n1
Agent: Cl
Product: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCCc6ccc(C(=O)O)cc6)C5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from ((1R,2S,3R,5S)-3-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(5-ethyl-tetrazol-2-yl)-cyclopentane-1,2-diol (Example 48) using a procedure analogous to that of 1-((R)-1-{6-(2,2-diphenyl-ethylamino)-9-[(1R,2S,3R,4S)-4-(5-ethyl-tetrazol-2-yl)-2,3-dihydroxy-cyclopentyl]-9H-purin-2-yl}-pyrrolidin-3-yl)-3-pyridin-2-ylmethyl-urea hydrochloride (Example 113) by replacing 2-aminomethyl pyridine with 4-(2-amino-ethyl)-benzoic acid. MS (ES+) m/e 787.51 (MH+)
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1(=[O:27])[O:26][C:24](=[O:25])[CH2:23][O:22][CH2:21]1>C1COCC1>[CH2:1]([O:8][C:9]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:24]([CH2:23][O:22][CH2:21][C:20]([OH:27])=[O:26])=[O:25])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCCCCCCNC(=O)OCc1ccccc1
Reactant: O=C1COCC(=O)O1
Solvent: C1CCOC1
Product: O=C(O)COCC(=O)NCCCCCCCNC(=O)OCc1ccccc1
Yield: 85.2 %

Procedure:
To the solution of 21 (350 mg, 1.324 mmol) in THF (4 mL) was added diglycolic anhydride (161 mg, 1.39 mmol) in one portion. The resultant mixture was stirred at ambient temperature for 12 h. After removed THF under reduced pressure, the residue was crystallized by EtOAc/hexane to give 429 mg white solid as first crop, in 85% yield. 1H NMR (400 MHz, DMSO-d6): δ12.79 (brs, 1H), 7.81 (t, J=5.52 Hz, 1H), 7.34-7.29 (m, 5H), 7.21 (t, J=5.46 Hz, 1H), 5.00 (s, 2H), 4.10 (s, 2H), 3.94 (s, 2H), 3.08 (q, J=6.56 Hz, 2H), 2.97 (q, J=6.28 Hz, 2H), 1.42-1.37 (m, 4H), 1.24 (m, 6H). 13C NMR (100 MHz, CDCl3): 171.43, 168.53, 156.06, 137.30, 128.27, 127.65, 70.18, 67.88, 65.04, 40.22, 38.08, 29.65, 29.00, 28.38, 26.28, 26.14. mp 74-74.5° C. IR v (Diamond, cm−1): 3374, 3331, 1726, 1688, 1608, 1548, 1249, 1236, 1135, 956, 701. MS (ESI) found 381.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])O.[Na+].Br[CH2:14][C:15]([C:17]1[CH:18]=[CH:19][C:20]2[S:25][C:24]3[N:26]=[CH:27][CH:28]=[N:29][C:23]=3[N:22]([CH2:30][O:31][CH3:32])[C:21]=2[CH:33]=1)=[O:16]>C(O)C.O1CCCC1>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH2:14][C:15]([C:17]1[CH:18]=[CH:19][C:20]2[S:25][C:24]3[N:26]=[CH:27][CH:28]=[N:29][C:23]=3[N:22]([CH2:30][O:31][CH3:32])[C:21]=2[CH:33]=1)=[O:16]
Reactant: COCN1c2cc(C(=O)CBr)ccc2Sc2nccnc21
Reactant: Nc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: COCN1c2cc(C(=O)CNc3ccccn3)ccc2Sc2nccnc21
Temperature: 25 °C
Yield: 53.6 %

Procedure:
To 3 ml of a solution of 140 mg of 2-aminopyridine in ethanol was added 130 mg of sodium hydrogencarbonate and the resulting mixture was stirred at room temperature. Next, 2 ml of a solution of 360 mg of bromomethyl(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)ketone in tetrahydrofuran was dropped thereinto and the resulting mixture was heated under reflux for 2 hours. Then the reaction mixture was brought back to room temperature and silica gel was added thereto. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give 200 mg of the title compound as yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[Cl:11]N1C(=O)CCC1=O>CC#N>[Cl:11][C:10]1[C:2](=[O:1])[NH:3][CH:4]=[C:5]([C:6]([OH:8])=[O:7])[CH:9]=1
Reactant: O=C(O)c1ccc(O)nc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: O=C(O)c1c[nH]c(=O)c(Cl)c1
Temperature: 80 °C

Procedure:
To a solution of 6-hydroxy nicotinic acid (0.500 g, 3.59 mmol, TCI) in MeCN (20 mL), was added N-chlorosuccinimide (0.436 mL, 5.39 mmol, Aldrich). The resulting mixture was then heated at 80° C. for 72 h. A white precipitate was present. The mixture was filtered and the white solid was washed with EtOAc (2×1 mL) and dried in vacuo to afford the title compound as a white solid. MS (ESI, positive ion) m/z: 174, 176 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][C:15]([F:18])([F:17])[F:16])[C:11]=1[O:12][CH3:13])[C:6](O)=[O:7])#[N:2].C1(C)C=CC=CC=1.S(Cl)([Cl:28])=O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][C:15]([F:18])([F:17])[F:16])[C:11]=1[O:12][CH3:13])[C:6]([Cl:28])=[O:7])#[N:2]
Reactant: O=S(Cl)Cl
Reactant: COc1c(C#N)cc(C(=O)O)cc1OC(F)(F)F
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1c(C#N)cc(C(=O)Cl)cc1OC(F)(F)F
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To 3-cyano-4-methoxy-5-trifluoromethoxybenzoic acid (500 mg), toluene (10 mL), N,N-dimethylformamide (3 droplets) and thionyl chloride (0.28 mL) were added, and then the mixture was stirred at 60° C. for 6 hours. The solvent was distilled off under reduced pressure and the obtained residue was azeotroped with toluene and used for the synthesis of (i).