Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][N:17]4[C:20]([C:23]5[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=5)=[CH:21][N:22]=[C:16]4[CH:15]=3)=[CH:10][N:9]=2)[CH2:4][CH2:3]1.ClC(Cl)(Cl)C[O:33][C:34](=O)[NH:35][C:36]1[CH:40]=[C:39]([C:41]([CH3:44])([CH3:43])[CH3:42])[O:38][N:37]=1.C(N(CC)CC)C>CS(C)=O>[C:41]([C:39]1[O:38][N:37]=[C:36]([NH:35][C:34]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([C:20]3[N:17]4[CH:18]=[CH:19][C:14]([C:11]5[CH:12]=[N:13][C:8]([N:5]6[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]6)=[N:9][CH:10]=5)=[CH:15][C:16]4=[N:22][CH:21]=3)=[CH:24][CH:25]=2)=[O:33])[CH:40]=1)([CH3:44])([CH3:42])[CH3:43]
Reactant: CN1CCN(c2ncc(-c3ccn4c(-c5ccc(N)cc5)cnc4c3)cn2)CC1
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)no1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN1CCN(c2ncc(-c3ccn4c(-c5ccc(NC(=O)Nc6cc(C(C)(C)C)on6)cc5)cnc4c3)cn2)CC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Combine the amine (0.323 g, 0.838 mmol), (5-tert-butyl-isoxazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (0.291 g, 0.922 mmol) and triethylamine (0.128 mL, 0.922 mmol) in DMSO (10 mL). Heat the mixture to 70° C., stir overnight, and cool to room temperature. Extract the mixture with ethyl acetate versus water. Wash the organic layer with saturated aqueous saturated sodium chloride. Dry the resulting organics over magnesium sulfate, filter, and concentrate. Purify by column chromatography (ethyl acetate→10% methanol in dichloromethane→10% 2 M NH3 in MeOH in dichloromethane) to afford product (0.057 g, 11%, two steps). MS(ES), m/z 552 (M+1).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11]2.[CH3:20][C:21]1[C:22]([CH:31]2[CH2:33][O:32]2)=[CH:23][C:24]2[CH2:28][O:27][C:26](=[O:29])[C:25]=2[CH:30]=1>CCO>[OH:32][CH:31]([C:22]1[C:21]([CH3:20])=[CH:30][C:25]2[C:26](=[O:29])[O:27][CH2:28][C:24]=2[CH:23]=1)[CH2:33][N:6]1[CH2:5][CH2:4][N:3]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11]3)[C:2](=[O:1])[CH2:7]1
Reactant: N#Cc1ccc2cc(N3CCNCC3=O)ccc2c1
Reactant: Cc1cc2c(cc1C1CO1)COC2=O
Solvent: CCO
Product: Cc1cc2c(cc1C(O)CN1CCN(c3ccc4cc(C#N)ccc4c3)C(=O)C1)COC2=O
Temperature: 140 °C

Procedure:
A mixture of 6-(2-Oxopiperazin-1-yl)naphthalene-2-carbonitrile [I-5] (40 mg, 0.16 mmol) and 6-methyl-5-(oxiran-2-yl)-2-benzofuran-1(3H)-one [I-16] (30 mg, 0.16 mmol of the fast eluting isomer) in EtOH (1.5 mL) was heated to 140° C. for 1 hour. The reaction mixture was concentrated to dryness, and dissolved in MeOH, filtered and shot into Mass-directed HPLC for purification to give the title product. LC-MS (IE, m/z): 442 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[Al+3].[Cl-].[Cl-].[Cl-].[Cl:15][CH2:16][C:17](Cl)=[O:18].Cl>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:17](=[O:18])[CH2:16][Cl:15]
Reactant: O=C(Cl)CCl
Reactant: COc1ccc(OC)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(OC)c(C(=O)CCl)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 63.3 %

Procedure:
In a three-neck round bottom 2 liter flask, 60.0 g (0.434 mol) of 1,4-dimethoxybenzene is added. To the flask is added 300 mL dry dichloromethane to dissolve the solid. When the solution is clear, 63.7 g (0.477 mol) of anhydrous AlCl3 is added through a powder funnel and the funnel is washed with dichloromethane. The resulting solution is yellowish in color. This solution is stirred at room temperature for 5 minutes and 40.0 mL (0.50 mol) chloroacetylchloride in 5 mL dichloromethane is added dropwise (total addition time 1 hour 30 minutes) and is stirred vigorously at room temperature. The color of the solution became is orange-red and then like red wine. The solution is stirred for 4 hours after addition at room temperature and then poured in to a mixture of crushed ice and 126 mL conc. HCl and stirred for 20 minutes again. The organic phase is separated and the aqueous phase is extracted with CH2Cl2 (100 mL×3). Total dichloromethane fractions are combined and washed with H2O (100 mL×2), cold 10% aq. NaOH (200 mL×1) and H2O (100 mL×2) and dried over anhydrous sodium sulfate. The organic phase is evaporated under reduced pressure and the thick solution is cooled to room temperature yielding a yellow solid (59.0 g, yield 64%). The crude product is crystallized from methanol (m.p. 89-91° C.).
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-:18])=[O:17])=[CH:6][C:5]([CH3:20])=[CH:4][N:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>N1C=CC=CC=1.CC1C=CC(C)=CC=1>[CH3:20][C:5]1[CH:6]=[C:7]2[N:8]=[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:16]([O-:18])=[O:17])[S:22][C:2]2=[N:3][CH:4]=1
Reactant: Cc1cnc(Cl)c(NC(=O)c2ccccc2[N+](=O)[O-])c1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Solvent: Cc1ccc(C)cc1
Product: Cc1cnc2sc(-c3ccccc3[N+](=O)[O-])nc2c1
Temperature: 140 °C
Reaction time: 20 h
Yield: 75.4 %

Procedure:
A mixture of N-(2-chloro-5-methylpyridin-3-yl)-2-nitrobenzamide (5.0 g, 17.1 mmol) and P2S5 (7.6 g, 34.2 mmol) in pyridine (50 mL) and p-xylene (200 mL) was stirred at 140° C. for 20 h. The hot solution was transferred to another flask and the solvent was removed in vacuo. The residue was purified by recrystallization from EtOH to afford 6-methyl-2-(2-nitrophenyl)thiazolo[5,4-b]pyridine as a yellow solid (3.5 g, yield: 75%).
Reaction SMILES: C(OC([NH:8][CH2:9][C@@H:10]([N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C.[ClH:21]>CO.C(O)(C)C>[ClH:21].[ClH:21].[NH2:8][CH2:9][C@H:10]([N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)[C@@H](CNC(=O)OC(C)(C)C)N1CCCCC1
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: COC(=O)[C@H](CN)N1CCCCC1
Temperature: 40 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
3.7 g (12.9 mmol) of methyl (R)-3-tert-butoxycarbonylamino-2-piperidin-1-ylpropanoate are placed in a mixture of 25 ml of methanol and 15 ml of hydrochloric acid in solution in isopropanol having a concentration of 5-6N. The reaction medium is stirred at 40° C. for 18 h and then concentrated under vacuum. 3.5 g (100%) of methyl(S)-3-amino-2-piperidin-1-ylpropanoate dihydrochloride are obtained in the form of a beige solid.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1>>[CH2:11]([C:9]1[S:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:15][CH:16]3[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]3)[C:3]=2[CH:10]=1)[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CC(C)Cc1cc2c(Cl)ncnc2s1
Product: CC(C)Cc1cc2c(NC3CCN(C(=O)OC(C)(C)C)CC3)ncnc2s1

Procedure:
The title compound was prepared (337 mg, 65%) from 4-chloro-6-isobutylthieno[2,3-d]pyrimidine (300 mg, 1.32 m. mol) and tert-butyl 4-aminopiperidine-1-carboxylate (400 mg, 1.99 m. mol) by following the general procedure described for Preparation 9. 1H NMR (400 MHz, CDCl3): δ 8.45 (s, 1H), 6.80 (s, 1H), 4.95 (m, 1H), 4.35 (m, 1H), 4.15 (m, 2H), 2.95 (m, 2H), 2.75 9d, 2H), 2.15 (m, 2H), 1.95 (m, 1H), 1.45 (s, 9H), 1.40-1.50 (m, 2H), 0.95 (d, 6H).
Reaction SMILES: [C:1]([CH2:5][S:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:16])[CH:14]=2)[N:9]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:8]=1[CH2:25][C:26]([CH3:32])([CH3:31])[C:27]([O:29][CH3:30])=[O:28])([O:3]C)=[O:2].[Li+].[OH-]>CO.O>[C:1]([CH2:5][S:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:16])[CH:14]=2)[N:9]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:8]=1[CH2:25][C:26]([CH3:32])([CH3:31])[C:27]([O:29][CH3:30])=[O:28])([OH:3])=[O:2]
Reactant: COC(=O)CSc1c(CC(C)(C)C(=O)OC)n(Cc2ccc(Cl)cc2)c2ccc(O)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)C(C)(C)Cc1c(SCC(=O)O)c2cc(O)ccc2n1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of diester from Step 3 (4.5 g, 9.46 mmol) in MeOH (90 mL) there was added 1N LiOH (50 mL) and the mixture was stirred for 1 hour at r.t. It was then diluted with H2O and extracted twice with Et2O. The aqueous fraction was then acidified with 6N HCl and extracted 4 times with Et2O. These extracts were washed 4 times with H2O, dried and evaporated to yield the title compound as a thick oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[CH2:7](Br)[CH:8]=[CH2:9].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:9]([N:5]1[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]1)[CH:8]=[CH2:7]
Reactant: C=CCBr
Reactant: Cc1c[nH]cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCn1cnc(C)c1
Yield: 38 %

Procedure:
4-Methylimidazole (2.0 g, 24.36 mmol), allyl bromide (2.2 mL, 24.36 mmol), N,N-diisopropylethylamine (5.0 mL, 29.24 mmol) in DMF (50 mL) were stirred at 80° C. overnight. Then the reaction mixture was cooled, quenched with saturated NaHCO3 (30 mL), and extracted with CH2Cl2 (4×40 mL). The combined organic layers were dried (MgSO4), filtered, concentrated, and dried in vacuo to afford a brown oil. Purification by flash column chromatography on silica using 2% CH3OH/CH2Cl2 afforded the product as a yellow oil (1.13 g, 40%). 1H NMR (CDCl3) (as a mixture of regio-isomers) δ 2.17 and 2.22 (s, total 3H), 4.44-4.48 (m, total 2H), 5.19-5.24 (m, total 2H), 5.89-6.00 (m, total 1H), 6.61 and 6.79 (s, total 1H), 7.35 and 7.39 (s, total 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.Cl[C:11]1[N:12]=[CH:13][C:14]2[C:19]([CH:20]=1)=[C:18]([C:21]1[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=1)[CH:17]=[CH:16][CH:15]=2>>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:11]2[N:12]=[CH:13][C:14]3[C:19]([CH:20]=2)=[C:18]([C:21]2[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=2)[CH:17]=[CH:16][CH:15]=3)=[CH:5][CH:4]=1
Reactant: Cn1cc(-c2cccc3cnc(Cl)cc23)cn1
Reactant: COc1ccc(N)cc1
Product: COc1ccc(Nc2cc3c(-c4cnn(C)c4)cccc3cn2)cc1

Procedure:
The title compound was prepared according to Method 3 (Example 27) using 4-methoxyaniline and 3-Chloro-5-(1-methyl-1H-pyrazol-4-yl)isoquinoline (Preparation 7).
Reaction SMILES: N1(S(N[C:9](=O)[C:10]2[CH:15]=C(Cl)C(OCC3(C(F)(F)F)CCCC3)=CC=2F)(=O)=O)CCC1.Cl[C:31]1[C:32]([O:45][C@H:46]2[CH2:51][CH2:50][C@H:49]([C:52]([F:55])([F:54])[F:53])[CH2:48][CH2:47]2)=[CH:33][C:34]([F:44])=[C:35]([CH:43]=1)[C:36]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])=[O:37]>>[CH:15]1([C:31]2[C:32]([O:45][C@H:46]3[CH2:51][CH2:50][C@H:49]([C:52]([F:55])([F:54])[F:53])[CH2:48][CH2:47]3)=[CH:33][C:34]([F:44])=[C:35]([CH:43]=2)[C:36]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])=[O:37])[CH2:10][CH2:9]1
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(O[C@H]2CC[C@H](C(F)(F)F)CC2)cc1F
Reactant: O=C(NS(=O)(=O)N1CCC1)c1cc(Cl)c(OCC2(C(F)(F)F)CCCC2)cc1F
Product: CS(=O)(=O)NC(=O)c1cc(C2CC2)c(O[C@H]2CC[C@H](C(F)(F)F)CC2)cc1F

Procedure:
Following the procedure as described in Example 165 and making variations as required to replace N-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-((1-(trifluoromethyl)-cyclopentyl)methoxy)benzamide with 5-chloro-2-fluoro-N-(methylsulfonyl)-4-((trans-4-(trifluoromethyl)cyclohexyl)oxy)benzamide, the title compound was obtained (0.24 g, 57%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.68 (d, J=16.2 Hz, 1H), 7.61 (d, J=9.0 Hz, 1H), 6.55 (d, J=14.7 Hz, 1H), 4.69-4.65 (m, 1H), 3.39 (s, 3H), 2.24-1.95 (m, 4H), 1.83-1.55 (m, 6H), 0.97-0.89 (m, 2H), 0.66-0.60 (m, 2H); MS (ES−) m/z 422.2 (M−1); MS (ES+) m/z 424.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[C:8]([O:15][CH3:16])=[C:7]([CH3:17])[C:4]=1[CH:5]=[O:6].Br[C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[O:29][CH2:28][CH2:27][O:26]2)=[CH:21][CH:20]=1.[Mg].O>C1COCC1>[OH:6][CH:5]([C:4]1[C:7]([CH3:17])=[C:8]([O:15][CH3:16])[C:9]([O:13][CH3:14])=[C:10]([O:11][CH3:12])[C:3]=1[O:2][CH3:1])[C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[O:26][CH2:27][CH2:28][O:29]2)=[CH:21][CH:20]=1
Reactant: COc1c(C)c(C=O)c(OC)c(OC)c1OC
Reactant: Brc1ccc(C2OCCO2)cc1
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C)c(C(O)c2ccc(C3OCCO3)cc2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.5 %

Procedure:
To an ice-cold solution of 2,3,4,5-tetramethoxy-6-methylbenzaldehyde (5.03 g, 20.94 mmol) in THF (200 ml) was added dropwise a Grignard reagent prepared from 2-(4-bromophenyl)-1,3-dioxolane (12.0 g, 52.4 mmol) and magnesium (1.40 g, 57.6 mmol), and then stirred at room temperature for 4 hours. The reaction mixture was poured into water and was extracted with ether. After the extract was washed with water and dried, and then the solvent was distilled off. The residue was purified by a silica gel column chromatography (hexane:ethyl acetate=3:1) to yield the title compound (7.80 g, 20.0 mmol, yield 96%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:5]=[CH:4][N:3]=1.[Br:12]N1C(=O)CCC1=O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1.O>[NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[N:6][C:5]([Br:12])=[CH:4][N:3]=1
Reactant: COC(=O)c1nccnc1N
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1nc(Br)cnc1N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Methyl 2-aminopyrazine-3-carboxylate (5.0 g, 32.65 mmol) was dissolved in 100 mL of THF and treated with N-Bromosuccinimide (6.9 g, 39.18 mmol) all at once. The mixture was stirred at room temperature for 1.5 hrs, and then another 0.5 equivalents of N-bromosuccinimide was added and stirring continued for 1 hr. 10 grams of sodium sulfate were added, the mixture was vigorously stirred for 15 minutes, and the solvent was removed in vacuo. The residue obtained was suspended in 250 mL of water and stirred rapidly. Filtration afforded the title compound, methyl 3-amino-6-bromopyrazine-2-carboxylate, as a tan solid (6.33 g).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:31]([NH2:34])[CH2:32][CH3:33]>>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([NH:34][CH2:31][CH2:32][CH3:33])=[O:16])[CH2:6][CH2:5]2
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Reactant: CCCN
Agent: O=C(n1ccnc1)n1ccnc1
Product: CCCNC(=O)C1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Yield: 63.3 %

Procedure:
Following the amide coupling procedure described in protocol A, 502.3 mg 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.01 mmol), 358 mg CDI (2.21 mmol) and 130 mg propylamine (2.20 mmol) produced 371 mg of 6-hydroxy-2,5,7,8-tetramethyl-N-propylchroman-2-carboxamide as an off white syrup.
Reaction SMILES: [CH3:1][O:2][C:3]1([CH2:13][O:14][CH3:15])[CH2:12][CH2:11][C:6]2(OCC[O:7]2)[CH2:5][CH2:4]1.CC(C)=O.O.CC1C=CC(S(O)(=O)=O)=CC=1>O>[CH3:1][O:2][C:3]1([CH2:13][O:14][CH3:15])[CH2:4][CH2:5][C:6](=[O:7])[CH2:11][CH2:12]1
Reactant: COCC1(OC)CCC2(CC1)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: COCC1(OC)CCC(=O)CC1

Procedure:
A mixture comprising 217 g (1.00 mol) 8-methoxy-8-(methoxymethyl)-1,4-dioxaspiro[4.5]decane (prepared according to intermediate example 16e), 1.7 L acetone, 0.86 L water and 30.5 g 4-methylbenzenesulfonic acid hydrate was stirred at 23° C. overnight. The acetone was removed, 0.5 L saturated aqueous sodium hydrogencarbonate added followed by 0.4 L brine. The mixture was extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. After filtration and removal of the solvent 180 g (max. 100%) of the title compound were obtained that was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:14]=[C:13]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].[N+:30]([CH3:33])([O-:32])=[O:31]>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:14]=[C:13]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:10]=1[CH:11]=[CH:33][N+:30]([O-:32])=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: CC(C)(C)c1cc(OCc2ccccc2)c(C=O)c(C(C)(C)C)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(OCc2ccccc2)c(C=C[N+](=O)[O-])c(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
To a mixture of 1.5 g (4.6 mmol) of the product of Step A and 2.0 g of ammonium acetate in 25 mL acetic acid was added 3 mL nitromethane. The reaction mixture was refluxed for 5 h, then cooled to room temperature and the volatiles were removed in vacuo. The residue was partitioned between EtOAc and water, then separated. The aqueous layer was re-extracted with EtOAc, the organic layers were combined, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified on a silica gel flash chromatography column eluted with 0-20% CH2Cl2-hexane. Combination of the purified fractions and drying in vacuo afforded the title compound.
Reaction SMILES: [I-].C[N+]1[CH:7]=[CH:6][N:5]([C:8](/[N:10]=[C:11]2\[S:12][C:13]([CH3:26])=[CH:14][N:15]\2[C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[O:9])[CH:4]=1.C(N(C(C)C)CC)(C)C.N1C2[C:39](=[CH:40][CH:41]=CC=2)[CH2:38][CH2:37]1>C(#N)C>[CH3:26][C:13]1[S:12]/[C:11](=[N:10]\[C:8]([N:5]2[C:4]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:7][CH2:6]2)=[O:9])/[N:15]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:14]=1
Reactant: c1ccc2c(c1)CCN2
Reactant: Cc1cn(-c2ccc(C(F)(F)F)cc2)/c(=N/C(=O)n2cc[n+](C)c2)s1
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cn(-c2ccc(C(F)(F)F)cc2)/c(=N/C(=O)N2CCc3ccccc32)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial, a solution of 3-methyl-1-({[(2Z)-5-methyl-3-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2(3H)-ylidene]amino}carbonyl)-1H-imidazol-3-ium iodide (62 mg, 0.13 mmol, Example 18B) dissolved in acetonitrile (0.6 mL) was added followed by the addition of diisopropylethylamine (28 μL, 0.16 mmol) dissolved in acetonitrile (0.6 mL). Then, to the solution was added indoline (17 mg, 0.14 mmol) dissolved in acetonitrile (0.7 mL). The vial was capped and shaken overnight at room temperature. The reaction was concentrated to dryness. The residue was purified by reverse phase HPLC (C18, gradient 10-95% acetonitrile/water/0.1% trifluoroacetic acid) to provide the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[N:16]=[C:15]2[C:11]([NH:12][CH:13]=[N:14]2)=[C:10]([Cl:17])[N:9]=1.[C:18]([O:26][CH2:27][CH2:28][O:29][CH2:30]Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O>[NH2:7][C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH2:30][O:29][CH2:28][CH2:27][O:26][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:10]([Cl:17])[N:9]=1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: O=C(OCCOCCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(Cl)c2ncn(COCCOC(=O)c3ccccc3)c2n1
Reaction time: 0.33 h
Yield: 19.6 %

Procedure:
A suspension of potassium carbonate (4.1 g) and 2-amino-6-chloropurine (5.0 g) in dry dimethylformamide (120 ml) was stirred for 20 minutes. 2-Benzoyloxyethoxymethyl-chloride (6.3 g) was added and the resulting pink suspension stirred at room temperature for 6 days. The reaction mixture was then poured into a mixture of ice and water (210 ml) with vigorous stirring. The aqueous mixture, was extracted with chloroform (3×200 ml), and the chloroform solution obtained was washed with a 5% acetic acid solution and then twice with water. The chloroform solution was dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was redissolved in a minimal amount of chloroform and the resulting solution applied to a column containing silica gel (200 g) in chloroform. The column was eluted with 2% methanol/98% chloroform and the eluant collected in 30 ml cuts. The fractions containing 2-amino-6-chloro-9-(2-benzoyloxyethoxymethyl)purine (determined by TLC) were combined, evaporated and the residue recrystallized from benzene to give 2-amino-6-chloro-9-(2-benzoyloxyethoxymethyl)purine (2.0 g., m.p. 130°-133.5° C.).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[CH:10]=[CH:9][N:8]([C:11]2[N:12]=[C:13]([CH2:38][CH2:39][CH3:40])[N:14]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]4[NH:37][N:36]=[N:35][N:34]=4)=[CH:23][CH:22]=3)[C:15]=2[C:16]([O:18]C)=[O:17])[CH:7]=1)([OH:3])=[O:2].[OH-].[Li+]>C(O)C.O>[C:1]([CH2:4][CH2:5][C:6]1[CH:10]=[CH:9][N:8]([C:11]2[N:12]=[C:13]([CH2:38][CH2:39][CH3:40])[N:14]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]4[NH:37][N:36]=[N:35][N:34]=4)=[CH:23][CH:22]=3)[C:15]=2[C:16]([OH:18])=[O:17])[CH:7]=1)([OH:3])=[O:2]
Reactant: CCCc1nc(-n2ccc(CCC(=O)O)c2)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCc1nc(-n2ccc(CCC(=O)O)c2)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 56.5 %

Procedure:
A solution of methyl 4-(3-carboxyethyl-1H-pyrrol-1-yl)-2-propyl-1-[(2'-(1H-tetrazol 5-yl)biphen-4-yl)methyl]-1H-imidazole-5-carboxylate (Example 73, 0.2 g) in ethanol (2.5 mL) and water (1.25 mL) was treated with lithium hydroxide (0.17 g) ant the reaction mixture stirred a room temperature for 3 days. The reaction mixture was diluted with water, extracted with ether, and the aqueous layer acidified to pH 2 with 1N HCl. The cloudy solution was extracted with ether and the combined organic layers dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue taken-up in ethyl acetate. Petroleum ether was added dropwise to precipitate the product which was collected by filtration to yield 0.11 g of the title compound 4-(3-carboxyethyl-1H-pyrrol-1-yl)-2-propyl-1-[(2'-(1H-tetrazol-5-yl)biphen-4-yl)methyl]-1H-imidazole-5-carboxylic acid. MS (CI, CH4 +NH4) 410 (M-CO2H, --CO2Et).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[S:8][C:9]3[N:10]=[C:11]([C:15]4[S:16][C:17](Br)=[CH:18][C:19]=4[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[S:12][C:13]=3[N:14]=2)=[C:4]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH:3]=1.C([Li])CCC.[CH3:54][Sn:55](Cl)([CH3:57])[CH3:56]>C(OCC)C>[CH3:54][Sn:55]([CH3:57])([CH3:56])[C:2]1[S:6][C:5]([C:7]2[S:8][C:9]3[N:10]=[C:11]([C:15]4[S:16][C:17]([Sn:55]([CH3:57])([CH3:56])[CH3:54])=[CH:18][C:19]=4[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[S:12][C:13]=3[N:14]=2)=[C:4]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH:3]=1
Reactant: CCCCCCCCCCCCCCc1cc(Br)sc1-c1nc2sc(-c3sc(Br)cc3CCCCCCCCCCCCCC)nc2s1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCCCCCCCCCCCCc1cc([Sn](C)(C)C)sc1-c1nc2sc(-c3sc([Sn](C)(C)C)cc3CCCCCCCCCCCCCC)nc2s1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a 100 mL Schlenk flask was placed 250 mg (0.29 mmol) of 2,5-bis(5-bromo-3-tetradecyl-2-thienyl)-thiazolo[5,4-d]thiazole. The flask was evacuated and refilled with Ar three times. 35 mL of dry THF was added to the flask. The flask was subsequently cooled to −78° C. n-Butyl lithium (0.64 mmol) was then added dropwise to the above solution. After the solution was stirred at −78° C. for 1 hour, 0.7 mL of 1.0 M solution of trimethyl tin chloride was syringed into the reaction mixture. After the solution was allowed to warm up to room temperature, 100 mL of diethyl ether was added to the solution. The solution was washed three times with 100 mL of water and then the organic layer was dried over anhydrous MgSO4. After the solvent was removed in vacuum, 2,5-bis(5-trimethylstannyl-3-tetradecyl-2-thienyl)-thiazolo[5,4-d]thiazole was isolated in quantitative yield.