Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[C:9]([C:18]([F:21])([F:20])[F:19])=[N:10][NH:11][C:12]=2[C:13]([O:15]CC)=O)=[O:7])=[C:4]([NH2:24])[CH:3]=1.OC1C=CC=CN=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6](=[O:7])[C:8]3[C:9]([C:18]([F:19])([F:20])[F:21])=[N:10][NH:11][C:12]=3[C:13](=[O:15])[NH:24][C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1[nH]nc(C(F)(F)F)c1C(=O)c1ccc(Cl)cc1N
Agent: Oc1ccccn1
Solvent: Cc1ccccc1
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)c2c(C(F)(F)F)n[nH]c12
Temperature: 170 °C
Yield: 39.4 %

Procedure:
To a solution of ethyl 4-(4-chloro-2-aminobenzoyl)-3-trifluoromethyl-1H-pyrazole-5-carboxylate (360 mg, 0.997 mmol) in toluene (50 mL) was added 2-hydroxypyridine (93.9 mg, 0.988 mmol). Toluene was removed by distillation and the residue was heated at 170° C. for 2 days. The flask was cooled to room temperature and dichloromethane (20 mL) was added. The insoluble material was filtered to give crude solid (284 mg). The crude material was continuously chromatographed eluting with dichloromethane (100 mL) and dichloromethane:2-propanol (98:2, 200 mL). The fractions were concentrated by rotary evaporation and were found to contain a contaminant from tygon tubing. The fractions were combined and flash chromatographed through a plug of silica gel to remove the contaminant, eluting with hexanes, hexanes:ethyl acetate (95:5, 90:10), dichloromethane, and dichloromethane:2-propanol (95:5, 90:10). The product fractions were concentrated by rotary evaporation to give the title compound as a white solid (124 mg, 37%, m.p. 337-339° C.).
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[CH3:9][O:10][C:11](=[O:25])[CH2:12][C:13]1[C:14]([F:24])=[C:15]2[C:20](=[CH:21][C:22]=1[F:23])[N:19]=[CH:18][CH:17]=[CH:16]2.CI>C1COCC1>[CH3:9][O:10][C:11](=[O:25])[CH:12]([C:13]1[C:14]([F:24])=[C:15]2[C:20](=[CH:21][C:22]=1[F:23])[N:19]=[CH:18][CH:17]=[CH:16]2)[CH3:2]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)Cc1c(F)cc2ncccc2c1F
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)c1c(F)cc2ncccc2c1F
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
To a solution of LDA (1.2 M in THF, 9.5 mL, 11.4 mmol) in dry THF (30 mL) at −78° C. was added a solution of (5,7-difluoroquinolin-6-yl)-acetic acid methyl ester (2.12 g, 9.5 mmol) in THF (20 mL) dropwise. After 30 min, MeI (0.9 mL, 14.2 mmol) was added dropwise, and the reaction mixture was allowed to rise to 0° C. naturally. After 1 h, the reaction was quenched by saturated aqueous NaHCO3 solution, and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography to afford 2.272 g (95%) of the title compound as a pale yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.93 (d, 1H), 8.39 (dd, 1H), 7.61 (dd, 1H), 7.41-7.46 (m, 1H), 4.29 (q, 1H), 3.73 (s, 3H), 1.62 (d, 3H). LCMS (method A): [MH]+=252, tR=5.09 min. (5,7-difluoroquinolin-6-yl)-acetic acid methyl ester was synthesized using the method described in WO2008/144767 p 108 (intermediate 2), followed by the method described for Intermediate 12, step 1 WO2008/144767 p 114.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[C:9](OC(=O)C)(=[O:11])[CH3:10].S(=O)(=O)(O)O>C(O)(=O)C>[C:9]([N:1]1[CH2:8][CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3])(=[O:11])[CH3:10]
Reactant: O=C1CCNC(=O)N1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)N1CCC(=O)NC1=O

Procedure:
57 gm (0.5 mol) of 5,6-dihydrouracil and 817 gm (8 mols) of acetic acid anhydride were heated to boiling for ten hours after adding 2 ml of concentrated sulfuric acid thereto. The acetic acid produced was continuously distilled off by means of a fractionating column. After the acylation reaction had been completed, the surplus acetic acid anhydride was distilled off in vacuo (15 Torr) and the residue was recrystallized from isopropanol. The product obtained had a melting point of 191° to 193° C, and the elementary analysis resulted in the following values:
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[OH-].[Na+].O.S(OCC)(O[CH2:17][CH3:18])(=O)=O>O1CCCC1>[CH2:17]([N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1)[CH3:18]
Reactant: CCOS(=O)(=O)OCC
Reactant: c1ccc2[nH]cnc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCn1cnc2ccccc21
Reaction time: 2 h
Yield: 88.4 %

Procedure:
To a flask were added 100 g benzimidazole, 44 g sodium hydroxide, 320 ml water and 480 ml tetrahydrofuran and the mixture was stirred under nitrogen. 157 g Diethyl sulfate were added slowly, maintaining a temperature of 40 C. After 2 hrs at 40 C, the reaction was quenched with slow addition of 100 ml concentrated hydrochloric acid. After washing with 150 ml hexane, the mixture was basified with 50 g sodium hydroxide and extracted with 275 ml ethyl acetate, then 225 ml ethyl acetate. The solvent was removed, leaving an orange oil, which was distilled under full vacuum to give 109.4 g clear colorless oil.
Reaction SMILES: [C:1]([C:3]([CH2:15][CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4](OCC)=[O:5])#[N:2].[NH3:17]>C(O)C>[C:1]([C:3]([CH2:15][CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4]([NH2:17])=[O:5])#[N:2]
Reactant: N
Reactant: CCOC(=O)C(C#N)(CC)c1ccccc1
Solvent: CCO
Product: CCC(C#N)(C(N)=O)c1ccccc1
Reaction time: 96 h
Yield: 80 %

Procedure:
A 10% solution of ethyl 2-cyano-2-ethyl-2-phenylacetate in ethanol is saturated with ammonia under cooling. The reaction mixture is allowed to stand at 5° C. for 96 hours, thereafter the solvent and the excess of ammonia are removed, and the product is filtered off. 2-Cyano-2-ethyl-2-phenylacetic acid amide is obtained with a yield of 80%; m.p.: 116.5°-117° C.
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:7])=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:29])C=1>C(Cl)Cl>[CH3:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([N+:8]([O-:29])([CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)[CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)=[O:7])=[CH:4][N:3]=1
Reactant: Cc1ccc(C(=O)N(C2CCCC2)C2CCCC2)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc(C(=O)[N+]([O-])(C2CCCC2)C2CCCC2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.7 %

Procedure:
To a solution of the product of Example A (0.5 g, 1.84 mmol) in methylene chloride (15 mL), m-chloroperbenzoic acid (485 mg. 85%, 2.38 mmol) was added. After stirring at room temperature for 18 h, the solvent was removed under reduced pressure. The colorless liquid obtained was then chromatographed (silica gel, methylene chloride/methanol 94/6) to give the title compound (460 mg, 87%). 1H NMR (CDCl3) 1.4-2.2(m, 16H), 2.53 (s, 3H), 3.6-3.85 (m,2H), 7.16(dd, J=3, 8 Hz, 1H), 7.25 (d,J=8 Hz, 1H), and 8.24 ppm (d, J=3 Hz, 1H).
Reaction SMILES: [Cl-].[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:3]=1.C([Li])CCC.[CH3:33][C:34]([CH3:56])([CH2:39][CH:40]([CH2:53][CH:54]=O)[CH2:41][CH2:42][CH2:43][CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[C:35]([O:37][CH3:38])=[O:36]>O1CCCC1.CCCCCC>[CH3:33][C:34]([CH3:56])([CH2:39][CH:40]([CH2:53][CH:54]=[CH:8][C:4]1[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=1)[CH2:41][CH2:42][CH2:43][CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[C:35]([O:37][CH3:38])=[O:36]
Reactant: COC(=O)C(C)(C)CC(CC=O)CCCCO[Si](C)(C)C(C)(C)C
Reactant: c1ccc([P+](Cc2cccnc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)C(C)(C)CC(CC=Cc1cccnc1)CCCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8.8 g (22.6 mmol) 3-pyridylmethyltriphenylphosphonium chloride in 40 ml dry tetrahydrofuran at 0° is added slowly 9.0 ml (22.5 mmol) of 2.5M n-butyllithium in hexane. After stirring the resulting deep red solution at room temperature for 0.5 h, a solution of 3.23 g (9 mmol) of methyl 2,2-dimethyl-4-formylmethyl-8-(t-butyldimethylsilyloxy)-octanoate in 10 ml dry tetrahydrofuran is added slowly and then stirred for 16 h. The reaction is quenched by addition of saturated ammonium chloride solution and then extracted thrice with ether. The combined organic extracts are washed with water and brine, dried, filtered and concentrated. The residue is taken up in ether and the resulting precipitate is removed by filtration. The filtrate is evaporated and the residue is purified by silica gel chromatography using 1:1 hexane/ether to give methyl 2,2-dimethyl-4-[3-(3-pyridyl)-2-propenyl]-8-(t-butyldimethylsilyloxy)-octanoate; NMR (CDCl3): delta 5.7-6.4 (m,2H), 3.63 and 3.60 (two s,3H), 1.2 and 1.15 (two s,6H).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:33]=[CH:32][C:31]([C@H:34]4[CH2:39][CH2:38][C@H:37]([C:40]([O:42]CC)=[O:41])[CH2:36][CH2:35]4)=[C:30]4[C:25]=3[C:26](=[O:46])[C:27]([CH3:45])=[CH:28][NH:29]4)[C:20]([C:47]([F:50])([F:49])[F:48])=[CH:19][N:18]=2)=[C:12]([O:51][CH3:52])[CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].O.[OH-].[Li+]>C1COCC1.CO.O>[CH2:7]([O:6][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:33]=[CH:32][C:31]([C@H:34]4[CH2:35][CH2:36][C@H:37]([C:40]([OH:42])=[O:41])[CH2:38][CH2:39]4)=[C:30]4[C:25]=3[C:26](=[O:46])[C:27]([CH3:45])=[CH:28][NH:29]4)[C:20]([C:47]([F:48])([F:50])[F:49])=[CH:19][N:18]=2)=[C:12]([O:51][CH3:52])[CH:11]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOC(=O)[C@H]1CC[C@H](c2ccc(Nc3nc(Nc4ccc(CP(=O)(OCC)OCC)cc4OC)ncc3C(F)(F)F)c3c(=O)c(C)c[nH]c32)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](C(=O)O)CC4)c4[nH]cc(C)c(=O)c34)n2)c(OC)c1)OCC
Temperature: 25 °C
Reaction time: 30 h

Procedure:
A solution of Ethyl trans-4-(5-{[2-({4-[(diethoxyphosphoryl)methyl]-2-methoxyphenyl}amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino}-3-methyl-4-oxo-1,4-dihydroquinolin-8-yl)cyclohexanecarboxylate (Example 304, 72.0 mg, 0.097 mmol) in THF (0.125 mL) and MeOH (0.129 mL) was charged with a solution of lithium hydroxide, monohydrate (20.2 mg, 0.48 mmol) in H2O (0.129 mL) and allowed to stir at rt for 30 hrs. The reaction was concentrated under reduced pressure. The material was purified on an Isco combi-flash unit using DCM/MeOH (100:0→95:5) as eluent to afford 45 mg (60%) of the desired product. 1H NMR (400 MHz, MeOD) δ ppm 1.24-1.33 (m, 6H) 1.66-1.86 (m, 4H) 1.96-2.04 (m, 2H) 2.12-2.14 (m, 3H) 2.15-2.22 (m, 2H) 3.39-3.43 (m, 1H) 3.46-3.50 (m, 1H) 3.91-3.94 (m, 3H) 4.05-4.11 (m, 4H) 6.88-6.94 (m, 1H) 7.03-7.07 (m, 1H) 7.47-7.52 (m, 1H) 7.83-7.86 (m, 1H) 8.01-8.06 (m, 1H) 8.33-8.35 (m, 1H) 8.50-8.59 (m, 1H). MS (ES+): m/z 718.22/719.26 (100/98) [MH+]. HPLC: tR=1.43 min (Micromass TOF: polar—3 min).
Reaction SMILES: [NH2:1][C:2]1([C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][CH2:18][CH3:19])[C:11](=[O:20])[N:10]([CH2:21][CH2:22][CH3:23])[C:9]=3[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.N1C=CC=CC=1.Cl.[C:31]([O:34][CH2:35][CH3:36])(=[O:33])C>O1CCCC1>[CH2:17]([N:12]1[C:13](=[O:16])[C:14]2[NH:15][C:7]([C:2]3([NH:1][C:31]([O:34][CH2:35][CH3:36])=[O:33])[CH2:3][CH2:4][CH2:5][CH2:6]3)=[N:8][C:9]=2[N:10]([CH2:21][CH2:22][CH3:23])[C:11]1=[O:20])[CH2:18][CH3:19]
Reactant: CCCn1c(=O)c2[nH]c(C3(N)CCCC3)nc2n(CCC)c1=O
Reactant: CCOC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCn1c(=O)c2[nH]c(C3(NC(=O)OCC)CCCC3)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 4.5 g of 8-(1-aminocyclopentyl)-1,3-dipropylxanthine in 45 ml of anhydrous tetrahydrofurane 1.83 ml of pyridine and 1.97 ml of ethyl chloroformiate are added. The mixture is stirred for 2 hours at room temperature, followed by the addition of 1N HCl and extraction with ethyl acetate. The organic phase is washed with water, dried and evaporated to obtain 4.2 g of raw product, which is finally crystallized from ethanol/water.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:25])[CH2:22][O:23][CH3:24])[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:32].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:32])[CH3:13])[C:9]([N:15]2[CH2:16][CH2:17][N:18]([C:21](=[O:25])[CH2:22][O:23][CH3:24])[CH2:19][CH2:20]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: [BH3-]C#N
Reactant: COCC(=O)N1CCN(c2c(C(C)=O)cc(Cl)c3cccnc23)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Solvent: C1CCOC1
Product: COCC(=O)N1CCN(c2c(C(C)N)cc(Cl)c3cccnc23)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-{5-chloro-8-[4-(methoxyacetyl)piperazin-1-yl]quinolin-7-yl}ethanone (0.023 g, 0.064 mmol) and ammonium acetate (0.0490 g, 0.636 mmol) in methanol (0.3 mL) and acetonitrile (0.3 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.16 mL, 0.16 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution, extracted with dichloromethane, dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C18H24ClN4O2 (M+H)+: m/z=363.2; Found: 363.1.
Reaction SMILES: [H-].[Na+].[CH:3]1([C:7]([O-:9])=O)[CH2:6][CH2:5][CH2:4]1.[C:10](#[N:12])[CH3:11].Cl>C1COCC1.O>[CH:3]1([C:7](=[O:9])[CH2:11][C:10]#[N:12])[CH2:4][CH2:5][CH2:6]1
Reactant: O=C([O-])C1CCC1
Reactant: CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#CCC(=O)C1CCC1

Procedure:
A 50 mL three necked round bottom flask containing NaH (980 mg, 60%, 24.50 mmol, 1.57 eq.) and THF (10 mL) was heated to reflux under nitrogen for about 30 min. Then a mixture of cyclobutanecarboxylate [CCLXVII] (2 g, 15.6 mmol, 1.00 eq.) and acetonitrile (1 g, 24.3 mmol, 1.56 eq.) in 20 mL of THF was added dropwise to the refluxing suspension. After addition, the resulting mixture was refluxed for 16 h and worked up with water. The pH value of the reaction solution was adjusted to 4 with aqueous HCl solution and extracted with ethyl acetate. The combined organic phases were dried and concentrated, the residue was applied onto a silica gel column with ethyl acetate/petroleum ether as the eluent to give Compound [CCLXVIII] as a yellow oil: 1H NMR (300 MHz, CDCl3) δ ppm 3.40-3.60 (m, 1H), 3.43 (s, 2H), 2.25-2.36 (m, 4H), 2.01-2.15 (m, 1H), 1.82-1.96 (m, 1H).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[N:11]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[C:14](=O)[CH2:13][CH2:12]2>>[Br:2][C:3]1[CH:8]=[CH:7][C:6]2[NH:9][C:14]3[CH:15]4[CH2:18][CH2:19][N:11]([CH2:12][C:13]=3[C:5]=2[CH:4]=1)[CH2:17][CH2:16]4
Reactant: O=C1CCN2CCC1CC2
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Product: Brc1ccc2[nH]c3c(c2c1)CN1CCC3CC1

Procedure:
4-Bromophenylhydrazine hydrochloride (4.33 g, 19.37 mmol; Aldrich) and the product of Example 1A (2.70 g, 19.37 mmol) were processed as described in Example 1B to provide the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 2.14-2.36 (m, 4 H), 3.17-3.25 (m, 1 H), 3.33-3.45 (m, 2 H), 3.45-3.65 (m, 2 H), 4.54 (s, 2 H), 7.18 (dd, J=8.8, 1.8 Hz, 1 H), 7.24 (d, J=9.1 Hz, 1 H), 7.51 (d, J=2.4 Hz, 1 H); MS (DCI) m/z 291/293 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[C:18]([F:19])[C:13]=3[N:12]([C:20]([CH3:31])([CH3:30])[CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[F:32][C:33]([F:44])([F:43])[C:34]1[CH:35]=[N:36][N:37]([CH2:39][C:40](O)=[O:41])[CH:38]=1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C1COCC1>[C:26]([Si:23]([CH3:24])([CH3:25])[O:22][CH2:21][C:20]([N:12]1[C:13]2[C:18]([F:19])=[CH:17][N:16]=[CH:15][C:14]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:40](=[O:41])[CH2:39][N:37]3[CH:38]=[C:34]([C:33]([F:43])([F:32])[F:44])[CH:35]=[N:36]3)[CH:7]=[N:6][CH:5]=2)=[O:9])=[CH:11]1)([CH3:31])[CH3:30])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N)c2)c2cncc(F)c21
Reactant: O=C(O)Cn1cc(C(F)(F)F)cn1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(NC(=O)Cn3cc(C(F)(F)F)cn3)c2)c2cncc(F)c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (5-amino-pyridin-3-yl)-{1-[2-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-7-fluoro-1H-pyrrolo[3,2-c]pyridin-3-yl}-methanone (Preparation 29, 35 mg, 79.1 μmol), (4-trifluoromethyl-pyrazol-1-yl)-acetic acid (20.7 mg, 106.9 μmol) and DIPEA (48 μL, 276.8 μmol) in THF (3 mL), T3P (166 μL, 276.8 μmol) was added and the mixture stirred at 25° C. for 18 hours. The reaction was evaporated under reduced pressure, the residue partitioned between water and ethyl acetate, the organic extracts washed with saturated sodium bicarbonate solution, dried over sodium sulphate, evaporated in vacuo and triturated with pentane-ether to afford the title compound as an off white solid (71%, 35 mg).
Reaction SMILES: C([O:7][CH2:8][CH2:9][C@H:10]1[C@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:13][C:12]2([CH2:24][CH2:23][CH2:22][CH2:21]2)[O:11]1)(=O)C(C)(C)C.C(OCC[C@H]1[C@H](C2C=CC=CC=2)OC(CC)(CC)O1)(=O)C(C)(C)C>>[C:15]1([C@@H:14]2[O:13][C:12]3([CH2:24][CH2:23][CH2:22][CH2:21]3)[O:11][C@H:10]2[CH2:9][CH2:8][OH:7])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)C(=O)OCC[C@@H]1OC2(CCCC2)O[C@H]1c1ccccc1
Agent: CCC1(CC)O[C@@H](CCOC(=O)C(C)(C)C)[C@H](c2ccccc2)O1
Product: OCC[C@@H]1OC2(CCCC2)O[C@H]1c1ccccc1
Yield: 80 %

Procedure:
The substantially same method as described in Example 297 was conducted, except that 2-((2S,3S)-3-phenyl-1,4-dioxaspiro[4.4]nonan-2-yl)ethyl pivalate (Preparation example 298) was used instead of that 2-((4S,5S)-2,2-diethyl-5-phenyl-1,3-dioxolan-4-yl)ethyl pivalate (Preparation example 296), to obtain the title compound (07 g, 80˜95%)
Reaction SMILES: [F:1][C:2]1[S:6][C:5]2[CH2:7][S:8][CH2:9][C:4]=2[C:3]=1[F:10].ClC1C=C(C=CC=1)C(OO)=O>>[F:1][C:2]1[S:6][C:5]2=[CH:7][S:8][CH:9]=[C:4]2[C:3]=1[F:10]
Reactant: Fc1sc2c(c1F)CSC2
Agent: O=C(OO)c1cccc(Cl)c1
Product: Fc1sc2cscc2c1F

Procedure:
In an alternate embodiment, a method is described of producing a monomer wherein the method begins by dissolving 3-fluoro-4,6 dihydrothieno[3,4-b]thiophene in tetrahydrofuran in a non-oxygen atmosphere to create a solution. An initiator of n-butyllithium is then added to the solution to produce an initiated solution. This is followed by adding N-fluorobenzenesulfonimide to the initiated solution to produce 2,3-difluoro-4,6-dihydrothieno[3,4-b]thiophene. 2,3-difluoro-4,6-dihydrothieno[3,4-b]thiophene is then oxidized with meta-chloroperoxybenzoic acid to produce 2,3-difluorothieno[3,4-b]thiophene. 2,3-difluorothieno[3,4-b]thiophene is then bromoated with N-bromosuccinimide to produce 4,6-dibromo-2,3-difluorothieno[2,3-c]thiophene. The final step involves debrominating 4,6-dibromo-2,3-difluorothieno[2,3-c]thiophene and adding an aryl group to produce the monomer
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[C:4]([C:16]2NN=N[N:17]=2)[CH:3]=1.[N-]=[N+]=[N-].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[C:4]([C:16]#[N:17])[CH:3]=1
Reactant: O=C(Nc1ccc(Br)cc1-c1nnn[nH]1)c1cccs1
Agent: Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: N#Cc1cc(Br)ccc1NC(=O)c1cccs1
Temperature: 10 °C

Procedure:
To a solution of 2-amino-5-bromobenzonitrile (1 g, 5.1 mmol) in 20 mL of DCM, DIPEA (27.9 mmol, 5.5 eq.) was added followed by thiophene-2-carbonyl chloride (25.4 mmol, 5.0 eq.). The reaction was stirred at room temperature overnight. The organic solution of the crude reaction mixture was extracted twice with aqueous HCl (0.1 M), twice with aqueous sodium hydroxide (0.1 M), and once with a saturated aqueous solution of sodium chloride. The organic layer was dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 20% EtOAc in hexane eluant) to afford 120 mg of N-(4-bromo-2-cyanophenyl)thiophene-2-carboxamide. MS (EI) for C12H7BrN2OS: 307 (M+H). Step 2: N-[4-Bromo-2-(1H-tetrazol-5-yl)phenyl]thiophene-2-carboxamide: To a mixture of the nitrile N-(4-bromo-2-cyanophenyl)thiophene-2-carboxamide (120 mg, 0.4 mmol), sodium azide (0.5 mmol, 1.3 eq.), and triethylamine hydrochloride (0.5 mmol, 1.3 eq.) in a sealed tube, 1 mL of toluene was added. The tube was tightly capped and the reaction was stirred and heated to 10° C. overnight. The mixture was cooled to room temperature, diluted with another 5 mL of toluene, transferred to a separatory funnel and washed 3×10 mL with water. The aqueous layer was collected and acidified to a pH of 4 with concentrated HCl. The solid was collected by filtration, washed with acetonitrile, and dried under vacuum to afford 18 mg of desired product. 1H-NMR (400 MHz, d6-DMSO): δ 11.60 (s, 1H), 8.44 (d, 1H), 8.23 (d, 1H), 7.99-7.95 (m, 21), 7.82 (dd, 1H), 7.33 (t, 1H). MS (EI) for C12H8BrN5OS: 350 (M+H).
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])([O-:3])=[O:2].[NH2:19][CH2:20][CH2:21][S:22][CH2:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1>C(#N)C>[N+:1]([CH:4]=[C:5]([NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])[NH:19][CH2:20][CH2:21][S:22][CH2:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1)([O-:3])=[O:2]
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1[nH]cnc1C
Reactant: NCCSCc1nccs1
Solvent: CC#N
Product: Cc1nc[nH]c1CSCCNC(=C[N+](=O)[O-])NCCSCc1nccs1

Procedure:
Reaction of 1-nitro-2-methylthio-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene wth an excess of 2-[(2-aminoethyl)thiomethyl]thiazole according to the procedure of Example 3, results in the production of 1-nitro-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]-2-[2-(2-thiazolylmethylthio)ethylamino]ethylene, m.p. 119°-120° (from acetonitrile).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][CH2:20]S)=[CH:11]1.C1C=CC2NC=C(CCO)C=2C=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:8]([O:7][C:1](=[O:6])[CH2:2][C:3]1([CH3:5])[C:11]2[NH:10][C:18]3[C:13]([C:12]=2[CH2:19][CH2:20][O:4]1)=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH3:9]
Reactant: CCOC(=O)CC(C)=O
Reactant: SCCc1c[nH]c2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: OCCc1c[nH]c2ccccc12
Solvent: c1ccccc1
Product: CCOC(=O)CC1(C)OCCc2c1[nH]c1ccccc21
Reaction time: 0.17 h

Procedure:
Ethyl acetoacetate (23.4 g., 0.18 moles) is added to a solution of the starting material of formula II, tryptophol (10.0 g., 0.06 moles), in 200 ml. of benzene. After standing for 10 minutes, p-toluenesulfonic acid (1.3 g.) and about 5 g. of hydrated alkali-aluminum silicate (Molecular Sieves No. 4) are added. The mixture is subjected to reflux for thirty minutes, 600 mg. more of p-toluenesulfonic acid is added and refluxing continued for 21/2 hours. The molecular sieves are collected and the benzene solution washed successively with 5% sodium bicarbonate and water, dried over sodium sulfate, and evaporated under reduced pressure to dryness affording an oil. The oil is subjected to chromatography on silica gel. Elution with 5% ether in benzene yields the ester, 1-methyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1-acetic acid ethyl ester, as an oil, νmaxCHCl3 1715 cm-1.