Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@@H:6]([NH:11][C:12](=[O:24])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]3[CH2:23][CH2:22]3)=[CH:15][CH:14]=1)[CH2:5]2.[C:25](=O)=[O:26].C[Li].C([Li])CCC>O.C(O)(=O)C.CN(C=O)C.C1COCC1>[CH:21]1([CH2:20][O:19][C:16]2[CH:17]=[CH:18][C:13]([C:12]([NH:11][C@H:6]3[CH2:5][C:4]4[C:8](=[CH:9][CH:10]=[C:2]([CH:25]=[O:26])[CH:3]=4)[CH2:7]3)=[O:24])=[CH:14][CH:15]=2)[CH2:23][CH2:22]1
Reactant: O=C(N[C@@H]1Cc2ccc(Br)cc2C1)c1ccc(OCC2CC2)cc1
Reactant: O=C=O
Agent: [Li]C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: O=Cc1ccc2c(c1)C[C@H](NC(=O)c1ccc(OCC3CC3)cc1)C2
Temperature: 25 °C

Procedure:
A mixture of N-((R)-5-bromoindan-2-yl)-4-cyclopropylmethoxybenzamide (6.70 g) and THF (67 ml) was cooled to −78° C. (dry ice bath), and a solution of methyllithium (7.5 ml; 3 M) was added dropwise. One minute after the addition had ended, a solution of butyllithium (10 ml; 2.5 M in toluene) was added dropwise. One minute after the addition had ended, DMF (3.8 g) and, after a further 30 seconds, acetic acid (1.5 ml) were added. After warming to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phases were dried over magnesium sulfate and concentrated. This afforded the product with the molecular weight of 335.41 (C21H21NO3); MS (ESI): 336 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([N:12]2[CH2:18][CH2:17][C:16]3[CH:19]=[CH:20][S:21][C:15]=3[CH2:14][CH2:13]2)[N:3]=1.[CH2:22](Br)[CH3:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:22]([O:8][C:6]1[N:7]=[C:2]([CH3:1])[N:3]=[C:4]([N:12]2[CH2:18][CH2:17][C:16]3[CH:19]=[CH:20][S:21][C:15]=3[CH2:14][CH2:13]2)[C:5]=1[N+:9]([O-:11])=[O:10])[CH3:23]
Reactant: Cc1nc(N2CCc3ccsc3CC2)c([N+](=O)[O-])c(=O)[nH]1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1nc(C)nc(N2CCc3ccsc3CC2)c1[N+](=O)[O-]

Procedure:
In analogy to the procedure described in example 2 2-methyl-5-nitro-6-(4,5,7,8-tetrahydro-thieno[2,3-d]azepin-6-yl)-3H-pyrimidin-4-one (example 9) was treated with ethyl bromide in N,N-dimethylformamide in the presence of potassium carbonate at room temperature to yield 6-(6-ethoxy-2-methyl-5-nitro-pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine as light yellow amorphous solid; MS: [M+H]+=335; and 3-ethyl-2-methyl-5-nitro-6-(4,5,7,8-tetrahydro-thieno[2,3-d]azepin-6-yl)-3H-pyrimidin-4-one as yellow foam; MS: [M+H]+=335.
Reaction SMILES: CC(C)(C)C[O:4][S:5]([C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=4)[N:21]=3)[CH:15]=2)[CH:11]=[CH:12][CH:13]=1)(=[O:7])=[O:6].C([O-])CC.[Na+].C(N(CC)CCS)C>O1CCOCC1>[F:29][C:26]([F:27])([F:28])[C:24]1[CH:23]=[C:22]([C:30]2[CH:31]=[CH:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=2)[N:21]=[C:20]([C:16]2[CH:15]=[C:14]([C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([S:5]([OH:7])(=[O:6])=[O:4])[CH:9]=3)[CH:19]=[CH:18][CH:17]=2)[N:25]=1
Reactant: CC(C)(C)COS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1
Agent: CCC[O-]
Agent: CCN(CC)CCS
Agent: [Na+]
Solvent: C1COCCO1
Product: O=S(=O)(O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1
Yield: 72.6 %

Procedure:
A stirred mixture of 3′-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-biphenyl-3-sulfonic acid 2,2-dimethyl-propyl ester (1.42 g, 2.39 mmol), 2M sodium propanolate solution (3 ml, 6 mmol), 2-(diethylamino)-ethanethiol (0.37 g, 2.75 mmol) and dioxane (15 ml) was heated under reflux conditions for 24 h and evaporated. Water (40 ml) was added and the mixture was extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with water (50 ml). The water layers were combined, acidified with 2N HCl and extracted with ethyl acetate (2×50 ml). The latter two organic layers were combined, washed with brine (50 ml), dried (MgSO4) and evaporated to yield the crude 3′-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-biphenyl-3-sulfonic acid as a brown solid (0.91 g, 51%). Thionyl chloride (20 ml) and DMF (4 drops) were added and the stirred mixture was heated under reflux conditions for 4 h, evaporated and purified by flash chromatography on silica gel (ethyl acetate/heptane) to yield the title compound as a light brown solid (0.43 g, 33%). MS (ISP) 542.2 [(M)+]; mp 176° C.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]([CH2:23][CH2:24][O:25][CH3:26])[C:20](=[O:27])[C@H:19]([NH:28]C(=O)OC(C)(C)C)[CH2:18][CH2:17]1>ClCCl>[NH2:28][C@@H:19]1[CH2:18][CH2:17][C@@H:16]([C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([F:15])[C:9]=2[F:8])[CH2:22][N:21]([CH2:23][CH2:24][O:25][CH3:26])[C:20]1=[O:27]
Reactant: COCCN1C[C@H](c2cccc(F)c2F)CC[C@@H](NC(=O)OC(C)(C)C)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCN1C[C@H](c2cccc(F)c2F)CC[C@@H](N)C1=O
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (2.5 mL) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-1-(2-methoxyethyl)-2-oxoazepan-3-ylcarbamate (99 mg, 0.248 mmol) in dichloromethane (5 mL). After 1 h, the solution was concentrated and azeotroped with toluene (2×). Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. MS 299.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:14])[C:10](OC)=[O:11])=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.Cl>CCOCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:14])[CH2:10][OH:11])=[CH:5][CH:4]=1
Reactant: COC(=O)C(C)c1ccc(OC)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: COc1ccc(C(C)CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
Methyl 2-(4-methoxyphenyl)propionate (11.39g; 0.0586 mol) was dissolved in dry ether (25 ml) and slowly added to a stirred suspension of lithium aluminium hydride (4.59g; 0.121 mol) in dry ether (60 ml); the temperature was maintained below 25° C by cooling. Stirring at ambient temperature was continued for 1 hour. Water was cautiously added dropwise to decompose the unreacted lithium aluminium hydride and the inorganic salts were dissolved by the addition of dilute hydrochloric acid. The ether was separated and the aqueous phase re-extracted with ether (2 × 100 ml). The combined ether extracts were washed with water, saturated sodium bicarbonate solution, water, and then dried over magnesium sulphate. The product was isolated as a pale yellow oil (8.72g) following evaporation of the solvent.
Reaction SMILES: C(O)(=O)C1C(=CC(=CC=1)C(O)=O)C(O)=O.[CH:16]1[C:25]2[C:20](=[CH:21][C:22]([C:26](O)=O)=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[C:29](O)=O.BrC1C2C(=CC(C(O)=O)=CC=2)C=CC=1C(O)=O.C(C1C=CC2C(=CC=C(C(O)=O)C=2)C=1)=O.C1C2C(=CC=CC=2)C=CC=1C(O)=O>>[CH3:26][C:22]1[CH:23]=[CH:24][C:25]2[C:20](=[CH:19][CH:18]=[C:17]([CH3:29])[CH:16]=2)[CH:21]=1
Reactant: O=C(O)c1ccc2cc(C(=O)O)ccc2c1
Agent: O=C(O)c1ccc(C(=O)O)c(C(=O)O)c1
Agent: O=C(O)c1ccc2c(Br)c(C(=O)O)ccc2c1
Agent: O=C(O)c1ccc2ccccc2c1
Product: Cc1ccc2cc(C)ccc2c1

Procedure:
In the following Examples, "TMLA" is trimellitic acid, "2,6-NDA" is 2,6-naphthalenedicarboxylic acid, "Br-NDA" is bromo-2,6-naphthalenedicarboxylic acid, "FNA" is 2-formyl-6-naphthoic acid and "2-NA" is 2-naphthoic acid. "Reactor Yield" or "Molar Reactor Yield," is the percent yield of each component listed in the oxidation reactor effluent and based on the moles of the component produced relative to the moles of 2,6-dimethylnaphthalene feedstock added. The values reported for carbon monoxide and carbon dioxide are the amounts of those oxidation products produced in gram moles per hour. "HCTP" corresponds to hydrocarbon throughput and is defined as the molar feed rate of 2,6-dimethylnaphthalene in pound moles per hour divided by the volume of solvent in the oxidation reactor. The units for HCTP are pound moles of 2,6-dimethylnaphthalene added to the reactor per cubic foot of reactor solvent in the reactor, per hour. "Solvent Ratio" is approximately the rate of removal of solvent by weight divided by the rate of addition of 2,6-dimethylnaphthalene by weight. This value approximately equals the rate of addition of oxidation reaction solvent divided by the rate of addition of 2,6-dimethylnaphthalene, by weight, i.e. the amount of solvent exiting the oxidation reactor may be greater than that added due to the formation of water in the reaction by the oxidation reaction. "Residence Time" is the oxidation reactor drain weight divided by the reaction mixture effluent rate in pounds per minute. "Wt. % Co" is the weight percent cobalt, measured as elemental cobalt, based on the oxidation reaction solvent added to the oxidation reactor. "Co:Mn:Br." is the gram atom ratio of cobalt:manganese:bromine in the catalyst added to the oxidation reaction mixture. The molten 2,6-dimethylnaphthalene (DMN) feed rate values are in pounds per hour.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:6][C@@H:5]([C:7]([O:9]C)=[O:8])[CH2:4][O:3]1.[OH-].[Na+:13]>O1CCOCC1>[CH3:1][C:2]1([CH3:11])[O:6][C@@H:5]([C:7]([O-:9])=[O:8])[CH2:4][O:3]1.[Na+:13]
Reactant: COC(=O)[C@H]1COC(C)(C)O1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC1(C)OC[C@H](C(=O)[O-])O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl (R)-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (1.00 g, 6.2 mmol) was dissolved in 80% aqueous 1,4-dioxane. 1.2 M aqueous NaOH solution was added (5.2 ml) and the reaction mixture was stirred at room temperature for 3 h. After that the solvents were removed under reduced pressure and a colourless solid was obtained (1.03 g, 6.1 mmol, 98%). The product was used immediately in the next reaction step without further purification.
Reaction SMILES: [F:1][C@H:2]1[C@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([F:15])[CH:9]=2)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.Cl>O1CCOCC1>[F:15][C:10]1[CH:9]=[C:8]([C@@H:7]2[CH2:6][CH2:5][NH:4][CH2:3][C@H:2]2[F:1])[CH:13]=[CH:12][C:11]=1[OH:14]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(O)c(F)c2)[C@H](F)C1
Agent: Cl
Solvent: C1COCCO1
Product: Oc1ccc([C@@H]2CCNC[C@H]2F)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 104.9 %

Procedure:
To (3S,4S)-tert-butyl 3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidine-1-carboxylate (3.01 g, 9.61 mmol) in dioxane (10 mL) was added HCl (4 M in Dioxane) (24 mL, 96 mmol) and the reaction was allowed to stir at room temperature for 5 h. The reaction was concentrated to an oil. The oil was taken up in saturated aqueous sodium bicarbonate and extracted with EtOAc/5% MeOH. The combined organic layers were concentrated in vacuo to afford 2-fluoro-4-((3S,4S)-3-fluoropiperidin-4-yl)phenol (2.15 g, quantitative yield): LC-MS [M+H]+=214.1; 1H NMR (500 MHz, DMSO-d6) δ 6.93 (d, J=12.4 Hz, 1H), 6.85-6.72 (m, 2H), 4.49 (td, J=9.9, 4.9 Hz, 1H), 4.39 (td, J=10.0, 5.0 Hz, 1H), 3.27-3.19 (m, 3H), 2.85 (d, J=11.4 Hz, 2H), 2.62-2.54 (m, 2H), 2.46-2.37 (m, 4H), 1.76-1.64 (m, 2H), 1.57-1.37 (m, 3H).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([C:18]#[N:19])[N:17]=2)[C:12]([NH2:14])=[O:13])[CH2:5][CH2:4]1.[Cl:20][C:21]1[C:25]([Cl:26])=[C:24]([CH3:27])[NH:23][C:22]=1[C:28](NC1CCN(C2C=C(SCC(NC)=O)C=C(Cl)N=2)CC1)=[O:29]>>[C:18]([C:16]1[CH:15]=[C:11]([CH:10]=[C:9]([N:6]2[CH2:5][CH2:4][CH:3]([NH:2][C:28]([C:22]3[NH:23][C:24]([CH3:27])=[C:25]([Cl:26])[C:21]=3[Cl:20])=[O:29])[CH2:8][CH2:7]2)[N:17]=1)[C:12]([NH2:14])=[O:13])#[N:19]
Reactant: CNC(=O)CSc1cc(Cl)nc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)c1
Reactant: N#Cc1cc(C(N)=O)cc(N2CCC(N)CC2)n1
Agent: Cl
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(N)=O)cc(C#N)n3)CC2)c(Cl)c1Cl

Procedure:
The title compound was synthesised by an analogous method to Example 18 starting from 2-(4-aminopiperidin-1-yl)-6-cyanoisonicotinamide hydrochloride salt (Intermediate 198) and 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:49]=[CH:48][C:6]([CH2:7][N:8]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=5)[C:33]([OH:35])=O)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[NH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>>[CH3:47][O:46][C:43]1[CH:44]=[CH:45][C:40]([CH2:39][N:8]([CH2:7][C:6]2[CH:48]=[CH:49][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:31]=[C:32]([C:33]([N:50]6[CH2:55][CH2:54][O:53][CH2:52][CH2:51]6)=[O:35])[CH:36]=[CH:37][CH:38]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:41][CH:42]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cccc(C(=O)O)c3)cn2)cc1
Reactant: C1COCCN1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cccc(C(=O)N4CCOCC4)c3)cn2)cc1
Yield: 87.7 %

Procedure:
Using 3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid (38.2 mg, 0.0579 mmol) obtained in Step A instead of 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid, and morpholine (10.1 μl, 0.116 mmol) instead of 3-(aminomethyl)pyridine, in the same manner as Step B in Example 1-D-19, amidation was carried out, to obtain a crude product of {3-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-phenyl}-morpholin-4-yl-methanone as a yellow liquid (37 mg), and then the PMB groups were removed according to the above Deprotection method 2, to obtain the desired compound (D-53) as a yellow powder (22.3 mg, 78%).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25]([OH:27])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.O[NH:29][C:30](=[NH:35])[CH2:31][CH2:32][O:33][CH3:34]>>[CH3:34][O:33][CH2:32][CH2:31][C:30]1[N:35]=[C:25]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:2][CH2:3][S:4][CH2:5][CH2:6]3)=[O:8])[CH2:10]2)[O:27][N:29]=1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Reactant: COCCC(=N)NO
Product: COCCc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCSCC3)C2)n1

Procedure:
According to General Method 6A, 600 mg (1.491 mmol) of the compound from Example 16A and 242 mg (1.640 mmol) of N-hydroxy-3-methoxypropanimidamide were reacted Yield: 350 mg (46% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[H][H]>N.CO>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1
Reactant: [H][H]
Agent: N
Solvent: CO
Product: NCc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 98.9 %

Procedure:
Sponge nickel from Comparative Example 1 (12 mg, 20 mol % Ni on substrate) was washed with MeOH three times to remove water and added to 4-chlorobenzonitrile (0.137 g, 1 mmol) dissolved in 7 N ammonia in MeOH (4 ml) in a pressure vessel. The vessel was sealed and purged twice with hydrogen then pressurised to 5-6 bar with hydrogen and the contents magnetically stirred at room temperature. Progress of reaction was carried out by GCMS analysis. After 24 h the hydrogen was vented and the Ni catalyst removed by filtration. The filtrate was concentrated on a rotary evaporator to give 4-chlorobenzylamine (0.14 g, 99%). GCMS purity 78%.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH3:7])[CH2:5][OH:6].[NH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13](F)[C:10]=1[C:11]#[N:12]>C1COCC1>[NH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([O:6][CH2:5][CH:4]([CH3:7])[CH3:3])[C:10]=1[C:11]#[N:12]
Reactant: CC(C)CO
Reactant: N#Cc1c(N)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)COc1cccc(N)c1C#N
Temperature: 35 °C

Procedure:
Sodium hydride (60% suspension in oil, 25.0 g, 0.625 mol) was suspended in anhydrous THF (1000 mL) under nitrogen and heated to an internal temperature of 40° C. to 45° C. 2-methylpropan-1-ol (61.2 mL, 0.661 mol) was then added slowly and portionwise. The mixture was heated at 40° C. to 45° C. for 1 hour, then cooled to 35° C. 2-amino-6-fluorobenzonitrile (50.0 g, 0.367 mol) was added and refluxed for 21 hours. The mixture was cooled to r.t., then ice (250 g), ice water (750 mL), and hexanes (1000 mL) was added. Insoluble solids were filtered out and the organic layer was separated. The aqueous layer was extracted once more with a mixture of diethyl ether (250 mL) and hexanes (250 mL). The combined organic layer was washed twice with a solution of citric acid (53 g) in water (500 mL), then washed with 80% brine (300 mL), then dried with magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in methanol (500 mL), and the immiscible oil carried through from the sodium hydride suspension was separated off in a separatory funnel. The solvent was evaporated under vacuum, and the residue was washed with hexanes (250 mL), after which the product 2-amino-6-isobutoxybenzonitrile was obtained as a viscous oil (46 grams, yield: 66%). 1H NMR (400 MHz, DMSO-d6) δ 7.16 (t, J=8.0 Hz, 1H), 6.33 (d, J=8.0 Hz, 1H), 6.17 (d, J=8.0 Hz, 1H), 5.97 (s, 2H), 3.75 (d, J=7.2 Hz, 2H), 2.00 (m, 1H), 0.97 (d, J=6.8 Hz, 6H) ppm. MS 191 (MH+).
Reaction SMILES: N([O-])=[O:2].[Na+].[C:5]([C:7]1[CH:15]=[CH:14][C:10]([C:11](N)=[O:12])=[CH:9][CH:8]=1)#[N:6]>S(=O)(=O)(O)O>[C:5]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:2])=[O:12])=[CH:9][CH:8]=1)#[N:6]
Reactant: N#Cc1ccc(C(N)=O)cc1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: N#Cc1ccc(C(=O)O)cc1
Yield: 94.2 %

Procedure:
Sodium nitrite (2.07 g) was dissolved in a 70 wt. % aqueous sulfuric acid solution (100 ml), and p-cyanobenzamide (2.92 g) was added to the resultant solution. The mixture was allowed to react at room temperature for one hour with stirring. The precipitated crystals were collected through filtration, washed with water, and dried, to thereby obtain 2.77 g of p-cyanobenzoic acid (yield 95%). High performance liquid chromatographic analysis revealed that the p-cyanobenzoic acid obtained had a purity of 99% or more.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:13][NH:14][CH3:15].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CC#N>[C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([N:14]([CH3:15])[CH3:13])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(=O)c1ccc(C(=O)N(C)C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 51.4 %

Procedure:
A mixture of 4-acetylbenzoic acid (40 g, 244 mmol), 40% aqueous dimethylamine (33.0 g, 292 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (56.1 g, 292 mmol), 1-hydroxybenzotriazole hydrate (44.8 g, 292 mmol) and N,N-diisopropylethylamine (85 mL, 487 mmol) in CH3CN (400 mL) was stirred at room temperature for 15 h then concentrated. The residue was dissolved in ethyl acetate (1000 mL), washed with H2O (2×200 mL), brine (200 mL), dried (MgSO4) and concentrated to provide 4-acetyl-N,N-dimethylbenzamide (24 g). The crude product was taken to the next step without purification.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][CH2:5][N:6]1[CH:11]=[C:10]([C:12]2[C:13]([F:19])=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[C:9](=[O:20])[NH:8][C:7]1=[O:21]>C1COCC1>[F:19][C:13]1[C:12]([C:10]2[C:9](=[O:20])[NH:8][C:7](=[O:21])[N:6]([CH2:5][CH2:4][CH:3]=[O:2])[CH:11]=2)=[CH:17][CH:16]=[C:15]([CH3:18])[N:14]=1
Reactant: COC(CCn1cc(-c2ccc(C)nc2F)c(=O)[nH]c1=O)OC
Solvent: C1CCOC1
Product: Cc1ccc(-c2cn(CCC=O)c(=O)[nH]c2=O)c(F)n1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
1-(3,3-Dimethoxy-propyl)-5-(2-fluoro-6-methyl-pyridin-3-yl)-1H-pyrimidine-2,4-dione (Prep16, 150 mg, 0.46 mmol) was dissolved in THF (4 ml) and then 1N HClaq (0.46 ml) was added. The solution was stirred at 40° C. for 1 hour. TEA (65 μl, 0.47 mmol) was added and the solvent was removed in vacuum at room temperature. Residue was freeze dried to give a white powder that was used in the next step without further purification (quantitative yield).
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:4]=[CH2:5].Br[CH2:18][C:19]#[CH:20]>CN(C=O)C.CCOCC>[CH2:3]([C:6]([CH2:20][C:19]#[CH:18])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:4]=[CH2:5]
Reactant: C#CCBr
Reactant: C=CCC(C(=O)OCC)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C#CCC(CC=C)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NaH (60%, 0.480 g) was added to a cold (0° C.) solution of diethyl 2-allylmalonate (2.002 g) in DMF (10 mL) and the mixture was allowed to warm to rt over 30 min. Then a solution of 3-bromoprop-1-yne (1.487 g) in DMF (3 mL) was added dropwise at 0° C. and the mixture was allowed to warm to rt and stirred at rt overnight. The reaction mixture was diluted with ether and then quenched with sat. NH4Cl, washed with water, brine and dried (Na2SO4). The crude product was purified by silica gel FCC (1:1 DCM-hexane) to afford diethyl 2-allyl-2-(prop-2-ynyl)malonate as a clear oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][S:9]([CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:11])=[O:10])[C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1.[CH2:27]([OH:30])[CH2:28][OH:29]>>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:3]2[C:4]([NH:8][S:9]([CH:12]=[CH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:11])=[O:10])=[N:5][CH:6]=[N:7][C:2]=2[O:29][CH2:28][CH2:27][OH:30])=[CH:21][CH:22]=1
Reactant: O=S(=O)(C=Cc1ccccc1)Nc1ncnc(Cl)c1-c1ccc(Cl)cc1
Reactant: OCCO
Product: O=S(=O)(C=Cc1ccccc1)Nc1ncnc(OCCO)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 17 h

Procedure:
6.20 g of 2-phenyl-ethenesulfonic acid [6-chloro-5-(4-chloro-phenyl)-pyrimidin-4-yl]-amide was added to a solution of 7.65 g of potassium-tert.-butylate in 100 ml of ethylene glycol. The resulting solution was heated to 110° C. and stirred for 17 h. The ethylene glycol was evaporated under high vacuum and the remaining residue was treated with 250 ml of cold water. The suspension was acidified by adding 10 g of citric acid monohydrate and stirred at 0° C. for 15 min. The precipitate was collected, washed with water and dried to give 6.71 g of 2-phenyl-ethenesulfonic acid [5-(4-chloro-phenyl)-6-(2-hydroxy-ethoxy)-pyrimidin-4-yl]-amide as a white powder. LC-MS: tR=4.55 min, [M+H]+=432.00 (ES+), [M−H]−=429.98 (ES−).
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-])=O.[CH2:12]([O:19][CH2:20][CH2:21][SH:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[K+]>CN(C=O)C.O>[CH2:12]([O:19][CH2:20][CH2:21][S:22][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[C:6]#[N:7])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1ccccc1[N+](=O)[O-]
Reactant: SCCOCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccccc1SCCOCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.6 %

Procedure:
A solution of 2-nitrobenzonitrile (5.85 g) in DMF (20 mL) was treated with 2-(benzyloxy)ethanethiol (Example 320a, 6.64 g) and a solution of potassium hydroxide (3.76 g) in water (5 mL) was added dropwise under nitrogen. The resulting mixture was stirred at 0° C. for 2 h. The reaction was quenched with water and extracted into ethyl acetate. The combined organics were washed with brine, dried (MgSO4), and concentrated in vacuo. The residue was purified (SiO2 chromatography eluting with 50% diethyl ether in iso-hexane) to afford the subtitle compound as a solid (7.08 g).