Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1Br)[CH3:2].C([Li])CCC.[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=[O:24]>O1CCCC1.CCCCCC>[CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:23]([C:22]1[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=1[F:20])[OH:24])[CH3:2]
Reactant: CCOC(OCC)c1ccccc1Br
Reactant: O=Cc1ccccc1F
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(OCC)c1ccccc1C(O)c1ccccc1F
Temperature: -25 °C
Reaction time: 0.5 h

Procedure:
A solution of 345 g of 2-bromobenzaldehyde diethyl acetal in 3 l of dry tetrahydofuran was cooled to −40° C. In one portion, 913 ml of a 1.6 M solution of butyllithium in hexane were added under vigorous stirring. The resulting solution was stirred for 0.5 h at −25° C., after which a solution of 140 ml of 2-fluorobenzaldehyde in 350 ml tetrahydrofuran was added drop-wise. In a period of 4 h, the mixture was allowed to reach room temperature. The resulting mixture was pored upon ice-water and extracted several times with ethyl acetate. The organic layers were combined, washed with water, dried over magnesium sulphate and evaporated to dryness under reduced pressure to yield 404 g of 2-(diethoxymethyl)-α-(2-fluorophenyl)-benzenemethanol as an oil, M.S. (C.I.) (M/Z): 305 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:19][C:20]#[N:21])=[CH:5][N:6]2[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[Cl:22]N1C(=O)CCC1=O>C(Cl)Cl>[NH2:1][C:2]1[C:10]([Cl:22])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:19][C:20]#[N:21])=[CH:5][N:6]2[CH2:11][C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13]
Reactant: CC(C)(C)OC(=O)Cn1cc(CC#N)c2c(N)cccc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Cn1cc(CC#N)c2c(N)c(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl [4-amino-3-(cyanomethyl)-1H-indol-1-yl]acetate from Step A (150 mg, 0.526 mmol) in CH2Cl2 (5 mL) was added N-chlorosuccinimide (70 mg, 0.526 mmol). The reaction mixture was stirred at ambient temperature for 30 min, then partitioned between saturated aqueous NaHCO3 (5 mL) and CHCl3 (15 mL). The aqueous phase was extracted further with CHCl3 (15 mL) and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound, which was of sufficient purity for use in the next step. MS: m/z=320 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]([CH3:14])[N:4]=1.[H-].[Na+].F[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1>CN(C=O)C>[CH3:14][N:5]1[N:4]=[C:3]([CH2:2][O:1][C:18]2[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:13]
Reactant: Cn1nc(CO)c2ccccc2c1=O
Reactant: O=Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1nc(COc2ccc(C=O)cc2)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 55.4 %

Procedure:
##STR29## To a stirred solution of 4-hydroxymethyl-2-methyl-1(2H)-pthalazinone (350 mg, 1.84 mmol) (prepared according to the procedure described in Chem. Pharm. Bull., 28 (1980) 2763) in dry DMF (30 mL) was added NaH (88 mg, 3.68 mmol) in portions over 30 min at 25-30° C., followed by 4-fluorobenzaldehyde (228 mg, 1.84 mmol) added dropwise, keeping the temperature between 0-15° C. The reaction mixture was stirred at room temperature further for 6 h. Ice (200 g) was added to the reaction mixture and extracted with EtOAc. The EtOAc layer was washed with water, dried over anhydrous Na2SO4 and concentrated to obtain the title compound (300 mg, 50%). mp: 168-170° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([NH:15][C:16]([NH:18][C:19]1[CH:24]=[C:23]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH:22]=[CH:21][N:20]=1)=[O:17])(=O)C1C=CC=CC=1.Cl>C(O)C>[CH3:34][O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][CH2:25][C:23]1[CH:22]=[CH:21][N:20]=[C:19]([NH:18][C:16]([NH2:15])=[O:17])[CH:24]=1
Reactant: COc1ccccc1CCc1ccnc(NC(=O)NC(=O)c2ccccc2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1ccccc1CCc1ccnc(NC(N)=O)c1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
Potassium carbonate (93.2 mg, 0.674 mmol) is added to a solution of the crude 1-benzoyl-3-{4-[2-(2-methoxy-phenyl)-ethyl]-pyridin-2-yl}-urea (211 mg) in absolute ethanol (3 mL), and the mixture is heated at 85° C. After 2 hours, the mixture is cooled to room temperature, neutralized with 1 M aqueous HCl to pH 7-8, and stirred over night. The mixture is filtered, and the solids are washed with EtOH (2×0.5 mL) and air dried. The solids are partitioned between ethyl acetate (10 mL) and saturated aqueous NaHCO3 (3 mL). The organic layer is dried over MgSO4, filtered and concentrated to give the titled product.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH:11]([C:17]3([C:21]([O:23][CH2:24]C)=[O:22])[CH2:20][CH2:19][CH2:18]3)[NH:10][CH2:9][CH2:8][C:7]2=1.Cl.[Cl:27]C1C=C2C(=CC=1)NC1C(C3(C(OC)=O)CCC3)NCCC2=1>>[ClH:27].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH:11]([C:17]3([C:21]([O:23][CH3:24])=[O:22])[CH2:20][CH2:19][CH2:18]3)[NH:10][CH2:9][CH2:8][C:7]2=1
Reactant: CCOC(=O)C1(C2NCCc3c2[nH]c2ccc(OC)cc32)CCC1
Reactant: COC(=O)C1(C2NCCc3c2[nH]c2ccc(Cl)cc32)CCC1
Agent: Cl
Product: COC(=O)C1(C2NCCc3c2[nH]c2ccc(OC)cc32)CCC1

Procedure:
The procedure is as in Example 23, starting from the compound of Example 7 and the reagent of Example 26.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([OH:14])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH:15]1[CH2:20][CH2:19][CH:18](O)[CH2:17][CH2:16]1>>[CH:1]1[C:13]2[CH:12]([O:14][CH:18]3[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: OC1CCNCC1
Reactant: OC1c2ccccc2-c2ccccc21
Product: c1ccc2c(c1)-c1ccccc1C2OC1CCNCC1
Yield: 38 %

Procedure:
Using 9-fluorenol and 4-piperidinol, the procedure of Reference Example 23 was otherwise repeated to provide the title compound. Yield 38%.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[S:7][C:6]1=[O:14].[Cl:15][C:16]1[CH:31]=[CH:30][C:19]2[N:20]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:21](=[O:23])[NH:22][C:18]=2[CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[Cl:15][C:16]1[CH:31]=[CH:30][C:19]2[N:20]([CH:24]3[CH2:25][CH2:26][N:27]([CH2:2][CH2:3][CH2:4][N:5]4[C:9]5[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=5[S:7][C:6]4=[O:14])[CH2:28][CH2:29]3)[C:21](=[O:23])[NH:22][C:18]=2[CH:17]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Reactant: O=c1sc2ccccc2n1CCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=c1sc2ccccc2n1CCCN1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1
Yield: 31 %

Procedure:
A mixture of 5.4 parts of 3-(3-bromopropyl)-2(3H)-benzothiazolone, 4.5 parts of 5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 5.3 parts of sodium carbonate, 0.1 parts of potassium iodide and 200 parts of 4-methyl-2-pentanone is stirred and refluxed for 3 hours with water-separator. After cooling, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2-propanone. The product is filtered off and dried, yielding 2.5 parts (31%) of 5-chloro-1,3-dihydro-1-{1-[3-(2-oxo-3(2H)-benzothiazolyl)propyl]-4-piperidinyl}-2H-benzimidazol-2-one; mp. 184.1° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[C:9]([CH:11]=[O:12])[CH:8]=[CH:7][C:6]=1[O:13][CH2:14][CH:15]([CH3:17])[CH3:16])(=[O:3])[CH3:2].P([O-])(O)(O)=[O:19].[Na+].OO.Cl([O-])=O.[Na+]>C(#N)C.O.C(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[CH:10]=[C:9]([CH:8]=[CH:7][C:6]=1[O:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:19])=[O:12])(=[O:3])[CH3:2]
Reactant: O=P([O-])(O)O
Reactant: CC(=O)Oc1cc(C=O)ccc1OCC(C)C
Agent: OO
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC#N
Product: CC(=O)Oc1cc(C(=O)O)ccc1OCC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
In 38 ml of acetonitrile is dissolved 4.1 g of 5-formyl-2-isobutoxyphenyl acetate. To the solution thus obtained, 6.8 g of sodium dihydrogenphosphate dissolved in 20 ml of water and 3.6 ml of 30% aqueous hydrogen peroxide are successively added at ambient temperature, and then 3.6 g of sodium chlorite dissolved in 18 ml of water is dropwise added at 5-10° C. The mixture thus obtained is stirred at ambient temperature for 2 hours. Chloroform and water are added to the reaction mixture, the organic layer is separated, the organic layer thus obtained is washed successively with 5% aqueous solution of sodium thiosulfate and saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. Thus, 4.0 g of 3-(acetyloxy)-4-isobutoxybenzoic acid is obtained as a light yellow solid product.
Reaction SMILES: [F:1][CH:2]([F:40])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([NH:26]C(=O)OC(C)(C)C)=[CH:22][CH:21]=3)[N:9]=2)[C:6]2[CH:34]=[CH:35][CH:36]=[C:37]([O:38][CH3:39])[C:5]=2[N:4]=1.C(O)(C(F)(F)F)=O.N>C(Cl)Cl>[F:40][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([C:20]3[CH:21]=[CH:22][C:23]([NH2:26])=[CH:24][CH:25]=3)[N:9]=2)[C:6]2[CH:34]=[CH:35][CH:36]=[C:37]([O:38][CH3:39])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(-c2ccc(NC(=O)OC(C)(C)C)cc2)nc(N2CCOCC2)n1
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(-c2ccc(N)cc2)nc(N2CCOCC2)n1
Yield: 88.3 %

Procedure:
Reaction of the above carbamate (300 mg, 0.542 mmol) with an excess of TFA (2 mL) in CH2Cl2 (10 mL) at room temperature for 3 hrs, followed by treatment with aq. NH3 gave 4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]aniline (217 mg, 88%), which was used in the next step without further purification: 1H NMR (DMSO-d6) δ 8.17 (d, J=8.7 Hz, 2H), 8.05 (dd, J=8.3, 0.4 Hz, 1H), 7.80 (t, JHF=52.9 Hz, 1H), 7.47 (t, J=8.2 Hz, 1H), 6.99 (d, J=7.8 Hz, 1H), 6.68 (d, J=8.8 Hz, 2H), 6.05 (s, 2H), 4.01 (br s, 2H), 3.99 (s, 3H), 3.88 (br s, 2H), 3.75 (m, 4H).
Reaction SMILES: ClC1C=CC([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:32])([F:31])[C:15]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])([OH:22])[CH2:16][N:17]3[CH:21]=[N:20][N:19]=[N:18]3)=[N:12][CH:13]=2)=C(F)C=1.BrC1C=CC(OC)=CN=1>>[F:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[C:15]([OH:22])([CH2:16][N:17]1[CH:21]=[N:20][N:19]=[N:18]1)[C:14]([F:32])([F:31])[C:11]1[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:13][N:12]=1
Reactant: OC(Cn1cnnn1)(c1ccc(F)cc1F)C(F)(F)c1ccc(OCc2ccc(Cl)cc2F)cn1
Agent: COc1ccc(Br)nc1
Product: COc1ccc(C(F)(F)C(O)(Cn2cnnn2)c2ccc(F)cc2F)nc1

Procedure:
Compound 8 was prepared in a similar manner to compound 1 from 2-bromo-5-methoxypyridine to afford a tan solid (28 mg, 10%). 1H NMR (500 MHz, CDCl3): δ 8.74 (s, 1H), 8.19 (s, 1H), 7.63 (br s, 1H), 7.51 (d, J=8.5 Hz, 1H), 7.34-7.33 (m, 1H), 7.24-7.23 (m, 1H), 6.75-6.74 (m, 1H), 6.67-6.66 (m, 1H), 5.58 (d, J=14.0 Hz, 1H), 5.07 (d, J=14.0 Hz, 1H), 3.88 (s, 3H). MS (ESI): m/z 382 [M+−1]. HPLC: 92.37%.
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.CN(C)CCC(N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1)=O.[CH:87]([N:90]1[CH2:95][CH2:94][N:93]([CH2:96][C:97]([OH:99])=O)[CH2:92][CH2:91]1)([CH3:89])[CH3:88]>>[CH:87]([N:90]1[CH2:91][CH2:92][N:93]([CH2:96][C:97]([NH:1][C@:2]23[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]2[C@@H:4]2[C@@:17]([CH3:20])([CH2:18][CH2:19]3)[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5]2)=[O:99])[CH2:94][CH2:95]1)([CH3:88])[CH3:89]
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC(C)N1CCN(CC(=O)O)CC1
Agent: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)CN3CCN(C(C)C)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 22 %

Procedure:
The title compound was prepared in 22% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except (4-isopropyl-piperazin-1-yl)-acetic acid was used instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 698.6 (M+H)+, 2.64 min (method 6). 1H NMR (500 MHz, 1:1 CDCl3:MeOD) δ=7.92 (d, J=8.2 Hz, 2H), 7.37 (br. s., 1H), 7.20 (d, J=8.2 Hz, 2H), 6.34-6.03 (m, 1H), 5.29 (d, J=4.6 Hz, 1H), 4.76 (br. s., 1H), 4.70 (br. s., 1H), 3.95 (br. s., 1H), 3.84-3.55 (m, 8H), 3.17 (q, J=7.2 Hz, 2H), 2.64 (d, J=13.1 Hz, 2H), 2.39 (dd, J=8.1, 11.4 Hz, 1H), 2.12 (dd, J=6.3, 17.2 Hz, 1H), 1.96-1.84 (m, 2H), 1.79 (d, J=12.5 Hz, 1H), 1.76-1.65 (m, 5H), 1.59-1.40 (m, 14H), 1.35 (t, J=7.2 Hz, 4H), 1.29-1.21 (m, 1H), 1.15 (d, J=6.1 Hz, 1H), 1.10 (br. s., 3H), 1.02 (s, 3H), 1.01 (br. s., 2H), 0.94 (br. s., 3H), 0.93 (br. s., 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH:8]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[C:10]3[CH2:25][CH2:26][C:27](=[O:28])[C:9]2=3)=[CH:4][CH:3]=1.[CH3:29][N:30](C)C=O>[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:14]=[C:12]1[N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=2)[C:10]2[CH2:25][CH2:26][C:27](=[O:28])[C:9]=2[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([C:29]#[N:30])=[N:7][CH:6]=2)[NH:13]1
Reactant: CN(C)C=O
Reactant: O=C1CCC2=C1C(c1ccc(Cl)nc1)NC(=O)N2c1cccc(C(F)(F)F)c1
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CC3)cn1
Temperature: 25 °C

Procedure:
Under an atmosphere of argon, a mixture of 4-(6-chloropyridin-3-yl)-1-(3-(trifluoro-methyl)phenyl)-3,4,6,7-tetrahydro-1H-cyclopenta[d]pyrimidine-2,5-dione (intermediate 11, a) 120 mg, 294 μmol), zinc cyanide (59 mg, 0.50 mmol) and tetrakis(triphenylphosphine)-palladium(0) (34 mg, 29 μmol) in N,N-dimethylformamide (2 mL) is heated at 110° C. for 24 h. The reaction mixture is cooled to room temperature and then purified by preparative reversed phase HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 10 mg; ESI mass spectrum [M+H]+=399; Retention time HPLC: 0.50 min (V012_S01).
Reaction SMILES: [O:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]([OH:14])=O)[C:2]1=[O:3].Cl.Cl.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>CCCCCC.C(OCC)(=O)C.O.CN(C)C=O>[O:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]([N:26]2[CH2:25][CH2:24][N:23]([CH2:22][C:21]3[CH:29]=[C:30]([O:34][CH3:35])[C:31]([O:32][CH3:33])=[C:19]([O:18][CH3:17])[CH:20]=3)[CH2:28][CH2:27]2)=[O:14])[C:2]1=[O:3]
Reactant: O=C(O)c1cc2ccccc2oc1=O
Reactant: COc1cc(CN2CCNCC2)cc(OC)c1OC
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COc1cc(CN2CCN(C(=O)c3cc4ccccc4oc3=O)CC2)cc(OC)c1OC
Reaction time: 1 h
Yield: 16.9 %

Procedure:
To a mixture of coumarin-3-carboxylic acid (0.9 g), 1(3,4,5-trimethoxybenzyl)piperazine dihydrochloride (1.7 g), triethylamine (1.8 g) and N,N-dimethylformamide (20 ml) is added dropwise at room temperature diethyl cyanophosphonate (1.8 ml), followed by stirring for one hour. After addition of water (50 ml), the reaction mixture is left standing for 30 minutes, followed by addition of water (150 ml), ethyl acetate (200 ml) and hexane (50 ml). The mixture is vigorously mixed and the organic layer is separated. The organic layer is washed with water, dried, and concentrated under reduced pressure. The residue is purified by means of a silica gel column chromatography(hexane:acetone=1:1-1:2) to give an oily product, which is crystallized from a mixture of acetone and ethyl ether to afford 1-(3-coumarinylcarbonyl)-4-(3,4,5-trimethoxybenzyl)piperazine (0.35 g) as colorless needles, m.p. 171°-173° C.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[NH2:21][C:22]1[C:27]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:37][CH3:38])=[O:29])=[C:26](Cl)[N:25]=[CH:24][N:23]=1.CCN(C(C)C)C(C)C.[F-].[Cs+]>C(O)(C)(C)C>[NH2:21][C:22]1[C:27]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:37][CH3:38])=[O:29])=[C:26]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[N:25]=[CH:24][N:23]=1
Reactant: COc1ccccc1NC(=O)c1c(N)ncnc1Cl
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: COc1ccccc1NC(=O)c1c(N)ncnc1N[C@@H](C)c1nn2ccc(C)c2c(=O)n1-c1ccccc1
Temperature: 150 °C
Yield: 36.5 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (97 mg, 0.36 mmol), 4-amino-6-chloro-N-(2-methoxyphenyl)pyrimidine-5-carboxamide (100 mg, 0.36 mmol), DIEA (400 μl, 2.3 mmol) and cesium fluoride (166 mg, 1.09 mmol) were suspended in tert-butanol (10 ml) and the mixture was heated at 150° C. in a microwave oven for 35 min. The solvent was evaporated under reduced pressure and the reaction mixture was diluted with ethyl acetate and washed with saturated ammonium chloride solution and brine. After evaporation of the solvent, the residue was purified by flash chromatography using SP1® Purification System (30% to 70%, dichloromethane-ethyl acetate) to obtain 67 mg (37% yield) of the title compound.
Reaction SMILES: COC(=O)C(O)=CC(=O)N(CC1C=CC(F)=CC=1)C.C=O.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][NH2:31].[F:32][C:33]1[CH:51]=[CH:50][C:36]([CH2:37][N:38]([CH3:49])[C:39]([C:41]2[CH2:42]N(C)[C:44](=[O:47])[C:45]=2[OH:46])=[O:40])=[CH:35][CH:34]=1>>[F:32][C:33]1[CH:51]=[CH:50][C:36]([CH2:37][N:38]([CH3:49])[C:39]([C:41]2[CH2:42][N:31]([CH2:30][CH2:29][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[Cl:22])[C:44](=[O:47])[C:45]=2[OH:46])=[O:40])=[CH:35][CH:34]=1
Reactant: CN1CC(C(=O)N(C)Cc2ccc(F)cc2)=C(O)C1=O
Reactant: NCCc1ccccc1Cl
Agent: C=O
Agent: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(F)cc1
Product: CN(Cc1ccc(F)cc1)C(=O)C1=C(O)C(=O)N(CCc2ccccc2Cl)C1

Procedure:
3-[(4-Fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 1-D) was treated with paraformaldehyde and 2-(2-chlorophenyl)-ethylamine as described in the preparation of Compound 1. HRMS (M+H) calcd for C21H21ClFN2O3: 403.1225. found: 403.1237. 1H NMR (500 MHz, CDCl3) δ: 2.96 (s, 3), 3.05 (t, 2, J=7), 3.75 (t, 2, J=7), 3.99 (s, 2), 4.58 (s, 2), 7.01–7.34 (overlapping m, 8). 13C NMR (125 MHz, CDCl3) δ: 32.37, 34.52, 42.90, 49.36, 51.47, 109.38, 115.66, 115.83, 127.18, 128.37, 129.26, 129.32, 129.67, 130.92, 132.13, 132.15, 134.01, 135.79, 152.71, 161.37, 163.33, 164.91, 166.11.
Reaction SMILES: [F:1][C:2]([F:13])([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3]([O-])=O.[Na+].[NH2:15][C:16]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([NH2:20])=[O:19]>O>[F:1][C:2]([F:13])([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3]1[NH:20][C:18](=[O:19])[C:17]2[C:16](=[C:24]([F:25])[CH:23]=[CH:22][CH:21]=2)[N:15]=1
Reactant: NC(=O)c1cccc(F)c1N
Reactant: O=C([O-])C(F)(F)c1ccc(F)cn1
Agent: [Na+]
Solvent: O
Product: O=c1[nH]c(C(F)(F)c2ccc(F)cn2)nc2c(F)cccc12
Temperature: 115 °C
Yield: 97 %

Procedure:
Sodium 2,2-difluoro-2-(5-fluoropyridin-2-yl)acetate from Example 2 Step B (51 mg, 0.24 mmol) and 2-amino-3-fluorobenzamide (31 mg, 0.2 mmol) were combined with polyphosphoric acid (1.0 g) and the mixture was heated at 115° C. for 20 h with vigorous stirring. The mixture was allowed to cool to rt, then water (3 mL) was added, resulting in a precipitate that was separated washing with DCE (2×8 mL). The combined DCE extracts were washed with brine (3 mL) and separated using Biotage Phase Separators. The organic fraction was concentrated using a Savant Speed Vac to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-fluoroquinazolin-4(3H)-one as an off-white solid (60 mg). LCMS (ESI) m/z 310 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]2[S:12][C:13]([S:16][C:17]#N)=[CH:14][N:15]=2)=[N:8][CH:9]=1)([O-:3])=[O:2].SC[C@H]([C@@H](CS)O)O.ClC1[CH:33]=[CH:32][N:31]=[C:30]([C:34]([O:36][CH3:37])=[O:35])[C:29]=1[F:38].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CO.O.CN(C=O)C>[F:38][C:29]1[C:30]([C:34]([O:36][CH3:37])=[O:35])=[N:31][CH:32]=[CH:33][C:17]=1[S:16][C:13]1[S:12][C:11]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=2)=[N:15][CH:14]=1
Reactant: COC(=O)c1nccc(Cl)c1F
Reactant: N#CSc1cnc(Nc2ccc([N+](=O)[O-])cn2)s1
Agent: O=P([O-])([O-])[O-]
Agent: O[C@H](CS)[C@H](O)CS
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1nccc(Sc2cnc(Nc3ccc([N+](=O)[O-])cn3)s2)c1F
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a stirring suspension of N-(5-nitropyridin-2-yl)-5-thiocyanatothiazol-2-amine (2.00 g, 7.16 mmol) in MeOH (72 mL) was added dithiothreitol (2.22 g, 14.39 mmol). After 5 minutes, methyl 4-chloro-3-fluoropicolinate (1.51 g, 7.97 mmol), K3PO4 (1.98 g, 9.33 mmol) and DMF (72 mL) were sequentially added. After 2 hours, the reaction was poured into an ice/water (˜1.4 L) mixture with stirring for 90 minutes, diluted to ˜3.5 L with water, allowed to sit overnight. The solid was collected by filtration, washed with water and allowed to air dry overnight. The product was obtained (2.384 g, 82%) as a solid: 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.68 (1H, s), 9.19 (1H, d, J=2.78 Hz), 8.53 (1H, dd, J=9.35, 2.78 Hz), 8.32 (1H, d, J=5.05 Hz), 7.96 (1H, s), 7.23 (1H, d, J=9.35 Hz), 7.15 (1H, t, J=5.43 Hz), 3.89 (3H, s); LC/MS (M+H)+: 408. HPLC ret. time (Condition B): 1.78 min.