Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([O:33][CH3:34])=[O:32])=[CH:21][CH:20]=2)[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]([S:10][CH2:11][CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4].C(Cl)Cl.ClC1C=CC=C(C(OO)=[O:46])C=1>O>[CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([O:33][CH3:34])=[O:32])=[CH:23][CH:24]=2)[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]([S:10]([CH2:11][CH3:12])=[O:46])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(SCC)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: CCCCc1nc(S(=O)CC)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Yield: 77.4 %

Procedure:
500 mg of product obtained in Example 5 with 5 cm3 of methylene chloride and 215 mg of meta chloroperbenzoic acid is agitated for 2 hours at ambient temperature. The mixture is poured into 50 cm3 of water, extracted 3 times with 50 cm3 of methylene chloride, the extracts are dried, filtered and brought to dryness under reduced pressure. The residue (675 mg) is chromatographed on silica (eluant: methylene chloride - acetone (6-4)). 400 mg of the desired product is obtained.
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[CH:24])[CH:18]=1>C(OCC)(=O)C.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:15][C:13]1[CH:12]=[N:11][CH:10]=[C:9]([C:24]#[C:23][C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[CH:18]=2)[CH:14]=1
Reactant: C#Cc1cccc(Cl)c1
Reactant: Brc1cncc(Br)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Clc1cccc(C#Cc2cncc(Br)c2)c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 46.2 %

Procedure:
Add triethylamine (2.38 mL, 16.88 mmol), copper (I) iodide (80.4 mg, 0.422 mmol) and bis(triphenylphosphine)palladium (II) dichloride (148 mg, 0.211 mmol) to a solution of 3,5-dibromopyridine (1 g, 4.22 mmol) and 1-chloro-3-ethynylbenzene, (prepared as described in PREPARATION 12), (574 mg, 4.22 mmol) in ethyl acetate (4.22 mL). Stir under nitrogen at 50° C. for 18 h. Concentrate and purify the residue by silica gel chromatography, eluting with 100:0 to 0:100 hexanes:ethyl acetate, to give the title compound (571 mg, 46%).
Reaction SMILES: [OH:1][C@@H:2]([CH2:26][OH:27])[CH2:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=3[F:25])=[CH:12][C:13](=[O:16])[N:14]([CH3:15])[C:7]=2[N:6]=[CH:5]1.[B-](F)(F)(F)[F:29].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CN(C=O)C.C(#N)C>[OH:1][C@@H:2]([CH2:26][OH:27])[CH2:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=3[F:25])=[C:12]([F:29])[C:13](=[O:16])[N:14]([CH3:15])[C:7]=2[N:6]=[CH:5]1
Reactant: F[B-](F)(F)F
Reactant: Cn1c(=O)cc(Nc2ccc(I)cc2F)c2c(=O)n(C[C@@H](O)CO)cnc21
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cn1c(=O)c(F)c(Nc2ccc(I)cc2F)c2c(=O)n(C[C@@H](O)CO)cnc21
Yield: 33 %

Procedure:
To a solution of (R)-3-(2,3-dihydroxypropyl)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (example 6) (1 g, 2.06 mmol, 1 eq) in DMF (19 mL) was added dropwise a mixture of Selectfluor (801 mg, 2.26 mmol, 1.1 eq) in acetonitrile (9 mL) and DMF (5 mL) at ambient temperature while stirring under nitrogen. The reaction mixture was stirred for 10 minutes at ambient temperature and filtered. The filtrate was purified by preparatory LC/MS (30-55% CH3CN in H2O) to give (R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (example 18) as an off-white solid. The recovered starting material was subjected to the same reaction conditions to produce a second crop of product. The total yield of product was 347 mg (33% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.36-3.40 (m, 1H) 3.43-3.50 (m, 1H) 3.58 (s, 3H) 3.61-3.72 (m, 1H) 3.72-3.82 (m, 1H) 4.27-4.37 (m, 1H) 4.78-4.87 (m, 1H) 5.14 (d, J=5.81 Hz, 1H) 6.93-7.03 (m, 1H) 7.53 (d, J=8.84 Hz, 1H) 7.65-7.74 (m, 1H) 8.52 (s, 1H) 10.25 (d, J=1.01 Hz, 1H). [M+H] calc'd for C17H15F2IN4O4, 505; found, 505.
Reaction SMILES: CCN(CCN[C:9]([C:11]1[CH:12]=[C:13](Cl)[C:14]([NH2:19])=C[C:16]=1[O:17]C)=O)CC.P(Cl)(Cl)(Cl)=[O:22]>C(Cl)(Cl)Cl>[C:16]([OH:17])(=[O:22])[C:11]1[CH:12]=[CH:13][CH:14]=[N:19][CH:9]=1
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OC
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C(O)c1cccnc1

Procedure:
(0.075 mole) and metoclopramide (14.9 grams; (0.95 mole) having the melting point of 148° C. are dissolved in 100 ml. of chloroform. At ambient temperature, 5.6 grams of phosphorous oxychloride are added drop by drop and the batch is heated for three more hours under reflux. After extraction with 80 ml. of 10% caustic soda solution, and subsequently with water, the chloroform solution is concentrated in a vacuum and the distillation residue having a boiling point of 100 to 140° C. is recrystallized from benzene. There is thus obtained 10.4 g. (51.4% of theory) of 4-nicotinoylamino-5-chloro-2-methyoxy-N-[2-(diethylamino)ethyl]benzamide having a melting point of 99° to 100° C.
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:7]([F:17])[CH:6]=1.[C:18](=[O:20])=[O:19]>C1COCC1>[F:17][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:18]([OH:20])=[O:19]
Reactant: O=C=O
Reactant: Fc1cc(Br)ccc1-c1ccccc1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccccc2)c(F)c1
Temperature: -10 °C
Yield: 740.3 %

Procedure:
A suspension of magnesium (0.968 g, 3.98 mmol) and a few crystals of iodine in anhyd THF (200 mL) were treated with dropwise addition of 10 mL of a solution of 4-bromo-2-fluorobiphenyl (10.0 g, 3.98 mmol) in THF (100 mL). The mixture was heated to gentle reflux and a reaction ensued. At that time, the remaining solution of 4-bromo-2-fluorobiphenyl was added dropwise to the flask over a 3-minute period. The contents were then stirred at reflux under argon until no magnesium consumption was observed. The reaction mixture was subsequently cooled to −10° C. and treated with dry ice (˜70 g). The reaction mixture was quenched with 20% aqueous hydrochloric acid (50 mL), and the layers were separated. The aqueous phase was extracted with ethyl acetate (2×20 mL), and the combined organic layer was washed with brine (30 mL), dried over anhyd sodium sulfate and concentrated to about ⅓ of its original volume. The contents were treated with hexane (200 mL), and the precipitate was filtered and dried under high vacuum to afford 3-fluoro-4-phenylbenzoic acid (6.37 g, 74%) as a white, crystalline solid. 1H-NMR (DMSO-d6): δ7.48 (m, 3H); 7.59 (m, 2H); 7.66 (dd, J=8.1, 8.1 Hz, 1H); 7.76 (dd, J=1.5, 11.6 Hz, 1H); 7.85 (dd, J=1.5, 8.1 Hz, 1H); 13.30 (br s, 1H). Anal. Calcd for C13H9FO2: C, 72.22; H, 4.20; F, 8.79. Found: C, 71.95; H, 4.11; F, 9.07.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH:47]1([CH2:50][NH:51][C:52]([C:54]2[N:55]=[C:56]([C:63]([F:66])([F:65])[F:64])[N:57]3[CH2:62][CH2:61][NH:60][CH2:59][C:58]=23)=[O:53])[CH2:49][CH2:48]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:47]1([CH2:50][NH:51][C:52]([C:54]2[N:55]=[C:56]([C:63]([F:64])([F:65])[F:66])[N:57]3[CH2:62][CH2:61][N:60]([C:4](=[O:5])[C:3]4[CH:7]=[C:8]([CH2:11][C:12]5[C:21]6[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=6)[C:15](=[O:22])[NH:14][N:13]=5)[CH:9]=[CH:10][C:2]=4[F:1])[CH2:59][C:58]=23)=[O:53])[CH2:49][CH2:48]1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: O=C(NCC1CC1)c1nc(C(F)(F)F)n2c1CNCC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1CC1)c1nc(C(F)(F)F)n2c1CN(C(=O)c1cc(Cc3n[nH]c(=O)c4ccccc34)ccc1F)CC2
Reaction time: 12 h
Yield: 30.3 %

Procedure:
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (300 mg, 1 mmol) was dissolved in 5 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (756 mg, 2 mmol), crude N-(cyclopropylmethyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide 24c (250 mg, 0.87 mmol) and N, N-diisopropylethylamine (0.5 mL, 3 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain N-(cyclopropylmethyl)-7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxamide 24 (150 mg, yield 30.0%) as a light yellow solid.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:16]=2[NH:15][C:14](=[O:17])[CH:13]=[CH:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>CN(C=O)C.C(=O)([O-])O.[Na+]>[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:16]=2[NH:15][C:14](=[O:17])[CH:13]=[CH:12]3)[CH2:2][CH2:3]1)=[O:29]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: O=c1ccc2cccc(N3CCNCC3)c2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1Cl)N1CCN(c2cccc3ccc(=O)[nH]c23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.9 %

Procedure:
8-(1-Piperazinyl)carbostyril (0.7 g, 2.26 mmols) and sodium hydrogencarbonate (0.2 g) were suspended in 5 ml of DMF and the suspension was stirred at room temperature for 30 minutes. To the resulting mixture was added 0.4 ml of triethylamine, and further a solution of 0.47 g of 2-chlorobenzoyl chloride in 5 ml of DMF dropwise, followed by stirring at room temperature for 30 minutes. The reaction mixture was poured in saturated aqueous sodium hydrogencarbonate and extracted with chloroform. The organic layer was washed with water and then with saturated aqueous sodium hydrogencarbonate and dried over sodium sulfate. After distilling off the solvent, ether was added to the residue to crystallize. The crystals thus obtained were recrystallized from ethanol to give 0.24 g of 8-[4-(2-chlorobenzoyl)-1-piperazinyl]carbostyril, m.p. 239°-240.5° C., colorless needles.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Br:10][CH2:11][CH2:12][CH2:13]Br>[OH-].[Na+]>[Br:10][CH2:11][CH2:12][CH2:13][C:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]=1
Reactant: BrCCCBr
Reactant: C1=Cc2ccccc2C1
Agent: [Na+]
Agent: [OH-]
Product: BrCCCC1=CCc2ccccc21
Reaction time: 6 h

Procedure:
The compound is prepared as described by Makoska in Tetrahedron Letters 38, 4621-4624 (1966) by adding a mixture of 580 g (5M) indene and 1010 g (5M) 1,3-dibromopropane to 1500 ml 50% aqueous NaOH containing 50 ml 40% methanolic Triton B. The temperature is held below 55° C. by cooling in an ice bath. After stirring 6 hours the reaction mixture is diluted to 4 l. The layers are separated and the aqueous layer is extracted two times with ether. The combined organic layers are extracted two times with water, dried over MgSO4, filtered and the solvent is removed. The oily product is distilled and redistilled at reduced pressure collecting 432 g (36.6%) boiling 126°-140°/0.1 mm.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1B(O)O.FC(F)(F)S(O[C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH2:19][C@H:20]([N:27]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:21][O:22]2)(=O)=O>>[CH2:35]([N:27]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@H:20]1[CH2:19][C:18]2[C:23](=[CH:24][CH:25]=[CH:26][C:17]=2[C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[CH3:1])[O:22][CH2:21]1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: Cc1cnccc1B(O)O
Reactant: O=S(=O)(Oc1cccc2c1C[C@H](N(Cc1ccccc1)Cc1ccccc1)CO2)C(F)(F)F
Product: Cc1cnccc1-c1cccc2c1C[C@H](N(Cc1ccccc1)Cc1ccccc1)CO2
Yield: 76 %

Procedure:
The title compound was synthesized as described for Intermediate example I-2 in 76% yield, starting from 3-methylpyridine-4-boronic acid and (3S)-3-(dibenzylamino)-3,4-dihydro-2H-chromen-5-yl trifluoromethanesulfonate; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.54 (d, 1 H), 8.46 (dd, 1 H), 7.25-7.32 (m, 8 H), 7.05-7.24 (m, 4 H), 6.76-6.83 (m, 1 H), 6.59-6.64 (m, 1 H), 4.26-4.34 (m, 1 H), 4.04-4.13 (m, 1 H), 3.55-3.68 (m, 4 H), 2.93-3.07 (m, 1 H), 2.34-2.43 (m, 1 H), 2.08-2.22 (m, 1 H), 1.92-2.02 (m, 3 H); MS (ESI) m/z 421[M+H+].
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][F:12])=[CH:6][CH:5]=1.O.[NH2:15][NH2:16]>C(O)C>[F:12][CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([NH:15][NH2:16])=[O:2])=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(OCF)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc(OCF)cc1
Yield: 1010.6 %

Procedure:
4-Fluoromethoxy-benzoic acid methyl ester (573 mg, 0.31 mmol) was dissolved in ethanol (10 ml) and heated under reflux with hydrazine monohydrate (0.8 ml, 1.55 mmol, 5 eq.) for 60 hrs. The volatiles were completely evaporated and the product was dried overnight under high vacuum at 40° C., to afford the title compound (577 mg, 100% yield) as a light brown solid. MS: m/e=184 (M+).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:5][O:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[F:25][C:26]([F:49])([F:48])[CH2:27][CH2:28][C@@H:29](OS(C(F)(F)F)(=O)=O)[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>C1COCC1.C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:6]([C@H:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:29]([CH2:28][CH2:27][C:26]([F:25])([F:48])[F:49])[C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])=[CH:5][O:4][N:3]=1
Reactant: O=C(OCc1ccccc1)[C@@H](CCC(F)(F)F)OS(=O)(=O)C(F)(F)F
Reactant: Cc1nocc1CC(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1nocc1[C@H](C(=O)OC(C)(C)C)[C@@H](CCC(F)(F)F)C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 61 %

Procedure:
In a 250 mL round-bottomed flask, a solution of tert-butyl 2-(3-methylisoxazol-4-yl)acetate (1.75 g, 8.87 mmol) in THF (56 mL) and toluene (27 mL) was cooled in a −78° C. bath and treated with a solution of 1M KHMDS (11.09 mL, 11.09 mmol) in THF dropwise over 2 minutes via syringe. After stirring for 15 minutes at −78° C., the reaction mixture was placed in a room temperature water bath for 15 minutes and then placed in a −78° C. bath for another 15 minutes before a solution of Intermediate S5D, (R)-benzyl 5,5,5-trifluoro-2-(trifluoromethylsulfonyloxy)pentanoate (4.55 g, 11.53 mmol) in 6 mL THF and 3 mL toluene was added over 2 minutes. The reaction mixture was stirred in −78° C. bath for 2 hours before being quenched with saturated aqueous NH4Cl and then warmed to room temperature. The mixture was diluted with brine and extracted with EtOAc. The organic layer was dried over MgSO4 filtered and concentrated. The residue was purified on silica gel column (330 g ISCO) eluting with a gradient of 0-30% EtOAc/CH2Cl2. Tubes were collected containing the product, which was concentrated to afford Intermediate S6A (2.394 g, 61% yield) containing about 30% of the (2R,3S) isomer.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([CH3:6])[C:3](Cl)=[O:4].[CH3:8][N:9]([CH3:12])[CH:10]=[O:11]>C(N(CC)CC)C>[CH3:8][N:9]([CH3:12])[C:10](=[O:11])[C:3](=[O:4])[C:2]([Cl:7])([Cl:1])[CH3:6]
Reactant: CN(C)C=O
Reactant: CC(Cl)(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)C(=O)C(C)(Cl)Cl

Procedure:
The procedure of Example 1 was followed using 32g (0.2 mole) of 2,2-dichloropropionyl chloride and 44g (0.6 mole) of dimethylformamide and 20g (0.2 mole) of triethylamine. Obtained following distillation was 12g of pure N,N-dimethyl-3,3-dichloro-2-oxobutyramide as a clear, colorless liquid: Bp: 68°-70° (0.2mm); ir (λmax, film) 5.7 (s), 6.1 (s), 7.1 (s), 9.3 (s), 9.9 (s), 12.6 (s) microns.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6]3[C:7](=[CH:16][CH:17]=[CH:18][C:5]=3[C:4](=[O:19])[N:3]1[CH2:20][CH2:21][NH:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:27][CH2:28][N:29]1[C:38](=[O:39])[C:37]3[CH:40]=[CH:41][CH:42]=[C:35]4[C:36]=3[C:31](=[C:32]3[CH:46]=[CH:45][CH:44]=[CH:43][C:33]3=[CH:34]4)[C:30]1=[O:47])[CH:8]=[C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]1=2.[CH2:48]=O>C(O)C>[O:47]=[C:30]1[C:31]2[C:36]3[C:35](=[CH:42][CH:41]=[CH:40][C:37]=3[C:38](=[O:39])[N:29]1[CH2:28][CH2:27][N:26]1[CH2:25][CH2:24][CH2:23][N:22]([CH2:21][CH2:20][N:3]3[C:4](=[O:19])[C:5]4[CH:18]=[CH:17][CH:16]=[C:7]5[C:6]=4[C:11](=[C:10]4[CH:12]=[CH:13][CH:14]=[CH:15][C:9]4=[CH:8]5)[C:2]3=[O:1])[CH2:48]1)[CH:34]=[C:33]1[CH:43]=[CH:44][CH:45]=[CH:46][C:32]1=2
Reactant: O=C1c2cccc3cc4ccccc4c(c23)C(=O)N1CCNCCCNCCN1C(=O)c2cccc3cc4ccccc4c(c23)C1=O
Reactant: C=O
Solvent: CCO
Product: O=C1c2cccc3cc4ccccc4c(c23)C(=O)N1CCN1CCCN(CCN2C(=O)c3cccc4cc5ccccc5c(c34)C2=O)C1
Yield: 58 %

Procedure:
A mixture of 0.5 g (0.8 mmol) of N,N'-Bis[2-(1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]isoquinolin-2-yl)ethyl]-1,3-propanediamine and 1 ml of 36% formaldehyde in 100 ml of ethanol was refluxed for 7 hours. The solid was filtered, washed, dried, and recrystallized from toluene. 0.3 g (58%) of N,N'-bis[2-(1,2-dihydro-1,3-dioxo-3H-dibenz[de,h]isoquinolin-2-yl)ethyl]hexahydropyrimidine were obtained. M.p. 222° C. (toluene).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([Cl:12])[C:6]=1[CH2:13]Br)(=[O:4])=[O:3].[CH3:15][O-:16].[Na+]>CO>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([Cl:12])[C:6]=1[CH2:13][O:16][CH3:15])(=[O:4])=[O:3]
Reactant: C[O-]
Reactant: CS(=O)(=O)c1ccc(Br)c(Cl)c1CBr
Agent: [Na+]
Solvent: CO
Product: COCc1c(S(C)(=O)=O)ccc(Br)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension comprising 8.5 g of 4-bromo-2-bromomethyl-3-chlorophenyl methyl sulfone and 100 ml of methanol, 1.5 g of sodium methoxide (95%) was added under cooling with ice, and then the mixture was stirred at room temperature overnight.
Reaction SMILES: Cl.Cl.[CH3:3][C@H:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][CH:9]=[N:8][C:7]=2[CH2:6][S:5]1.[C:19]([O:23][C:24]([N:26]([CH:39]([CH3:41])[CH3:40])[CH2:27][CH:28]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:29](O)=[O:30])=[O:25])([CH3:22])([CH3:21])[CH3:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH:28]([C:29]([N:16]2[CH2:17][CH2:18][N:13]([C:11]3[C:12]4[C@H:4]([CH3:3])[S:5][CH2:6][C:7]=4[N:8]=[CH:9][N:10]=3)[CH2:14][CH2:15]2)=[O:30])[CH2:27][N:26]([CH:39]([CH3:40])[CH3:41])[C:24](=[O:25])[O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[CH:33][CH:34]=1
Reactant: CC(C)N(CC(C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reactant: C[C@@H]1SCc2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)N(CC(C(=O)N1CCN(c2ncnc3c2[C@H](C)SC3)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
To a solution of (S)-5-methyl-4-(piperazin-1-yl)-5,7-dihydrothieno[3,4-d]pyrimidine dihydrochloride (0.5 g, 1.62 mmol) and 3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (0.7 g, 2.05 mmol) in DCM (40 mL) were added HBTU (1.0 g, 2.64 mmol) and triethylamine (1.38 mL, 9.88 mL). The mixture was stirred at room temperature for 1 hour. The solvent was removed, and the residue was dissolved in ethyl acetate (200 mL) and washed with brine (5×100 mL) and water (3×100 mL). The organic phase was dried and concentrated. The residue was purified by silica gel chromatography, eluting with Hexane/ethyl acetate (2:1-0:1) to give tert-butyl 2-(4-chlorophenyl)-3-(4-((S)-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (0.63 g, 70%). 1H NMR (CDCl3, 400 MHz) δ 8.50 (d, J=5.6 Hz, 1H), 7.31-7.23 (m, 4H), 4.76 (m, 1H), 4.18 (m, 3H), 4.92-3.25 (m, 10H), 1.48 (m, 12H), 0.99 (m, 3H), 0.69 (m, 3H). MS (APCI+) [M+H]+ 561.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[NH:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][CH2:13]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:12]1[CH2:13][CH2:14][CH:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:16][CH2:17]1)(=[O:10])=[O:9]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccccc2Br)CC1

Procedure:
A solution of 2-bromobenzene-1-sulfonyl chloride (50 mg, 0.20 mmol), tert-butyl piperidin-4-ylcarbamate (49 mg, 0.25 mmol), and diisopropylethyl amine (0.101 mL, 0.59 mmol) in CH2Cl2 was stirred for 90 min at rt. The reaction mixture was then concentrated to dryness to give the title compound in quantitative yield. The product was used without further purification.
Reaction SMILES: O1CCCC1.[CH2:6]([OH:9])[CH2:7][OH:8].[H-].[Na+].[Cl:12][C:13]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[C:17](Cl)[N:16]=[CH:15][N:14]=1>C(O)(=O)C>[Cl:12][C:13]1[N:14]=[CH:15][N:16]=[C:17]([O:8][CH2:7][CH2:6][OH:9])[C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1
Reactant: Cc1ccc(-c2c(Cl)ncnc2Cl)cc1
Reactant: OCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1ccc(-c2c(Cl)ncnc2OCCO)cc1

Procedure:
To a mixture of tetrahydrofuran (400 ml) and ethylene glycol (60 ml) is added with stirring sodium hydride (60% dispersion, 3.38 g) under ice-cooling, and thereto is added 4,6-dichloro-5-(4-methylphenyl)pyrimidine (20.0 g). The mixture is stirred under ice-cooling for 30 minutes, and then stirred at room temperature for two hours. The mixture is weakly acidified with acetic acid, and concentrated under reduced pressure. The residue is dissolved in ethyl acetate, and washed, dried, and concentrated to dryness under reduced pressure. The residue is crystallized from hexane to give 2-{6-chloro-5-(4-methylphenyl)pyrimidin-4-yloxy}ethanol (21.85 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:19][S:20]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([NH:29][NH2:30])=[O:28])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([NH:30][NH:29][C:27](=[O:28])[C:26]2[CH:25]=[CH:24][C:23]([S:20]([CH3:19])(=[O:21])=[O:22])=[CH:32][CH:31]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CS(=O)(=O)c1ccc(C(=O)NN)cc1
Reactant: Cc1c(N[C@@H](C(=O)O)[C@H](C)O)ccc(C#N)c1Cl
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(S(C)(=O)=O)cc2)[C@H](C)O)ccc(C#N)c1Cl
Yield: 83.2 %

Procedure:
(2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (813 mg, 3.0 mmol) and 4-(methylsulfonyl)benzohydrazide (648 mg, 3.0 mmol) were coupled in a procedure analogous to that described for the preparation of intermediate 3b. The crude product was recrystalized from hot chloroform (100 mL to yield product as a white solid (1.16 g, 82%). 1H NMR (500 MHz, acetone-d6, δ in ppm) 9.83 (br s, 2H), 8.14 (AA′XX′, J=8.5 Hz, 2H), 8.06 (AA′XX′, J=8.5 Hz, 2H), 7.53 (d, J=8.6 Hz, 1H), 6.70 (d, J=8.7 Hz, 1H), 5.57 (d, J=7.0 Hz, 1H), 4.40 (m, 1H), 4.14 (dd, J=3.4, 6.9 Hz, 1H), 3.19 (s, 3H), 2.90 (br s, 1H), 2.36 (s, 3H), 1.36 (d, J=6.4 Hz, 3H).