Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[NH:8][C:7](=[O:13])[CH2:6][CH2:5]2.[CH3:14]C(C)([O-])C.[K+].CI.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[N:8]([CH3:14])[C:7](=[O:13])[CH2:6][CH2:5]2
Reactant: CC(C)(C)[O-]
Reactant: O=C1CCc2cc(Br)cc(F)c2N1
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)CCc2cc(Br)cc(F)c21
Reaction time: 2 h
Yield: 81.1 %

Procedure:
A solution of 6-bromo-8-fluoro-3,4-dihydro-1H-quinolin-2-one (0.21 g, 0.86 mmol) in DMF (2 mL) was treated with potassium tert-butoxide (0.19 g, 1.72 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 30 min before methyl iodide (0.18 g, 1.29 mmol) was added. After stirring for 2 h, the reaction mixture was treated with water, extracted with EtOAc, washed with water and brine in sequence, and dried over anhy. Na2SO4. After removal of the solvents under reduced pressure, the crude product (0.18 g, 80% yield) was obtained as a white solid. MS: 258.0 (M+H)+.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1.[NH2:25][CH:26]([CH3:29])[CH2:27][OH:28]>>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:25][C@H:26]([CH3:29])[CH2:27][OH:28])=[O:24])=[CH:5][N:6]=3)=[CH:16][O:15][N:14]=2)=[CH:22][CH:21]=1
Reactant: CC(N)CO
Reactant: COC(=O)c1ccc(OCc2conc2-c2ccc(F)cc2)nc1
Product: C[C@H](CO)NC(=O)c1ccc(OCc2conc2-c2ccc(F)cc2)nc1
Yield: 41 %

Procedure:
As described for example 325, 6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (60 mg, 0.18 mmol) was converted, using D-alaminol instead of rac-2-amino-1-propanol, to the title compound (28 mg, 41%) which was obtained as a white solid MS: m/e=372.1 [M+H]+.
Reaction SMILES: [C:1](/[C:9](=[C:12](/OC)\[CH3:13])/[C:10]#[N:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([NH2:20])[CH2:17][CH2:18][CH3:19]>>[C:1](/[C:9](=[C:12](/[NH:20][CH2:16][CH2:17][CH2:18][CH3:19])\[CH3:13])/[C:10]#[N:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO/C(C)=C(\C#N)C(=O)c1ccccc1
Reactant: CCCCN
Product: CCCCN/C(C)=C(\C#N)C(=O)c1ccccc1

Procedure:
A sample of 2.5 g. of 2-benzoyl-3-methoxycrotononitrile is dissolved in 10 ml. of n-butylamine. The solution is sealed in a stainless steel bomb and heated on a steam bath overnight. The bomb is then opened and the solvent evaporated under reduced pressure. A greenish oil is obtained which is distilled on a Kugelrohr apparatus at 200° C./0.1 mm. to obtain the yellow oily product.
Reaction SMILES: [Li].[N:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[C:15]([OH:17])=O)=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[CH3:22][C:23]1([CH3:34])[C:32]2[C:27](=[CH:28][C:29]([NH2:33])=[CH:30][CH:31]=2)[NH:26][CH2:25][CH2:24]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:22][C:23]1([CH3:34])[C:32]2[C:27](=[CH:28][C:29]([NH:33][C:15](=[O:17])[C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[NH:12][C:8]3[CH:7]=[C:6]4[C:11](=[CH:10][CH:9]=3)[N:2]=[CH:3][N:4]=[CH:5]4)=[CH:30][CH:31]=2)[NH:26][CH2:25][CH2:24]1
Reactant: CC1(C)CCNc2cc(N)ccc21
Reactant: O=C(O)c1ccccc1Nc1ccc2ncncc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Li]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(C)CCNc2cc(NC(=O)c3ccccc3Nc3ccc4ncncc4c3)ccc21

Procedure:
A mixture of the lithium salt of 2-(quinazolin-6-ylamino)-benzoic acid (Step B, 533 mg, 0.72 mmol), 4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-ylamine (127 mg, 0.72 mmol), TBTU (462 mg, 1.44 mmol) and DIEA (0.25 mL, 1.44 mmol) in 3 mL of DMF was submitted to microwave irradiation (80° C., 30 min). Water (5 mL) was added to the mixture, and the resultant precipitate was filtered and dried. The crude material was purified with flash chromatography (SiO2, 50% EtOAc/hexane) to afford a white solid. MS (ES+): 424.0 (M+H)+. Calc'd for C26H25N5O: 423.51.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14](=[CH2:25])[CH2:15][O:16]C(=O)C1C=CC=CC=1.[O:26]=[C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](=[O:36])[N:28]1[CH2:37][C:38](=[CH2:50])[CH2:39][CH2:40][O:41]C(=O)C1C=CC=CC=1.[OH-].[Na+]>CO.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[OH:16][CH2:15][C:14](=[CH2:25])[CH2:13][CH2:12][N:3]1[C:4](=[O:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]1=[O:1].[OH:41][CH2:40][CH2:39][C:38](=[CH2:50])[CH2:37][N:28]1[C:29](=[O:36])[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:27]1=[O:26]
Reactant: C=C(CCN1C(=O)c2ccccc2C1=O)COC(=O)c1ccccc1
Reactant: C=C(CCOC(=O)c1ccccc1)CN1C(=O)c2ccccc2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: C=C(CCO)CN1C(=O)c2ccccc2C1=O
Product: C=C(CO)CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29 %
Yield: 7 %

Procedure:
To an ˜3:1 mixture of benzoic acid 4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-methylene-butyl ester and benzoic acid 3-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-but-3-enyl ester (4.11 g, 12.3 mmol) in methanol (123 mL) was added NaOH (1.21 g, 30.3 mmol) and the mixture was stirred at room temperature for 30 minutes. The mixture was diluted with ethyl acetate (250 mL) and saturated aqueous NaHCO3 (125 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (3×30 mL), dried (MgSO4), and concentrated. Purification of the crude material by column chromatography on silica gel (2:1 hexanes-ethyl acetate) provided 0.83 g (29%) of 2-(3-Hydroxymethyl-but-3-enyl)-isoindole-1,3-dione as a white solid and 0.19 g (7%) of 2-(4-Hydroxy-2-methylene-butyl)-isoindole-1,3-dione as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:4]([N+:16]([O-])=O)[CH:3]=1.O.O.Cl[Sn]Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CN(c1ccccc1)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CN(c1ccccc1)c1ccc(Cl)cc1N
Temperature: 40 °C
Reaction time: 6 h
Yield: 86.3 %

Procedure:
To a solution of 4-chloro-N-methyl-2-nitro-N-phenylphenylamine (12.5 g, 46.3 mmol) in ethanol (250 mL) was added SnCl2.2H2O (37.5 gr., 0.17 mol). The solution was heated to 40° C. and stirred for 6 h. The reaction mixture was concentrated in vacuo and subsequently diluted with ethyl acetate (500 mL) and washed with H 20 (500 mL), a cooled (0° C.) aq. solution of NaOH (1 M, 200 mL), H2O (500 mL) and brine (500 mL). The organic layer was dried (Na2SO4), filtered and concentrated under reduced presssure. The crude compound was applied onto a silica column and eluted with heptane/ethyl acetate (8/2, v/v) affording the title compound (9.3 g, 87% yield). Data: Rf 0.65 (heptane/ethyl acetate, 7/3, v/v), (m/z)=233 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:37])[C@:4]1([OH:36])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@:18]([F:24])([C@@H:19]([OH:23])[CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:25])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][C@H:5]1[O:26][CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[CH2:29].ClC1C=CC=C(C(OO)=[O:46])C=1>ClCCl>[Cl:1][CH2:2][C:3](=[O:37])[C@:4]1([OH:36])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@:18]([F:24])([C@@H:19]([OH:23])[CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:25])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][C@H:5]1[O:26][CH2:27][C:28]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:29][O:46]1
Reactant: C=C(CO[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CCl)c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](OCC4(c5ccccc5)CO4)[C@](O)(C(=O)CCl)[C@@]3(C)C[C@H](O)[C@@]12F
Yield: 116.5 %

Procedure:
A solution of 4.0 g of 21-chloro-9-fluoro-11β,17-dihydroxy-16α-[(2-phenyl-2-propenyl)oxy]pregna-1,4-diene-3,20-dione in 100 ml of dichloromethane is stirred with 1.6 g of m-chloroperbenzoic acid for 1 hour at room temperature. The resulting solution is washed with a mixture of 100 ml each of 5% sodium sulfite solution and 5% sodium bicarbonate solution, dried, and evaporated in vacuo to give 4.8 g of crude 21-chloro-9-fluoro-11β,17-dihydroxy-16α-[(2-phenyloxiranyl)methoxy]pregna-1,4-diene-3,20-dione.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][C:17]1([CH3:23])[NH:21][C:20](=[O:22])[CH2:19][NH:18]1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([N:18]1[CH2:19][C:20](=[O:22])[NH:21][C:17]1([CH3:23])[CH3:16])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CC1(C)NCC(=O)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC1(C)NC(=O)CN1C(=O)CNC(=O)OCc1ccccc1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
To an ice-cold solution of N-(benzyloxycarbonyl) glycine (9 g) and 2,2-dimethyl-4-imidazolidinone (5 g) in tetrahydrofuran (THF) (150 ml) a solution of dicyclohexylcarbodiimide (DCC) (9 g) in THF (50 ml) was added dropwise. After stirring for 3 hours at 20° C., the precipitate was filtered off, the filtrate was evaporated to dryness and the residue was crystallized from 2-propanol affording 12 g of the title compound, m.p. 135°-136° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]2=[O:12].Cl.Cl[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]Cl>>[CH2:13]([N:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[N:1]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:7]1=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCCNCCCl
Reactant: Nc1cccc2c(=O)n(Cc3ccccc3)ccc12
Agent: Cl
Product: O=c1c2cccc(N3CCNCC3)c2ccn1Cc1ccccc1

Procedure:
5-Amino-2-benzyl-2H-isoquinolin-1-one (0.687 g, 2.75 mmol)) from step 4 was combined with excess bis-(2-chloroethyl)-amine hydrochloride and heated to a melt for 5 minutes. TLC analysis showed one major product and several minor side products. The reaction mixture was chromatographed over silica gel (CH2Cl2/MeOH, 95:5) to afford 2-benzyl-5-piperazin-1-yl-2H-isoquinolin-1-one (0.103 mg, 0.32 mmol); M+H=320.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]2[C:13]3=[C:14]([F:22])[CH:15]=[N:16][C:17]4[CH:18]=[CH:19][C:20](=[O:21])[N:11]([C:12]=43)[CH2:10]2)[CH2:4][C@H:3]1[OH:23].C(OC(=O)NC1CCNCC1O)(C)(C)C.[O:39]1[C:44]2=[CH:45][N:46]=[C:47]([CH:49]=O)[CH:48]=[C:43]2[CH2:42][CH2:41][CH2:40]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(Cl)(Cl)[Cl:66]>CO>[ClH:66].[F:22][C:14]1[CH:15]=[N:16][C:17]2[CH:18]=[CH:19][C:20](=[O:21])[N:11]3[CH2:10][CH:9]([CH2:8][N:5]4[CH2:6][CH2:7][C@H:2]([NH:1][CH2:49][C:47]5[CH:48]=[C:43]6[CH2:42][CH2:41][CH2:40][O:39][C:44]6=[CH:45][N:46]=5)[C@H:3]([OH:23])[CH2:4]4)[C:13]=1[C:12]=23
Reactant: N[C@H]1CCN(CC2Cn3c(=O)ccc4ncc(F)c2c43)C[C@H]1O
Reactant: O=Cc1cc2c(cn1)OCCC2
Reactant: ClC(Cl)Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)(C)OC(=O)NC1CCNCC1O
Agent: [Na+]
Solvent: CO
Product: Cl
Product: O=c1ccc2ncc(F)c3c2n1CC3CN1CC[C@H](NCc2cc3c(cn2)OCCC3)[C@H](O)C1
Yield: 70 %

Procedure:
A mixture of 4-{[(3R,4S)-4-amino-3-hydroxy-1-piperidinyl]methyl}-3-fluoro-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-7-one Diastereomer 1 (54 mg), 3,4-dihydro-2H-pyrano[2,3-c]pyridine-6-carbaldehyde (for a synthesis see WO2004058144, Example 126(c)) (20.6 mg) and 3A molecular sieves in chloroform (1 ml) and methanol (1 ml) was heated at 65° C. for 5 h, cooled and then sodium triacetoxyborohydride (53 mg) was added. The general procedure of Example 72 was then followed to obtain the free base of the title compound (41 mg, 70%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:9][CH2:8][CH2:7][C@H:6]2[N:3]1[C:4](=[O:13])[C@@H:5]2[NH:10][CH:11]=O.N1C(C)=CC=CC=1C.P(Cl)(Cl)(Cl)=O>C(OCC)(=O)C>[CH3:1][C:2]1([CH3:14])[O:9][CH2:8][CH2:7][C@H:6]2[N:3]1[C:4](=[O:13])[C@@H:5]2[N+:10]#[C-:11]
Reactant: CC1(C)OCC[C@@H]2[C@@H](NC=O)C(=O)N21
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Solvent: O=P(Cl)(Cl)Cl
Product: [C-]#[N+][C@H]1C(=O)N2[C@@H]1CCOC2(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 65.4 %

Procedure:
To a solution of (6R,7R)-2,2-dimethyl-7-formamido-1-aza-3-oxabicyclo[4.2.0]octan-8-one (345 mg) were added 2,6-lutidine (2.05 ml) and phosphorus oxychloride (0.52 ml) at 0° C. After stirring for 3 hours at 0° C., the mixture was poured into a mixture of ethyl acetate (80 ml) and ice-water. The organic layer was separated, washed in turn with 10% phosphoric acid, water, brine, an aqueous mixture of sodium bicarbonate and sodium chloride (1:1), and brine, dried over magnesium sulfate, and evaporated in vacuo. The crystalline residue was washed with a mixture of petroleum ether and ether (1:1) and dried over phosphorus pentoxide to give (6R,7R)-2,2-dimethyl-7-isocyano-1-aza-3-oxabicyclo[4.2.0]octan-8-one (205 mg).
Reaction SMILES: [NH:1]([C:5]1[S:6][C:7]([C:11]([NH:13][C:14]2[CH:15]=[C:16]([CH:26]=[CH:27][CH:28]=2)[O:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[O:12])=[C:8]([CH3:10])[N:9]=1)[C:2]([NH2:4])=[NH:3].FC(F)(F)C(O)=O>C(Cl)Cl>[NH:1]([C:5]1[S:6][C:7]([C:11]([NH:13][C:14]2[CH:15]=[C:16]([CH:26]=[CH:27][CH:28]=2)[O:17][CH2:18][C:19]([OH:21])=[O:20])=[O:12])=[C:8]([CH3:10])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: Cc1nc(NC(=N)N)sc1C(=O)Nc1cccc(OCC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(NC(=N)N)sc1C(=O)Nc1cccc(OCC(=O)O)c1
Yield: 82.5 %

Procedure:
142 mg of tert-butyl {3-[(2-guanidino-4-methyl-thiazole-5-carbonyl)-amino]-phenoxy}-acetate is stirred in 1.1 ml of methylene chloride and 1.1 ml of trifluoroacetic acid (TFA) for 2 hrs. at RT. The reaction mixture is evaporated in a vacuum, the residue is taken up in water and the solution is evaporated to dryness. The solid is suspended in water, adjusted to pH 8 with 1N ammonia while stirring, filtered off under suction, washed with water and dried. There are obtained 101 mg of [3-[(2-guanidino-4-methyl-thiazole-5-carbonyl)-amino]-phenoxy]-acetic acid, m.p. 284° C., MS: 350 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[C:7]([OH:9])[CH:6]=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C>[CH2:15]([O:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:10])[F:11])[N:8]=1)[C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)CBr
Reactant: Oc1cccc(C(F)(F)F)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)COc1cccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-(trifluoromethyl)pyridin-2-ol (5.00 g, 30.7 mmol) in dry DMF (50 mL) was added NaH (3.71 g, 92.1 mmol) under N2 and the mixture was stirred at rt for 1 h. Then 1-bromo-2,2-dimethylpropane (11.6 g, 76.7 mmol) was added and the resulting mixture was heated at 100° C. overnight, cooled, quenched with water (10 mL) and extracted with EA twice. The combined organic layers were washed with brine (3×), concentrated and purified by CC on NH silica gel (PE/EA=100/1) to give compound P12a (1.05 g, 15%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH3:9][C:10]([CH3:14])([CH3:13])[C:11]#[CH:12].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>COC(C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:12]#[C:11][C:10]([CH3:14])([CH3:13])[CH3:9])[N:5]=[CH:4][N:3]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: C#CC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Solvent: CC#N
Product: CC(C)(C)C#Cc1cc(Cl)ncn1
Temperature: 45 °C
Reaction time: 6 h
Yield: 47.8 %

Procedure:
Under an atmosphere of a nitrogen gas, 2.98 g of 4,6-dichloropyrimidine, 1.81 g of 3,3-dimethyl-1-butyne, 351 mg of dichlorobis(triphenylphosphine)palladium, 381 mg of copper iodide, 4.05 g of triethylamine and 525 mg of triphenylphosphine was added to 20 ml of acetonitrile and the suspension was stirred for 6 hours at 45° C. After cooling the reaction mixture was diluted with t-butyl methyl ether and washed three times with water. The organic layers were dried over sodium sulfate and concentrated. The residue was subjected to silica gel thin layer chromatography to give 1.86 g of 4-chloro-6-(3,3-dimethyl-1-butynyl)pyrimidine.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][C:5]2[S:8][C:9]([C:11]([O-:13])=O)=[N:10][C:4]=2[CH2:3]1.[Li+].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[C:28]([S:33]([N:36]1[CH2:41][CH2:40][NH:39][CH:38]([C:42]([N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[O:43])[CH2:37]1)(=[O:35])=[O:34])[CH:27]=[CH:26]2>>[ClH:22].[Cl:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[C:28]([S:33]([N:36]1[CH2:41][CH2:40][N:39]([C:11]([C:9]3[S:8][C:5]4[CH2:6][NH:7][CH:2]([CH3:1])[CH2:3][C:4]=4[N:10]=3)=[O:13])[CH:38]([C:42]([N:44]3[CH2:45][CH2:46][O:47][CH2:48][CH2:49]3)=[O:43])[CH2:37]1)(=[O:34])=[O:35])[CH:27]=[CH:26]2
Reactant: O=C(C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1)N1CCOCC1
Reactant: CC1Cc2nc(C(=O)[O-])sc2CN1
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Product: CC1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3C(=O)N3CCOCC3)sc2CN1
Product: Cl

Procedure:
Starting materials: lithium 6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate, 4-[[1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-3-yl]carbonyl]morpholine trifluoroacetate
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]2[N:22]3[C:17]([C:18]([NH2:23])=[N:19][CH:20]=[N:21]3)=[C:16](Br)[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:25]([N:32]1[CH:40]=[C:39]2[C:34]([CH:35]=[C:36](B3OC(C)(C)C(C)(C)O3)[CH:37]=[CH:38]2)=[N:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]2[N:22]3[C:17]([C:18]([NH2:23])=[N:19][CH:20]=[N:21]3)=[C:16]([C:36]3[CH:37]=[CH:38][C:39]4[C:34]([CH:35]=3)=[N:33][N:32]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:40]=4)[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cc(Br)c3c(N)ncnn23)C1
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Cc2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 110 °C
Yield: 46.2 %

Procedure:
To a stirred solution 3-(4-Amino-5-bromo-pyrrolo[2,1-f][1,2,4]triazin-7-ylmethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.49 g, 1.24 mmol), Intermediate C (0.62 g, 1.86 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.37 g, 0.32 mmol) in degassed DMF (8 mL) was added aqueous Na2CO3 (2M, 2.00 mL). The resulting mixture was heated at 110° C. for 3 h and then cooled to rt. The reaction mixture was diluted with EtOAc and filtered through a Celite® pad. The organic layer was separated and concentrated in vacuo. The residue was purified by silica-gel column using a gradient of 50% to 100% EtOAc in hexanes to afford 0.30 g (46%) of the product. LC-MS [M+H]+=524.1, RT=3.19 min.
Reaction SMILES: Cl[C:2]1[C:3]([CH:8]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[C:28]([C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)=[O:29].C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>O>[NH:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[C:28]([C:30]1[CH:35]=[CH:34][C:33]([O:36][C:2]2[C:3]([CH:8]3[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]3)=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:32][CH:31]=1)=[O:29]
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CC(c2nccnc2Cl)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC(c2nccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)C1
Temperature: 120 °C
Yield: 100 %

Procedure:
To a vial with tert-butyl 3-(3-chloropyrazin-2-yl)azetidine-1-carboxylate (100 mg, 0.371 mmol), (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (265 mg, 1.112 mmol) and cesium carbonate (362 mg, 1.112 mmol) under N2 is added DMSO (1.0 mL). The reaction is heated to 120° C. in an oil bath 1 h. The reaction was cooled to rt, added to H2O (5 mL), and extracted with EtOAc (3×5 mL). The combined organic layers were dried (MgSO4) and concentrated to give tert-butyl 3-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)azetidine-1-carboxylate (175 mg) as a yellow oil which was carried on to the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].C([O-])([O-])O[CH2:12][CH3:13].[N+:16]([N:19]=[C:20]1[NH:24]C[CH2:22][NH:21]1)([O-:18])=[O:17].CN1CCN(C)C1=O>S(=O)(=O)(O)O.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([N:5]=[CH:22][N:21]2[CH2:13][CH2:12][NH:24][C:20]2=[N:19][N+:16]([O-:18])=[O:17])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: O=[N+]([O-])N=C1NCCN1
Reactant: Cc1ccc(N)cc1C
Reactant: CCOC([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CN1CCN(C)C1=O
Product: Cc1ccc(N=CN2CCNC2=N[N+](=O)[O-])cc1C
Reaction time: 1 h
Yield: 44.5 %

Procedure:
A mixture of 60.6 g of 3,4-dimethylaniline, 200 g of ethyl orthoformate and 0.05 g of sulfuric acid was placed in a reactor equipped with Dean's stark tube and agitated at 140° to 165° C. for about 1 hour. After concentration of the reaction solution under reduced pressure, 45 g of nitroiminoimidazolidine and 70 g of 1,3-dimethyl-2-imidazolidinone were added and agitated at 140° to 160° C. for 2 hours. The reaction mixture was poured into 200 ml of a saturated saline solution, to which 150 ml of ethyl acetate was added. The resultant crystals were collected by filtration, washed with ethyl acetate and dried to give 40.2 g of 1-(3,4-dimethylphenyliminomethyl)-2-nitroiminoimidazolidine.
Reaction SMILES: [NH2:1][N:2]([CH2:8][CH2:9][C:10]([OH:18])([CH3:17])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:3](=O)[O:4]CC.[CH3:19][N:20]=[C:21]=[S:22].CC(C)([O-])C.[K+].Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[OH:18][C:10]([CH3:17])([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:8][N:2]1[C:3](=[O:4])[N:20]([CH3:19])[C:21](=[S:22])[NH:1]1
Reactant: CN=C=S
Reactant: CCCCCCC(C)(O)CCN(N)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCCCCC(C)(O)CCn1[nH]c(=S)n(C)c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of ethyl N-amino-N-(3'-hydroxy-3-methylnonyl)carbamate (1.812 g; 6.97 mmole), and methyl isothiocyanate (764 mg; 10.5 mmole) in dry toluene (25 ml) was heated under refulx for 2 hrs and then allowed to cool to room temperature. Potassium t-butoxide (1,56 g; 13.96 mmole) was added and the mixture stirred at 25° for 16 hr. The mixture was portitioned between water (100 ml) and ethyl acetate (100 ml) and acidified with 5 M HCl. The aqueous layer was extracted with ethyl acetate (50 ml) and the combined organic layers washed with water (2×100 ml) and brine (100 ml), dried (Na2SO4), and evaporated to dryness and chromatography of the residue on Kieselgel 60 (10 g) in chloroform gave 2-(3'-hydroxy-3'-methylnonyl)-4-methyl-1,2,4-triazolidine-3-one-5-thione as a gum (1.83 g; 91%).