Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]([C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH:14]=[CH:15][CH:16]=1)#[CH:10]>C1COCC1.C(Cl)Cl.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>[Cl:1][C:2]1[N:7]=[C:6]([CH:10]=[CH:9][C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:23])[C:19]([F:20])([F:21])[F:22])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C#Cc1cccc(NC(=O)C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(Nc1cccc(C=Cc2ccnc(Cl)n2)c1)C(F)(F)F
Temperature: 50 °C

Procedure:
To a mixture of 2,4-dichloropyrimidine (14.5 g, 97.5 mmol), dichlorobis(triphenyl-phosphine)palladium(II) (1.3 g, 2.6 mmol), and copper(I) iodide (25 mg, 0.13 mmol) in degassed THF was added TEA (34 mL, 263 mmol), and the mixture was heated to 50° C. A solution of N-(3-ethynyl-phenyl)-2,2,2-trifluoro-acetamide (14 g, 65 mmol) in THF was added to the mixture over 45 minutes. After several h, the reaction was cooled to rt and diluted with DCM. The organic mixture was washed with water and brine, dried over MgSO4 and concentrated. The crude material was purified through silica to give the title compound as an off-white solid. 1H NMR (400 MHz, d6-DMSO): δ 11.43 (s, 1H), 8.83 (d, J=4.8 Hz, 1H), 8.00 (s, 1H), 7.80 (d, J=4.8 Hz, 1H), 7.76 (m, 1H), 7.54-7.52 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[N:7][C:6]([CH3:9])=[CH:5][N:4]=1.C([N:18]=[C:19]=[S:20])(=O)C1C=CC=CC=1.N>CO>[CH3:9][C:6]1[N:7]=[CH:8][C:3]([CH2:2][NH:1][C:19]([NH2:18])=[S:20])=[N:4][CH:5]=1
Reactant: Cc1cnc(CN)cn1
Reactant: O=C(N=C=S)c1ccccc1
Agent: N
Solvent: CO
Product: Cc1cnc(CNC(N)=S)cn1
Yield: 91 %

Procedure:
The title compound was prepared in accordance with the general method described in Example 12(a) by using 2-(aminomethyl)-5-methylpyrazine (1.00 g, 7.89 mmol), benzoyl isothiocyanate (1.20 mL, 8.90 mmol) and ammonia in methanol (7 N, 27 mL) with the exception that the crude product isolated by filtration (1.30 g, 91% yield) was used in the next step without further purification.
Reaction SMILES: O.[Cl:2][C:3]1[C:8]([CH2:9][OH:10])=[CH:7][N:6]=[C:5]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:4]=12>C1(C)C=CC=CC=1.O=[Mn]=O>[Cl:2][C:3]1[C:8]([CH:9]=[O:10])=[CH:7][N:6]=[C:5]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:4]=12
Reactant: CCn1ncc2c(Cl)c(CO)cnc21
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCn1ncc2c(Cl)c(C=O)cnc21
Reaction time: 6 h
Yield: 67.5 %

Procedure:
Wet MnO2 (110 g) was refluxed for 90 minutes in 1 L of toluene with a Dean-stark trap for the separation of water. This suspension was then cooled and the 4-chloro-1-ethyl-1H-pyrazolo-[3,4-b]pyridine-5-methanol (17.5 g, 82.7 mmole) was added in 50 ml of toluene. The reaction mixture was then stirred for 6 hours and filtered with the aid of a filter pad. The toluene was evaporated and the residue added again to 100 g of wet MnO2 freshly prepared in the above manner. After additional 4 hours the reaction was briefly warmed at 55° and then filtered again through a filter pad. The residue which remained after evaporation of the toluene was purified by preparative high performance liquid chromatography (10% ethyl acetate/hexane, 250 ml/min) to yield 11.70 g of 4-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxaldehyde, mp 89°-90° C.
Reaction SMILES: [N:1]([O-])=O.[Na+].[C:5]1([NH2:15])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1>O.Cl>[C:5]1([NH:15][NH2:1])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: O=N[O-]
Reactant: Nc1cccc2ccccc12
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1cccc2ccccc12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Sodium nitrite (4.8 g) in water (20 ml) was added over 15 minutes to a stirred ice-cold suspension of 1-naphthylamine (9.58 g) in 6M hydrochloric acid (80 ml). After an additional 30 minutes in the ice bath, stannous chloride (44.5 g) in 6M hydrochloric acid (80 ml) was added slowly and the resulting suspension was stirred at 0° for 3 hr. The resulting solid was filtered off and dissolved in a mixture of 40% potassium hydroxide solution (100 ml) and ethyl acetate (150 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3×100 ml). The combined organic extracts were dried and concentrated under reduced pressure to afford the title compound as a purple solid (10.58 g Rf =0.1 in EA/CH (1/4)).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:24]([F:27])([F:26])[F:25])=[C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=3)=[CH:10][N:4]2[N:3]=1.[Cu](C#N)[C:29]#[N:30].CN1CCOCC1>CCOCC.C([O-])(O)=O.[Na+]>[C:29]([C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:24]([F:27])([F:26])[F:25])=[C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=3)=[CH:10][N:4]2[N:3]=1)#[N:30]
Reactant: CC(C)(C)C(=O)Nc1cc(-c2cn3nc(Cl)ccc3n2)ccc1C(F)(F)F
Reactant: N#C[Cu]C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CN1CCOCC1
Product: CC(C)(C)C(=O)Nc1cc(-c2cn3nc(C#N)ccc3n2)ccc1C(F)(F)F
Temperature: 215 °C
Reaction time: 4 h
Yield: 25.8 %

Procedure:
An 8 mL vial is charged with N-[5-(6-chloroimidazo[2,1-f]pyridazin-2-yl)-2-(trifluoromethyl)phenyl]-2,2-dimethyl-propanamide (0.059 g, 0.15 mmol), copper cyanide (0.035 g, 0.3 mmol), and 4-methylmorpholine (0.43 mL). The mixture is stirred at 215° C. for 4 hr in the microwave, then cooled, diluted with Et2O, sat. aqueous NaHCO3 and the biphasic mixture is filtered. Organics are collected and aqueous layer is extracted twice more with Et2O. Organics are combined, dried, concentrated, and purified by prep plate TLC (1:1 Hex:EtOAc) to give the title compound (15 mg, 26% yield). LCMS m/z=388.5 [M+H]+, tR=2.56 min. (compound same as Example 173)
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[C:6]([C:11](OC)=[O:12])=[N:7][CH:8]=[CH:9][CH:10]=1.CO>C(O)C>[OH:12][CH2:11][C:6]1[C:5]([O:4][CH3:3])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: COC(=O)c1ncccc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: COc1cccnc1CO
Reaction time: 8 h
Yield: 57.5 %

Procedure:
Sodium borohydride (6.3 g) was added slowly over 75 minutes to a solution of 3-methoxy-2-methoxycarbonylpyridine (9.2 g) in ethanol. Methanol (100 ml) was then added and after the initial vigorous reaction had subsided, further sodium borohydride (8.3 g) was added over a further 3 hours, and the mixture was left to stand overnight. The solvent was evaporated, the residue dissolved in water and extracted with chloroform and the chloroform solution dried. Evaporation, and crystallisation from ether gave 2-hydroxymethyl-3-methoxypyridine (4.4 g) m.p. 72.5°-73.5°.
Reaction SMILES: [NH3:1].[C:2]([C:4]([C:9]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12])=[CH:5]OCC)#[N:3]>CO>[NH2:1][C:11]1[C:10]2[C:9](=[CH:16][C:15]([F:17])=[CH:14][CH:13]=2)[C:4]([C:2]#[N:3])=[CH:5][N:12]=1
Reactant: N
Reactant: CCOC=C(C#N)c1cc(F)ccc1C#N
Solvent: CO
Product: N#Cc1cnc(N)c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 40 %

Procedure:
A solution of ammonia in MeOH (7 N, 20 mL) is added to 2-(1-cyano-2-ethoxy-vinyl)-4-fluoro-benzonitrile (0.88 g, 4 mmol). The reaction mixture is stirred at RT for 5 h. The orange precipitate is collected by vacuum filtration to afford 0.297 g (40%) of 1-amino-6-fluoro-isoquinoline-4-carbonitrile as an orange solid. LC/MS m/z=188 [M+H]+, RT=2.10-2.15 min. 1H NMR (CDCl3, 25 deg, 500 MHz): δ 8.44 (dd, 2H), 8.18 (t, 1H), 8.04 (bs, 4H), 7.73 (d, 1H), 7.63 (dt, 1H), 7.53 (dt, 2H), 7.43 (dd, 2H)
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH2:15])(=[O:14])=[O:13])[C:2](=[O:4])[CH3:3].[CH2:16](O)[CH2:17][OH:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH3:3][C:2]1([CH2:1][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:12]([NH2:15])(=[O:14])=[O:13])[O:18][CH2:17][CH2:16][O:4]1
Reactant: CC(=O)COc1ccccc1S(N)(=O)=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC1(COc2ccccc2S(N)(=O)=O)OCCO1

Procedure:
A mixture of 4.58 g of 2-(2-propanon-1-yloxy)phenylsulfonamide, 2 ml of ethylene glycol, 0.02 g of p-toluenesulfonic acid and 30 ml of toluene is heated for 7 hours to reflux while simultaneously separating the water of reaction. The cooled solution is taken up in 80 ml of ethyl acetate and the organic phase is washed with saturated sodium bicarbonate solution and water, dried and concentrated, affording 5 g of 2-(2-methyl-1,3-dioxolan-2-yl-methoxy)phenylsulfonamide in the form of a yellow viscous oil which can be further used without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14])[CH2:6][C:5]2([CH3:20])[CH3:19].N1C=CC=CC=1.[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34](Cl)(=[O:36])=[O:35]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][S:34]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[F:27])(=[O:36])=[O:35])[CH2:6][C:5]2([CH3:20])[CH3:19]
Reactant: CC1(C)CC(c2ccccc2N)Nc2ccc(Cl)cc21
Reactant: O=S(=O)(Cl)c1ccccc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)CC(c2ccccc2NS(=O)(=O)c2ccccc2F)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)aniline (100 mg, 0.35 mmol) in dichloromethane (5 mL) was added pyridine (0.6 mL) and 2-fluorobenzenesulfonyl chloride (68 mg, 0.35 mmol) at ice-bath. The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with water. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed by brine, dried over anhydrous sodium sulfate, concentrated in vacuo. The residue was purified by HPLC to give N-[2-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-2-fluoro-benzenesulfonamide. LC/MS m/e obsd. (ESI+) [(M+H)+] 445.1.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[C:8]([CH3:18])[C:6]=2[N:7]=1.C(N(CC)CC)C.[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:38]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)(=[O:40])=[O:39])[CH2:14][CH2:13]3)=[C:8]([CH3:18])[C:6]=2[N:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1c(CN2CCNCC2)sc2c(N3CCOCC3)nc(Cl)nc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(CN2CCN(S(=O)(=O)c3ccccc3)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Temperature: 25 °C

Procedure:
To 2-Chloro-7-methyl-4-morpholin-4-yl-6-piperazin-1-ylmethyl-thieno[3,2-d]pyrimidine (100 mg) in anhydrous DCM (2 ml) and triethylamine (1.5 equiv., 60 μl) at 0° C. was added benzenesulfonyl chloride (1.3 equiv., 45.5 μl) and the reaction mixture was allowed to warm up to room temperature overnight. Chloroform/brine extraction and purification on silica gave 2-chloro-6-(4-benzenesulfonyl-piperazin-1-ylmethyl)-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (104 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][NH:6][S:7]([C:10]1[S:11][CH:12]=[CH:13][C:14]=1[CH:15]1OCC[O:16]1)(=[O:9])=[O:8])[CH3:2].Cl>C1COCC1.[Cl-].[Na+].O>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][NH:6][S:7]([C:10]1[S:11][CH:12]=[CH:13][C:14]=1[CH:15]=[O:16])(=[O:9])=[O:8])[CH3:2]
Reactant: CCOC(=O)CNS(=O)(=O)c1sccc1C1OCCO1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CNS(=O)(=O)c1sccc1C=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.8 %

Procedure:
To a solution of the product from Step A (31.0 g 97.0 mmol) in THF (100 mL) was added 3N HCl and the mixture stirred for 6 h at room temperature. Brine (100 mL) was added and the mixture extracted with ethyl acetate (3×100 mL). The combined extracts were washed with brine (20.0 mL), dried (MgSO4) and evaporated to yield a white solid (22.0 g, 82%): mp 74°-76° C.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][C:10]#[N:11])[CH:4]=1.Br[CH2:13][C:14]([O:19][CH3:20])([O:17][CH3:18])[CH2:15]Br.O>CN(C=O)C>[CH3:18][O:17][C:14]1([O:19][CH3:20])[CH2:15][C:9]([C:5]2[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=2)([C:10]#[N:11])[CH2:13]1
Reactant: COC(CBr)(CBr)OC
Reactant: N#CCc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC1(OC)CC(C#N)(c2cccnc2)C1
Temperature: 60 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
To a stirred suspension of NaH (1.466 g, 36.6 mmol, 60% in mineral oil) in DMF (25 mL) was added 2-(pyridin-3-yl)acetonitrile (1.954 mL, 18.32 mmol) followed by 1,3-dibromo-2,2-dimethoxypropane (4 g, 15.27 mmol) and the reaction mixture was warmed to 60° C. and stirred for 12 h. The reaction mixture was cooled to RT, poured into water (250 mL) and extracted with EtOAc (3×50 mL). The organic layer was separated, washed with water, brine, dried over Na2SO4, filtered and the filtrate concentrated. The crude product was purified by silica gel chromatography (40 g REDISEP® column, eluting with 50% EtOAc in hexanes). Fractions containing the product were combined and evaporated to afford Intermediate 311A as a white solid (2 g, 60%). MS(ES): m/z=219.2 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.71 (dd, J=0.8, 2.6 Hz, 1H), 8.58 (dd, J=1.7, 4.7 Hz, 1H), 7.89 (s, 1H), 7.51-7.45 (m, 1H), 3.19 (s, 3H), 3.08 (s, 3H), 2.89 (s, 1H), 2.83 (s, 1H), 2.78 (s, 1H), 2.73 (d, J=0.8 Hz, 1H).
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S.C(N)=O.[C:18]([C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:30])[CH2:28]Br)=[CH:23][CH:22]=1)(=O)[CH3:19].[CH:31]([NH2:33])=[S:32].[OH-].[Na+]>O1CCOCC1>[S:32]1[CH:19]=[C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27](=[O:30])[CH3:28])=[CH:23][CH:22]=2)[N:33]=[CH:31]1
Reactant: NC=S
Reactant: CC(=O)c1ccc(C(=O)CBr)cc1
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [Na+]
Agent: [OH-]
Solvent: NC=O
Solvent: C1COCCO1
Product: CC(=O)c1ccc(-c2cscn2)cc1
Temperature: 25 °C
Yield: 36 %

Procedure:
To a stirred suspension of phosphorus pentasulfide (24.5 g, 110 mmol) in dioxane (250 ml) was added formamide (28.4 g. 630 mmol), and the mixture was heated at reflux temperature for 2 hours. The reaction mixture was cooled down to room temperature, and the solution was decanted away from solids. To a stirred solution of 1-(4-acetylphenyl)-2-bromo-1-ethanone (2.0 g, 8.3 mmol) in dioxane (80 ml) was added the thioformamide solution, and the mixture was heated at reflux temperature for 13 hours. The reaction mixture was cooled down to room temperature, and made basic by addition of 0.5M NaOH aqueous solution. The whole was extracted with diethylether. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:4) to give the title compound (610 mg, 36% yield).
Reaction SMILES: [N:1]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[C:26](=[O:27])[CH:25]=[CH:24][CH:23]=[N:22]4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][C@@H:3]2[CH2:6][NH:7][CH2:8][C@H:2]12.[CH:28](=O)[CH3:29].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C([O-])(O)=O.[Na+]>[CH2:28]([N:7]1[CH2:6][C@@H:3]2[C@@H:2]([N:1]([C:9]3[CH:14]=[CH:13][C:12]([C:15]4[CH:20]=[CH:19][C:18]([N:21]5[C:26](=[O:27])[CH:25]=[CH:24][CH:23]=[N:22]5)=[CH:17][CH:16]=4)=[CH:11][CH:10]=3)[CH2:5][CH2:4]2)[CH2:8]1)[CH3:29]
Reactant: CC=O
Reactant: O=c1cccnn1-c1ccc(-c2ccc(N3CC[C@@H]4CNC[C@@H]43)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCN1C[C@H]2CCN(c3ccc(-c4ccc(-n5ncccc5=O)cc4)cc3)[C@H]2C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The product from Example 85B (0.050 g, 0.140 mmol) and acetaldehyde (10.0 μL, 0.140 mmol) were combined in 5 mL of dichloroethane containing 3 drops of HOAc and stirred at ambient temperature for 10 minutes. Sodium triacetoxyborohydride (0.039 g, 0.182 mmol) was added and the mixture was stirred for 3 hours. The mixture was diluted with 20 mL of aqueous NaHCO3 and extracted three times with 25 mL of 5% n-propanol in CHCl3 and the combined extracts were dried over Na2SO4, filtered, and absorbed on silica gel. The crude material was chromatographed, eluting with 1% aqueous NH4OH in EtOAc/MeOH (9:1), to provide the title compound, 1H NMR (300 MHz, CDCl3) δ ppm 7.91 (d, J=2.0 Hz, 1H), 7.63 (s, 4H), 7.50 (d, J=8.5 Hz, 2H), 7.23 (d, J=3.7 Hz, 1H), 7.07 (d, J=9.2 Hz, 1H), 6.65 (d, J=8.8 Hz, 2H), 4.11-4.25 (m, 1H), 3.47-3.60 (m, 1H), 3.24-3.39 (m, 1H), 2.88-3.05 (m, 1H), 2.78 (dd, J=9.5, 6.4 Hz, 1H), 2.56-2.70 (m, 2H), 2.35-2.56 (m, 3H), 2.10-2.25 (m, 1H), 1.85-2.02 (m, 1H), 1.26 (s, 1H), 1.09 (t, J=7.1 Hz, 2H). MS (ESI+) m/z 387 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH2:5])=[O:4].[CH3:6][N:7]([C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[N:8]([CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1)[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].N1C=CC=CC=1>C1C=CC=CC=1>[CH3:6][N:7]([C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[N:8]([CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](=[O:25])[NH:5][C:3]([NH:2][CH3:1])=[O:4])=[CH:22][CH:21]=1)[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: CN(C(=O)OCc1ccccc1)N(Cc1ccc(C(=O)Cl)cc1)C(=O)OCc1ccccc1
Reactant: CNC(N)=O
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CNC(=O)NC(=O)c1ccc(CN(C(=O)OCc2ccccc2)N(C)C(=O)OCc2ccccc2)cc1

Procedure:
7.4 g. of methyl urea, 46.7 g. of 4-[(2-methyl-1,2-dicarbobenzoxy-hydrazino)-methyl]-benzoyl chloride, 8 g. of pyridine and 200 ml. of benzene were mixed and refluxed for 8 hours. After cooling down, the mixture was poured onto water and extracted with an ether/methylene chloride mixture. The extract was washed with water, with 1 N hydrochloric acid and again with water, dried over sodium sulfate and freed of the solvent by distillation. The residue crystallized upon triturating with methanol. The crystals were filtered off and dried, yielding 1-methyl-2-[4-(4-methyl-allophanoyl)-benzyl]-1,2-dicarbobenzoxy-hydrazine melting at 141°-142°. 25 g. thereof were dissolved in 50 ml. of glacial acetic acid and to it were added 100 ml. of a 33% solution of hydrobromic acid in glacial acetic acid. After 4 hours standing, the crystals formed were filtered off, washed with glacial acetic acid and ether, and recrystallized from methanol, yielding 1-methyl-2-[4-(4-methyl-allphanoyl)benzyl]-hydrazine hydrobromide of melting point 183°-183.5°.
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[CH3:9][Si:10]([C:13]#[C:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][C:22]([O:24][CH3:25])=[O:23])([CH3:12])[CH3:11].CI>C1COCC1>[CH3:11][Si:10]([C:13]#[C:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]([CH3:2])[C:22]([O:24][CH3:25])=[O:23])([CH3:12])[CH3:9]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)Cc1ccccc1C#C[Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)c1ccccc1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2 M LDA solution (1.24 mL, 2.48 mmol) was added to solution of methyl 2-(2-((trimethylsilyl)ethynyl)phenyl)acetate (I10) (0.306 g, 1.24 mmol) in THF (10 mL) at −78° C. and the mixture stirred for 30 minutes. Methyl iodide was then added (0.155 mL, 2.48 mmol) and the reaction mixture slowly warmed to room temperature over 1.5 hours. The reaction mixture was then left to stir at room temperature for 18 hours before quenching with a saturated solution of NH4Cl (20 mL). EtOAc (20 mL) was then added and the layers separated. The aqueous layer was further extracted with EtOAc (2×20 mL). The solvent was removed in vacuo to give a brown oil which was purified by column chromatography on silica gel (0-5% EtOAc in petroleum benzine 40-60° C.) to afford the title compound (I50) (0.297 g, 92%) as a yellow oil; 1H NMR (400 MHz, CDCl3) δ7.49-7.44 (m, 1H), 7.33-7.24 (m, peaks obscured by CDCl3), 7.21-7.17 (m, 1H), 4.25 (q, J=7.2 Hz, 1H), 3.67 (s, 3H), 1.51 (d, J=7.2 Hz, 3H), 0.26 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([NH:46][S:47]([CH2:50][CH2:51][CH2:52][CH3:53])(=[O:49])=[O:48])[CH:34]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:35]2[CH:34]=[C:33]([NH:46][S:47]([CH2:50][CH2:51][CH2:52][CH3:53])(=[O:48])=[O:49])[CH:32]=[C:31]([O:30][CH3:29])[CH:36]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: CCCCS(=O)(=O)Nc1cc(OC)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCCS(=O)(=O)Nc1cc(OC)cc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 79.9 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (120 mg, 0.27 mmol) were added N-(3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butane-1-sulfonamide (121 mg, 0.33 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (22 mg, 0.03 mmol) and 273 μl of a 2M aqueous solution of cesium carbonate in dioxane (5 ml). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude was purified using SP1® Purification System (0 to 80%, hexane-ethyl acetate) to give 130 mg (79% yield) of the title compound as a white solid. Purity 100%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:9][S:10]([C:13]2[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=2[CH3:22])(=[O:12])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.C(P(CCCC)CCCC)CCC.[CH2:36](O)[CH2:37][CH2:38][OH:39].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.CCCCCC>[CH3:1][C:2]1[CH:3]=[C:4]([O:9][S:10]([C:13]2[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=2[CH3:22])(=[O:12])=[O:11])[CH:5]=[C:6]([CH:7]=1)[O:8][CH2:36][CH2:37][CH2:38][OH:39]
Reactant: OCCCO
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2cc([N+](=O)[O-])ccc2C)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cc([N+](=O)[O-])ccc2C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
To a solution of 5-methyl-3-(2-methyl-5-nitrophenylsulfonyloxy)phenol (1.46 g, 5.0 mmol), as prepared in the preceding step, tri-n-butylphosphine (1.6 g, 8.0 mmol) and 1,3-propanediol (2.3 g, 30 mmol) in anhydrous tetrahydrofuran (50 mL) was added 1,1'-(azodicarbonyl)dipiperidine (2.0 g, 8.0 mmol). The mixture was stirred at ambient temperature overnight. Hexane (80 mL) was added to the mixture, and the precipitates were removed by filtration. The filtrate was evaporated in vacuo, and the residue was purified by flash column chromatography (1:1 hexane/ethyl acetate) to give the title compound as a yellow oil (920 mg, 48%). 1H-NMR (300 MHz, CDCl3) δ 8.72 (s, 1H), 8.37 (d, J=8.3 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 6.63 (s, 1H), 6.43 (s, 1H), 6.40 (s, 1H), 4.02 (t, J=6.0 Hz, 2H), 3.81 (t, J=6.0 Hz, 2H), 2.89 (s, 3H), 2.25 (s, 3H), 1.99 (m, 2H), 1.58 (s, 1H).