Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:17]1[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:20]=[C:19]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:18]=1[OH:31])[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]=1[OH:16].C(N(CC)CC)C.Cl[C:40]1[C:41]([C:67]([CH3:70])([CH3:69])[CH3:68])=[CH:42][C:43]2[C:49]3[CH:50]=[C:51]([C:58]([CH3:61])([CH3:60])[CH3:59])[CH:52]=[C:53]([C:54]([CH3:57])([CH3:56])[CH3:55])[C:48]=3[O:47][PH:46][O:45][C:44]=2[C:62]=1[C:63]([CH3:66])([CH3:65])[CH3:64].C(#N)C>C1(C)C=CC=CC=1>[C:58]([C:51]1[CH:52]=[C:53]([C:54]([CH3:57])([CH3:56])[CH3:55])[C:48]2[O:47][P:46]([O:31][C:18]3[C:19]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:20][C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:22][C:17]=3[CH2:1][C:2]3[CH:7]=[C:6]([C:8]([CH3:11])([CH3:9])[CH3:10])[CH:5]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]=3[OH:16])[O:45][C:44]3[C:62]([C:63]([CH3:65])([CH3:64])[CH3:66])=[CH:40][C:41]([C:67]([CH3:70])([CH3:69])[CH3:68])=[CH:42][C:43]=3[C:49]=2[CH:50]=1)([CH3:61])([CH3:60])[CH3:59]
Reactant: CC(C)(C)c1cc(C(C)(C)C)c2o[pH]oc3c(C(C)(C)C)c(Cl)c(C(C)(C)C)cc3c2c1
Reactant: CC(C)(C)c1cc(Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CC(C)(C)c1cc(Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2Op2oc3c(C(C)(C)C)cc(C(C)(C)C)cc3c3cc(C(C)(C)C)cc(C(C)(C)C)c3o2)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 84.9 %

Procedure:
Into a solution of 21.23 g (50 mmol) of 2,2'-methylenebis(4,6-di-tert-butylphenol) and 7 mL (50 mmol) of triethylamine in 200 mL of toluene is added dropwise a solution of 23.84 g (50 mmol) of 3-chloro-2,4,8,10-tetra-tert-butyl-dibenzo[d,f][1,3,2]dioxaphosphepin in 100 mL of toluene at ambient temperature. After 20 hours of stirring at ambient temperature, the reaction mass is filtered to remove triethylamine hydrochloride and the filtrate is concentrated in vacuo to give a brownish oil. Trituration of the crude oil with 200 mL of acetonitrile gives 36.65 g (85% yield) of a white solid: m.p.=195°-205° C.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[O:15]=[C:16]([CH3:25])[CH2:17][C:18]([O:20][CH2:21][CH:22]1[CH2:24][CH2:23]1)=[O:19].C(O)(=O)C.N1CCCCC1>ClCCl>[CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:17]([C:16](=[O:15])[CH3:25])[C:18]([O:20][CH2:21][CH:22]1[CH2:24][CH2:23]1)=[O:19]
Reactant: CC(=O)CC(=O)OCC1CC1
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(=O)OCC1CC1

Procedure:
500 mg (2.65 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde, 798 mg (2.65 mmol) of cyclopropylmethyl 3-oxobutanoate, 38 μl (0.66 mmol) of acetic acid and 66 μl (0.66 mmol) of piperidine in 25 ml of anhydrous dichloromethane are heated after addition of 4 Å molecular sieves (1.5 g) under reflux for 24 h. After cooling, the suspension is filtered with suction and the filtrate is washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated. The residue is purified by preparative HPLC. 650 mg (74% of theory) of the title compound are obtained as an E/Z mixture.
Reaction SMILES: [Li]CCCC.CCCCCC.[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][C:18]([CH3:22])=[CH:19][CH:20]=2)[C:15]2[C:23]3[C:28]([CH2:29][C:14]1=2)=[CH:27][CH:26]=[CH:25][CH:24]=3.[C:30]([NH:34][Si:35]([CH3:38])([CH3:37])Cl)([CH3:33])([CH3:32])[CH3:31]>CCOCC>[CH3:37][SiH:35]([N:34]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:29]1[C:14]2[N:13]([CH3:12])[C:21]3[C:16]([C:15]=2[C:23]2[C:28]1=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:17][C:18]([CH3:22])=[CH:19][CH:20]=3)[CH3:38]
Reactant: CC(C)(C)N[Si](C)(C)Cl
Reactant: Cc1ccc2c(c1)c1c(n2C)Cc2ccccc2-1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: Cc1ccc2c(c1)c1c(n2C)C(N([SiH](C)C)C(C)(C)C)c2ccccc2-1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.8 %

Procedure:
6.66 mL of n-BuLi 2.5 M in hexane (16.65 mmol) were added dropwise at 0° C. to a solution of 3.53 g of N-methyl-2-methyl-5,6-dihydroindeno[2,1-b]indole (Mw=233.32, purity 99.0%, 15.13 mmol) in Et2O. At the end of the addition, the reaction mixture was allowed to warm up to room temperature and stirred for two hours. Subsequently, 3.34 g of (tert-butylamino)dimethylchlorosilane (Mw=165.74, purity 75.0% mol., d=0.887, 20.17 mmol) were added at 0° C. to the Li salt suspension and the resulting mixture was allowed to warm up to room temperature. After three hours stirring, the solvents were evaporated under reduced pressure and the residue was dissolved in 50 mL of toluene, obtaining a dark brown suspension, which was filtered. The filtrate was evaporated to dryness under reduced pressure, obtaining 5.86 g of a dark brown oil, which resulted to be 86.5% wt. pure (calculated by 1H-NMR). Yield=92.4%.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].C1(C)C(S([N:19]=C=O)(=O)=O)=CC=CC=1.[H-].[Na+].O1[CH2:29][CH2:28]CC1>>[C:6]([O:5][C:1]([C:2]1[CH:29]=[CH:28][NH:19][CH:3]=1)=[O:4])([CH3:9])([CH3:8])[CH3:7]
Reactant: Cc1ccccc1S(=O)(=O)N=C=O
Reactant: C=CC(=O)OC(C)(C)C
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)c1cc[nH]c1
Reaction time: 2 h

Procedure:
A solution of tert-butyl acrylate (10.5 g) and toluenesulfonylisocyanate (16 g) in tetrahydrofuran (210 ml) was added dropwise at 70° C. to a suspension of sodium hydride (3.9 g) in tetrahydrofuran (200 ml) over 0.5 hour and stirred at the same temperature for two hours. After completion of the reaction, the solvent was evaporated, water was added to the residue and extracted with ethyl acetate three times. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) and recrystallized (n-hexane/ethyl acetate) to give the titled compound (5.27 g) as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH3:12])[CH2:4][C:5]#[C:6][CH2:7][CH2:8][CH:9]=O)[CH3:2].[CH2:13]([SH:17])[CH2:14][CH2:15][SH:16].B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:1]([N:3]([CH2:11][CH3:12])[CH2:4][C:5]#[C:6][CH2:7][CH2:8][CH:9]1[S:17][CH2:13][CH2:14][CH2:15][S:16]1)[CH3:2]
Reactant: SCCCS
Reactant: CCN(CC)CC#CCCC=O
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCN(CC)CC#CCCC1SCCCS1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.8 %

Procedure:
To a solution of 6-diethylaminohex-4-ynal (50 g, 290 mmol) in methylene chloride (600 mL) was added 1,3-propanedithiol (30 mL, 290 mmol). The solution was stirred at room temperature for 1 hour and then cooled in an ice-bath. Boron trifluoride etherate (40 mL, 290 mmol) was added and the solution was stirred at room temperature overnight. The mixture was washed with water (150 mL), 10% potassium hydroxide solution (2×300 mL), brine (3×100 mL) and dried (MgSO4). Evaporation of the solvent afforded an oil which was Kugelrohr distilled (oven 120° C., 0.1 mm Hg) to give 20 g of product. The residue was chromatographed on basic alumina (activity I) eluting with methylene chloride and the oil was redistilled by Kugelrohr to afford 14 g (45%) of product. 1H NMR (CDCl3) δ: 1.14 (t, 6H), 1.80-1.90 (m, 1H), 1.91 (q, 2H), 2.05-2.15 (m, 1H), 2.43 (t, 2H), 2.52 (q, 4H), 2.81-2.90 (m, 4H), 3.39 (d, 2H), 4.17 (t, 1H) ppm.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>CN(C)C=O>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:8][CH:7]=1)[C:3]([O:5][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:4]
Reactant: CC(C)Cc1ccc(C(O)C(=O)O)cc1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Cc1ccc(C(O)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of 2-hydroxy-2-(4-isobutylphenyl)acetic acid (3.8 g) in N,N-dimethylformamide (30 ml) was added potassium carbonate (7.6 g) and benzylbromide (2.2 ml). The mixture was stirred at room temperature for 4.5 hours and poured into ice water and 7% hydrochloric acid. The organic layer was extracted with ethyl acetate, washed with aqueous sodium bircarbonate solution and water, dried over magnesium sulfate and evaporated. The residual white powder was collected with n-hexane by filtration to give benzyl 2-hydroxy-2-(4-isobutylphenyl)acetate as a white powder (4.42 g).
Reaction SMILES: [CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]4[O:22][CH:6]5[C:7]([CH:9]=[CH:10][C@:11]2([OH:23])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8].[H][H]>O.C(O)(=O)C.[Pd]>[CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]4[O:22][C@H:6]5[C:7]([CH2:9][CH2:10][C@:11]2([OH:23])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8]
Reactant: [H][H]
Reactant: COc1ccc2c3c1OC1C(=O)C=C[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Yield: 79 %

Procedure:
The 14-hydroxycodeinone (39.45 g of the damp solid) was dissolved in water (81.13 ml) and 80% acetic acid (16.17 ml). 10 wt % palladium on carbon catalyst (0.33 g wet weight, 0.16 g dry weight) was added and hydrogen was passed through the mixture for about 6 hours at about 12 psi. The mixture was filtered to remove the catalyst. An ammonium hydroxide solution was added to the mixture up to pH 9. The solid precipitate was washed with water and with ethanol, and was dried. The product was oxycodone (18.8 g, 79% yield).
Reaction SMILES: C1C(=O)N(Cl)C(=O)C1.[CH:9](=[N:16][OH:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Br:18][C:19]1[N:20]=[C:21]([C:40]#[CH:41])[C:22]([N:25]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[N:23][CH:24]=1.CCN(CC)CC>CN(C=O)C>[Br:18][C:19]1[N:20]=[C:21]([C:40]2[O:17][N:16]=[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:41]=2)[C:22]([N:25]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[N:23][CH:24]=1
Reactant: ON=Cc1ccccc1
Reactant: C#Cc1nc(Br)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1-c1cc(-c2ccccc2)no1
Temperature: 55 °C
Reaction time: 0.75 h
Yield: 44.3 %

Procedure:
NCS (12.19 g, 91.26 mmol) was added to a solution of benzaldehyde oxime (10.05 g, 82.96 mmol) in DMF (40.20 mL) and the mixture heated at 55° C. for 15 minutes. The reaction mixture was cooled to ambient temperature and tert-butyl N-(5-bromo-3-ethynyl-pyrazin-2-yl)-N-tert-butoxycarbonyl-carbamate (36.34 g, 91.26 mmol) and DMF (30.15 mL) were added followed by the dropwise addition of Et3N (10.07 g, 13.87 mL, 99.55 mmol). The reaction mixture was stirred at ambient temperature for 45 minutes and then heated to 65° C. for 1 hour. The reaction mixture was cooled to ambient temperature and the solvent removed under high vacuum. The residue was taken up in ethyl acetate (50 ml). Remaining solid was filtered off and the filtrate concentrated in vacuo and then purified by column chromatography on silica using the ISCO column companion system, eluting with ethyl acetate/petroleum ether (0-40% EtOAc). Product fractions were combined and concentrated in vacuo to give tert-butyl (5-bromo-3-(3-phenylisoxazol-5-yl)pyrazin-2-yl)-N-tert-butoxycarbonyl-carbamate as a pale yellow solid (19 g, 46%). LC/MS m/z 419 [M−100+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:41]=[CH:40][C:7]([C:8]([O:10][C@@:11]([C:18]2[N:19]=[N:20][N:21]([CH2:23][C:24]3[CH:33]=[C:32]4[C:27]([C:28]([C:36](=O)[CH2:37]Br)=[CH:29][C:30]([C:34]#[N:35])=[N:31]4)=[CH:26][CH:25]=3)[CH:22]=2)([C:14]([F:17])([F:16])[F:15])[CH2:12][CH3:13])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:42]([NH2:45])(=[S:44])[CH3:43]>CN(C=O)C.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][C@@:11]([C:18]2[N:19]=[N:20][N:21]([CH2:23][C:24]3[CH:33]=[C:32]4[C:27]([C:28]([C:36]5[N:45]=[C:42]([CH3:43])[S:44][CH:37]=5)=[CH:29][C:30]([C:34]#[N:35])=[N:31]4)=[CH:26][CH:25]=3)[CH:22]=2)([C:14]([F:16])([F:17])[F:15])[CH2:12][CH3:13])=[O:9])=[CH:40][CH:41]=1)([O-:3])=[O:2]
Reactant: CC[C@](OC(=O)c1ccc([N+](=O)[O-])cc1)(c1cn(Cc2ccc3c(C(=O)CBr)cc(C#N)nc3c2)nn1)C(F)(F)F
Reactant: CC(N)=S
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC[C@](OC(=O)c1ccc([N+](=O)[O-])cc1)(c1cn(Cc2ccc3c(-c4csc(C)n4)cc(C#N)nc3c2)nn1)C(F)(F)F

Procedure:
A solution of 1-(1-{[4-(bromoacetyl)-2-cyanoquinolin-7-yl]methyl}-1H-1,2,3-triazol-4-yl)-1-(trifluoromethyl)propyl 4-nitrobenzoate (see Example 52, Step 2) (65 mg, 0.1 mmol) and thioacetamide (9 mg, 0.11 mmol) in DMF (1 mL) was stirred at 100° C. overnight. The reaction mixture was diluted in ethyl acetate, washed with water, brine and dried over MgSO4. The crude compound was purified on silica gel (eluting solvent: 3% acetone in dichloromethane) to give the desired product. 1H NMR (acetone-d6): δ 8.85 (d, 1H), 8.52 (s, 1H), 8.42 (d, 2H), 8.30 (d, 2H), 8.17 (d, 2H), 8.05 (s, 1H), 7.75 (d, 1H), 6.05 (s, 2H), 3.05 (m, 1H), 2.85 (s, 3H), 2.85 (m, 1H), 1.15 (t, 3H).
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH:13]([NH2:16])([CH3:15])[CH3:14].[Cl:17][CH2:18][CH2:19][N:20]=[C:21]=[O:22]>>[Cl:17][CH2:18][CH2:19][NH:20][C:21]([N:16]([CH:13]([CH3:15])[CH3:14])[CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])=[O:22]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CC(C)N
Reactant: O=C=NCCCl
Product: CC(C)N(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 73.5 %

Procedure:
3.6 g of D-glucose, 2.0 g of isopropylamine and 2.5 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 5-(1). 4.8 g of 1-(2-chloroethyl)-3-isopropyl-3-D-glucopyranosylurea are obtained as colorless caramel.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]([N:15]=1)=[C:13]1[C:8]([CH:9]=[CH:10][C:11](=O)[N:12]1C)=[CH:7][CH:6]=2.P(Cl)(Cl)([Cl:20])=O.P(Cl)(Cl)(Cl)(Cl)Cl>>[Cl:20][C:11]1[CH:10]=[CH:9][C:8]2[C:13](=[C:14]3[C:5](=[CH:6][CH:7]=2)[CH:4]=[CH:3][C:2]([Cl:1])=[N:15]3)[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1c(=O)ccc2ccc3ccc(Cl)nc3c21
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: Clc1ccc2ccc3ccc(Cl)nc3c2n1
Yield: 94 %

Procedure:
Under a stream of argon, to compound (5) (4.26 g; 17.4 mmol), phosphorus oxychloride (39 mL) and phosphorus pentachloride (4.48 g; 21.8 mmol) were added in an ice bath. The resulting reaction mixture was stirred and refluxed for 7 hours, and then evaporated under reduced pressure to remove phosphorus oxychloride. To the resulting residue, ice water and concentrated aqueous ammonia were added and the resulting reaction mixture was made alkaline. The solids which precipitated out were separated by filtration and washed with water, and then dried under reduced pressure to give 4.06 g (yield: 94%) of the title compound (6).
Reaction SMILES: CO[C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[O:12]C(C)(C)CN=1.[CH:18]([Mg]Cl)([CH3:20])[CH3:19].CC[O:25]CC.[Cl-].[NH4+]>O1CCCC1>[CH:18]([C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]([OH:12])=[O:25])([CH3:20])[CH3:19]
Reactant: CC(C)[Mg]Cl
Reactant: CCOCC
Reactant: COc1cccc(C2=NCC(C)(C)O2)c1OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cccc(C(=O)O)c1C(C)C
Temperature: 10 °C
Reaction time: 8 h

Procedure:
A 500 mL round-bottom flask equipped with nitrogen purge, septum inlet, and magnetic stirring, was dried under an atmosphere of nitrogen and charged with 5 g (21.2 mmoles) of 2-(2,3-dimethoxyphenyl)-5,5-dimethyloxazoline (which was synthesized in a like manner according to EXAMPLE 10) and 100 mL of tetrahydrofuran. The solution was cooled to 10° C. and 58 mL of 2N isopropylmagnesium chloride/ether was added. The mixture was stirred at room temperature overnight and poured into a 1:1 mixture of saturated ammonium chloride and ice. The mixture was extracted twice with ether; the organic layers were combined, dried over magnesium sulfate, and the solvent was removed in vacuo to yield 5.3 g of a yellow oil. This was dissolved in 200 mL of 6N hydrochloric acid and heated at reflux for 8.5 hours. The mixture was extracted several times with ether, and the combined organic phases were dried over sodium sulfate. The solvent was removed in vacuo to yield 4.6 g of oil which crystallized on standing. 1H NMR (200 MHz, CDCl3), δ=7.29 (1H, dd, 1.5, 7.5 Hz), 7.21 (1H, t, 7.5 Hz), 7.01 (1H, dd, 1.5, 7 Hz), 3.85 (3H, s), 3.65 (1H, m), 1.37 (6H, d, 7 Hz) ppm.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[N:16]3[C:11]([C:12]([NH2:17])=[N:13][CH:14]=[N:15]3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.C(Cl)Cl.[C:28](OC([O-])=O)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>C1COCC1>[NH2:17][C:12]1[C:11]2=[CH:10][CH:9]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH2:2]3)[N:16]2[N:15]=[CH:14][N:13]=1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: Nc1ncnn2c(CN3CCNCC3)ccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc3c(N)ncnn23)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a cooled (0° C.) solution of 7-(piperazin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (0.85 g, 3.66 mmol) and triethylamine (0.56 mL, 4.03 mmol) in THF (8.5 mL)/DCM (8.5 mL) was added iii-tert-butyl dicarbonate (0.88 g, 4.03 mmol) and the mixture was allowed to warm to rt and further stirred for 18 h and concentrated. The residue was taken up in ethyl acetate, washed with water and dried over Na2SO4 and concentrated (used in the next step without further purification). LC-MS [M+H]+=332.8, RT=1.17 min
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:7][O:6][C:5]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([N+:20]([O-])=O)[CH:14]=2)([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[O:4][CH2:3]1.[H][H]>[Ni].CO>[CH3:1][C:2]1([CH3:23])[CH2:3][O:4][C:5]([C:13]2[CH:14]=[C:15]([NH2:20])[C:16]([NH2:19])=[CH:17][CH:18]=2)([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[O:6][CH2:7]1
Reactant: [H][H]
Reactant: CC1(C)COC(c2ccc(N)c([N+](=O)[O-])c2)(c2cccs2)OC1
Agent: [Ni]
Solvent: CO
Product: CC1(C)COC(c2ccc(N)c(N)c2)(c2cccs2)OC1
Yield: 100 %

Procedure:
A mixture of 5.04 parts of 4-[5,5-dimethyl-2-(2-thienyl)-1,3-dioxan-2-yl]-2-nitrobenzenamine and 120 parts of methanol is hydrogenated at normal pressure and at room temperature with 3 parts of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated, yielding 4.5 parts (100%) of 4-[5,5-dimethyl-2-(2-thienyl)-1,3-dioxan-2-yl]-1,2-benzenediamine; mp. 178° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[NH:9][C:8](=[O:11])[NH:7][C:6]=2[CH:5]=[C:4]([CH3:12])[CH:3]=1.[H-].[Na+].Br[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>CN(C=O)C.O>[CH3:1][C:2]1[C:10]2[NH:9][C:8](=[O:11])[N:7]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:6]=2[CH:5]=[C:4]([CH3:12])[CH:3]=1
Reactant: Cc1cc(C)c2[nH]c(=O)[nH]c2c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)c2[nH]c(=O)n(CC(=O)OC(C)(C)C)c2c1
Reaction time: 0.33 h

Procedure:
To a stirred solution of 4,6-dimethyl-1,3-dihydro-2H-benzimidazol-2-one from Step A (7.15 g, 44.1 mmol) in DMF (200 mL) was added sodium hydride (1.76 g of a 60% dispersion in mineral oil, 44.1 mmol) over 2 min. The mixture was stirred for 20 min, then tert-butyl bromoacetate (8.17 g, 41.9 mmol) in DMF (40 mL) was added and stirring was continued for 1 h. The reaction mixture was diluted with H2O (400 mL) carefully and a solid precipitated. The mixture was aged for 5 min, then filtered to give a crude solid, which was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:EtOAc—100:0 to 40:60, to provide the title compound. MS: m/z=277 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:11])[CH:5]=[CH:6][C:7]=1[CH:8]=O.Cl.Cl.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][C:24]1([CH3:30])[CH3:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO.C(Cl)Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C@@H:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:11])[CH:5]=[CH:6][C:7]=1[CH2:8][N:26]1[CH2:27][CH2:28][N:23]([CH3:22])[C:24]([CH3:30])([CH3:29])[CH2:25]1
Reactant: CN1CCNCC1(C)C
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C=O)c(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(CN2CCN(C)C(C)(C)C2)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
A solution of (S)-tert-butyl 1-(3-fluoro-4-formylphenyl)ethylcarbamate (267 mg, 1 mmol) and 1,2,2-trimethylpiperazine dihydrochloride (402 mg, 2 mmol) in THF (5 mL) was stirred at room temperature for 1 h and treated with sodium triacetoxyborohydride (848 mg, 4 mmol). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated aqueous solution of NaHCO3 (15 mL) and extracted with EtOAc (3×mL). Combined organics were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (MeOH/CH2Cl2 0 to 10%) provided (S)-tert-butyl 1-(3-fluoro-4-((3,3,4-trimethylpiperazin-1-yl)methyl)phenyl)ethylcarbamate as a white solid (186 mg, 49% yield). 1H NMR (400 MHz, CDCl3) δ 7.35 (t, J=7.7 Hz, 1H), 7.03 (dd, J=7.9, 1.9 Hz, 1H), 6.95 (dd, J=11.1, 1.8 Hz, 1H), 4.77 (s, 1H), 3.49 (s, 2H), 2.56 (br s, 4H), 2.24 (br s, 5H), 1.42 (br s, 12H), 1.04 (s, 6H); MS m/z 380.4 (M+H).
Reaction SMILES: Cl.Cl[C:3]1[N:16]2[C:7](=[N:8][C:9]3[C:14]([C:15]2=[O:17])=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]2[CH:18]=[CH:19][N:20]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:5]=2[N:4]=1.[CH3:31][N:32]([CH2:34][C:35]([N:37]1[C:45]2[C:40](=[CH:41][C:42]([O:47][CH3:48])=[C:43]([NH2:46])[CH:44]=2)[CH2:39][CH2:38]1)=[O:36])[CH3:33].[NH4+:49].[OH-]>C1COCC1.CCOC(C)=O>[CH3:33][N:32]([CH3:31])[CH2:34][C:35]([N:37]1[C:45]2[C:40](=[CH:41][C:42]([O:47][CH3:48])=[C:43]([NH:46][C:3]3[N:16]=[C:7]([NH:8][C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=4[C:15]([NH2:49])=[O:17])[C:6]4[CH:18]=[CH:19][N:20]([S:21]([C:24]5[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=5)(=[O:23])=[O:22])[C:5]=4[N:4]=3)[CH:44]=2)[CH2:39][CH2:38]1)=[O:36]
Reactant: [NH4+]
Reactant: COc1cc2c(cc1N)N(C(=O)CN(C)C)CC2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2nc(Cl)n2c(=O)c4ccccc4nc32)cc1
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1Nc1nc(Nc3ccccc3C(N)=O)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n1)N(C(=O)CN(C)C)CC2
Temperature: 80 °C

Procedure:
A mixture of 5-chloro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one hydrogen chloride (500 mg, 1.084 mmol) and 1-[(dimethylamino)acetyl]-5-(methyloxy)-2,3-dihydro-1H-indol-6-amine (270 mg, 1.084 mmol) in THF (50 mL) was heated at 80° C. for 7.5 h. More 1-[(dimethylamino)acetyl]-5-(methyloxy)-2,3-dihydro-1H-indol-6-amine (270 mg, 1.084 mmol) was added and the reaction mixture was heated at 80° C. for 1 h. The resulting mixture was diluted to a total of 70 mL of which 40 mL was diluted with a 27% aqueous NH4OH solution (100 mL), maintained at rt for 3 days, and diluted with EtOAc (200 mL) and washed with a saturated NaCl solution (4×125 mL). The organic layer was concentrated onto Celite and purified by silica gel chromatography using 1-10% MeOH (containing 0.2% NH3)/CH2Cl2, followed by trituration using a mixture of CH2Cl2 and Et2O to obtain 2-({2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzamide as a white solid (101 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.24 (s, 6H), 2.35 (s, 3H), 3.14-3.28 (m, 4H), 3.74 (s, 3H), 4.24 (t, J=8.33 Hz, 2H), 6.47 (d, J=3.85 Hz, 1H), 6.91-7.03 (m, 1H), 7.08 (s, 1H), 7.24 (t, J=7.60 Hz, 1H), 7.29-7.42 (m, 3H), 7.70-7.87 (m, 2H), 7.98 (d, J=8.24 Hz, 2H), 8.23 (s, 1H), 8.31 (br s, 1H), 8.37 (s, 1H), 8.70 (d, J=8.42 Hz, 1H), 12.22 (s, 1H); ESIMS (M+H)+=655.37.