Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][OH:22])=[CH:15][C:14]=1[F:23].Cl([O-])=[O:25].[Na+].CC(=CC)C.P([O-])(O)(O)=O.[Na+]>O.C(O)(C)(C)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:25])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][OH:22])=[CH:15][C:14]=1[F:23]
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1c[nH]c2cc(Cl)c(-c3ccc(OCCO)cc3F)cc12
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(OCCO)cc3F)cc12
Temperature: 25 °C
Reaction time: 10 h
Yield: 33.4 %

Procedure:
To a solution of 6-chloro-5-[2-fluoro-4-(2-hydroxyethoxy)phenyl]-1H-indole-3-carbaldehyde (40 mg, 0.12 mmol) in water (1 mL) and t-butanol (1 mL) was added sodium chlorite (210 mg, 2.30 mmol), 2-methyl-2-butene (0.5 mL) and sodium dihydrogen phosphate (350 mg, 2.30 mmol). The reaction solution was stirred at room temperature for 10 hrs. The reaction was diluted with water (5 mL) and extracted with dichloromethane (20 mL×3). The combined organic phase was washed with water (20 mL), brine (20 mL) dried over sodium sulfate and concentrated to give a crude product. The crude was purified by reverse phase HPLC to give the title compound (14 mg, 59% yield) as an off-white solid. MS (ES−) 348.1 (M−H)−. 1H NMR (400 MHz, CD3OD) δ 8.04 (s, 2H), 7.63 (s, 1H), 7.28 (s, 1H), 6.91 (dd, 2H), 6.86 (dd, 2H), 4.16 (t, 2H), 3.96 (t, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:23])[C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[C:13]([N+:20]([O-])=O)[CH:12]=2)=[N:7][CH:8]=1)#[N:2].C(O)(=O)C>C(O)C.[Fe]>[NH2:20][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[NH2:17])[C:10]([NH:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=1)=[O:23]
Reactant: N#Cc1ccc(NC(=O)c2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)nc1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: N#Cc1ccc(NC(=O)c2ccc(N)c(N)c2)nc1

Procedure:
Prepared analogously to example 91a from N-(5-cyano-pyridin-2-yl)-3,4-dinitro-benzamide, iron powder and glacial acetic acid in ethanol.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][OH:12])=[CH:2]1.[CH3:13][CH:14]([NH:18][C:19](=[O:21])[CH3:20])[C:15](=O)[CH3:16]>B(F)(F)F.CCOCC.C1C=CC=CC=1>[CH3:16][C:15]1([CH:14]([NH:18][C:19](=[O:21])[CH3:20])[CH3:13])[C:2]2[NH:1][C:9]3[C:4]([C:3]=2[CH2:10][CH2:11][O:12]1)=[CH:5][CH:6]=[CH:7][CH:8]=3
Reactant: OCCc1c[nH]c2ccccc12
Reactant: CC(=O)NC(C)C(C)=O
Agent: FB(F)F
Solvent: c1ccccc1
Solvent: CCOCC
Product: CC(=O)NC(C)C1(C)OCCc2c1[nH]c1ccccc21

Procedure:
A mixture of indole-3-ethanol (16.1 g), benzene (1200 ml), N-(1-methyl-2-oxopropyl)-acetamide[12.7 g, described by A. Triebs and W. Sutter, Chem. Ber. 84, 96(1951)] and boron trifluoride-etherate (5 drops) is refluxed using a water separating condenser for 60 minutes. After cooling, the mixture is washed with concentrated sodium bicarbonate, dried over magnesium sulfate and evaporated. The residue is chromatographed on silica gel using chloroform. The eluates are evaporated to give a residue of the title compound as a 1:1 mixture of diastereoisomers:
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:19]([OH:21])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN([C:25]([O:29][N:30]1N=NC2C=CC=C[C:31]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.CNOC>C(Cl)Cl>[C:1]([NH:8][CH:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[CH:15][CH:16]=1)[C:19]([N:30]([O:29][CH3:25])[CH3:31])=[O:21])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C#N)cc1)C(=O)O
Agent: CNOC
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)C(Cc1ccc(C#N)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2 g of (N-Boc)-4-cyanophenylalanine, 2.32 g of TBTU, 2.40 ml of DIPEA and 806 mg of N,O-dimethylhydroxylamine hydrochloride are mixed together in 30 ml of DCM. After stirring for 24 hours at RT, the reaction mixture is concentrated to dryness and the residue is then extracted with EtOAc. The organic phase is washed with a pH 2 buffer solution, a saturated NaHCO3 solution and then a saturated NaCl solution. The expected compound crystallizes from a mixture of isopropyl ether and pentane (1.89 g).
Reaction SMILES: [Na+].[I-].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[H][H]>O>[OH:6][CH:5]([CH3:7])[CH2:4][C:3]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC(C)=O
Reactant: [H][H]
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CC(C)O
Temperature: 65 °C
Reaction time: 40 h
Yield: 62.6 %

Procedure:
Under a nitrogen gas atmosphere, 0.0096 g (7.3×10-6 mol) of [RuI(p-Cymene)((+)-SO3Na-BINAP)]I, 0.1164 g (7.8×10-4 mol) of NaI, 1 ml (7.5×10-3 mol) of ethyl acetoacetate, and 1.5 ml of water were charged in a 100 milli-liter autoclave. After displacing the inside atmosphere of the autoclave with a hydrogen gas, the autoclave was pressed at a hydrogen pressure of 50 kg/cm2 and the mixture was stirred for 40 hours at 65° C. After the reaction was over, the hydrogen gas was removed, and after added thereto 100 ml of water and 100 ml of ether, the ether extraction was carried out. The ether extract was recovered, dried with anhydrous sodium sulfate, and further ether was distilled off to provide 0.62 g (percent yield 63%) of ethyl 3-hydroxybutyrate. By the analysis of gas chromatography (PEG-HT), the conversion ratio was determined to be 99%.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([C:22]4[C:31]5[C:26](=[CH:27][C:28](F)=[CH:29][CH:30]=5)[N:25]=[CH:24][N:23]=4)[CH2:18][CH2:17]3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]1[CH2:39][CH2:40][OH:41]>>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([C:22]4[C:31]5[C:26](=[CH:27][C:28]([O:41][CH2:40][CH2:39][CH:34]6[CH2:35][CH2:36][CH2:37][CH2:38][NH:33]6)=[CH:29][CH:30]=5)[N:25]=[CH:24][N:23]=4)[CH2:18][CH2:17]3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(Nc1ccc(N2CCOCC2)cc1)N1CCC(c2ncnc3cc(F)ccc23)CC1
Reactant: OCCC1CCCCN1
Product: O=C(Nc1ccc(N2CCOCC2)cc1)N1CCC(c2ncnc3cc(OCCC4CCCCN4)ccc23)CC1

Procedure:
Prepared from 4-(7-Fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-morpholin-4-yl-phenyl)-amide, synthesized as described in the previous step, and 2-piperidin-2-yl-ethanol using the protocol described in Example 67a. 1H NMR (CD3OD) δ 9.03 (s, 1H), 8.34 (d, J=9.31 Hz, 1H), 7.37 (dd, J=9.19 and 2.54 Hz, 1H), 7.33 (d, J=2.47 Hz, 1H), 7.26 (d, J=9.06 Hz, 2H), 6.93 (d, J=9.10 Hz, 2H), 4.34 (m, 2H), 4.28 (m, 2H), 3.94 (m, 1H), 3.82 (t, J=4.69 Hz, 4H), 3.16 (m, 2H), 3.08 (t, J=4.78 Hz, 4H), 3.04 (m, 1H), 2.82 (m, 1H), 2.66 (m, 1H), 1.40-2.10 (12H). Calcd for C31H41N6O3 (MH+) 545.3, found 545.1.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[Si:23]([O:40][C:41]1[CH:42]=[C:43]([CH:51]=[CH:52][CH:53]=1)[CH2:44][CH:45]1[CH2:49][CH2:48][O:47][C:46]1=[O:50])([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(OCC)(=O)C>C1COCC1.O>[C:1]1([C:7]2[N:8]=[C:9]([CH:46]([OH:50])[CH:45]([CH2:49][CH2:48][OH:47])[CH2:44][C:43]3[CH:42]=[C:41]([O:40][Si:23]([C:36]([CH3:38])([CH3:39])[CH3:37])([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:53]=[CH:52][CH:51]=3)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)[Si](Oc1cccc(CC2CCOC2=O)c1)(c1ccccc1)c1ccccc1
Reactant: c1ccc(-c2ncoc2-c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)[Si](Oc1cccc(CC(CCO)C(O)c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
To a solution of 4,5-diphenyloxazole (5.3 g) in THF (50 ml) at −78° C. under N2 was added n-butyllithium (1.6 M in hexane, 9.2 ml). After 30 minutes, a solution of 3-(3-t-butyldiphenylsilyloxybenzyl)-2-oxotetrahydrofuran (3.3 g) in THF (30 ml) was added thereto and stirred for 1 hour at the same temperature. The reaction mixture was poured into the mixture of ethyl acetate and water. The organic layer was washed with 1N-HCl solution, sat. NaHCO3 and brine, dried over MgSO4, and evaporated in vacuo. The oily residue was dissolved in THF (100 ml) and LiAlH4 was added to the solution at 0° C. After being stirred for 2 hours, the mixture was poured into a mixture of ethyl acetate and 1N-HCl solution. The organic layer was washed with sat. NaHCO3 and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 3-[3-(4,5-diphenyloxazol-2-yl)-3-hydroxy-2-(2-hydroxyethyl)propyl]-1-(t-butyldiphenylsilyloxy)benzene (4.3 g).
Reaction SMILES: Br[C:2]1[C:7]([NH2:8])=[C:6]([Br:9])[CH:5]=[C:4]([CH2:10][CH3:11])[N:3]=1.[S-:12][CH2:13][CH3:14].[Na+].O>CN(C=O)C>[Br:9][C:6]1[CH:5]=[C:4]([CH2:10][CH3:11])[N:3]=[C:2]([S:12][CH2:13][CH3:14])[C:7]=1[NH2:8]
Reactant: CC[S-]
Reactant: CCc1cc(Br)c(N)c(Br)n1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1nc(CC)cc(Br)c1N
Temperature: 50 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
2,4-Dibromo-6-ethyl-pyridin-3-ylamine (105 mg, 0.38 mmoles) was combined with 80% sodium thioethoxide (50 mg, 0.48 mmoles) in anhydrous DMF (2 mL) and was stirred at 50° C. under nitrogen for 2 hours. After this period the reaction mix was combined with water (20 mL) and was extracted with EtOAc (3×20 mL). The combined EtOAc layer was washed with water (3×1 5 mL) and brine. After drying over anhydrous Na2SO4 the organic layer was evaporated in vacuo to yield crude product. The crude product was purified using flash silica chromatography (0-15% EtOAc/Hexane) to yield 4-bromo-6-ethyl-2-ethylsulfanyl-pyridin-3-ylamine (83 mg, 84%) as a clear residue. 1H-NMR (CDCl3): δ 6.94 (s, 1H), 4.34 (br s, 2H), 2.95 (q, J=7.3 Hz, 2H), 2.68 (q, J=7.6 Hz, 2H), 1.33 (t, J=7.3 Hz, 3H), 1.24 (t, J=7.6 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[CH2:18]([NH:21][CH2:22][CH2:23][CH3:24])[CH2:19][CH3:20]>>[CH2:18]([N:21]([CH2:22][CH2:23][CH3:24])[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16])[CH2:19][CH3:20]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Reactant: CCCNCCC
Product: CCCN(CCC)c1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
Each of two samples of the treated 1-chloro-2,6-dinitro-4-(trifluoromethyl)benzene was reacted with di-n-propylamine, yielding N,N-di-n-propyl-2,6-dinitro-4-(trifluoromethyl)aniline. Each product was analyzed for N-nitroso-N,N-di-n-propylamine by each of three different analytical laboratories (twice, in the GC-TEA method). The results were as follows.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][C@@H:15]2[CH2:17][C@@H:16]2[CH:18]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]([F:28])([F:27])[F:26])[CH2:20][CH2:19]2)[CH:9]=[C:8]([F:29])[C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+].Cl>CO.CCOC(C)=O>[F:29][C:8]1[CH:9]=[C:10]([O:12][CH2:13][CH2:14][C@@H:15]2[CH2:17][C@@H:16]2[CH:18]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]([F:28])([F:26])[F:27])[CH2:20][CH2:19]2)[CH:11]=[C:2]([F:1])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1c(F)cc(OCC[C@@H]2C[C@@H]2C2CCN(CC(F)(F)F)CC2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)c1c(F)cc(OCC[C@@H]2C[C@@H]2C2CCN(CC(F)(F)F)CC2)cc1F
Temperature: 60 °C

Procedure:
A solution of methyl 2,6-difluoro-4-(2-{(1S,2R)-2-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]cyclopropyl}ethoxy)benzoate (16.0 mg, 0.038 mmol) in MeOH (0.75 mL) was treated with NaOH aqueous solution (0.076 mL, 5 M, 0.38 mmol). It was heated at 60° C. for 4 hours. The mixture was cooled to RT, acidified with 2N HCl, diluted with EtOAc, washed with water, brine, dried with sodium sulfate. The solvent was removed under reduced pressure to yield Example 2. LCMS calc: 407.37; obs: 408.01 (M+1).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([OH:13])=O)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH:14]1([NH2:21])[CH2:19][CH2:18][CH2:17][CH:16]([NH2:20])[CH2:15]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:20][CH:16]1[CH2:17][CH2:18][CH2:19][CH:14]([NH:21][C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([Br:1])[N:3]=3)[NH:8][CH:9]=2)=[O:13])[CH2:15]1
Reactant: O=C(O)c1c[nH]c2ncc(Br)nc12
Reactant: NC1CCCC(N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[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: NC1CCCC(NC(=O)c2c[nH]c3ncc(Br)nc23)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.2 g, 0.83 mmol), cyclohexane-1,3-diamine (0.473 g, 4.15 mmol), HATU (0.475 g, 1.25 mmol), DIPEA (0.322 g, 2.5 mmol) in 15 mL of DMF were stirred at room temperature overnight. The solvent was removed under reduced pressure at 70° C. to give N-(3-aminocyclohexyl)-2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide as a crude which was used to the next step without further purification. MS: (M+H)+=338.1.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[N:16][C:8]=3[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:5]2=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O)C.C(=O)(O)[O-].[Na+].CC1(C)C(C)(C)OB([C:42]2[CH:47]=[CH:46][C:45]([C@@H:48]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH3:49])=[CH:44][CH:43]=2)O1>C1(C)C=CC=CC=1>[C:20]1([C:3]2[N:4]=[C:5]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[NH:9][C:8]4[N:16]=[CH:17][CH:18]=[CH:19][C:7]=4[N:6]3[C:2]=2[C:42]2[CH:43]=[CH:44][C:45]([C@@H:48]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH3:49])=[CH:46][CH:47]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Brc1c(-c2ccccc2)nc2n1-c1cccnc1Nc1ccccc1-2
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(-c2c(-c3ccccc3)nc3n2-c2cccnc2Nc2ccccc2-3)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 30.7 %

Procedure:
To a suspension of 3-bromo-2-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepine (0.60 g, 1 eq.) in a mixture of toluene (10 mL), ethanol (10 mL), and saturated sodium bicarbonate (3 mL) was added (S)-tert-butyl (1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)carbamate (1.31 g, 2.45 eq.). The reaction was degassed (nitrogen) for 5 minutes and tetrakis(triphenylphosphine)palladium(0) added (0.3 g). The reaction was again degassed for 5 minutes and stirred at 100° C. overnight. The reaction mixture was cooled to room temperature and poured onto water (50 mL). The aqueous phase was extracted with dichloromethane (2×50 mL) and the organic extracts were combined and washed with water (1×50 mL), brine (1×50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (25-75% ethyl acetate in hexanes) gave the product which was triturated with ether to give (S)-tert-butyl (1-(4-(2-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)phenyl)ethyl)carbamate (0.251 g, 31%). LCMS: 530 [M+H].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:15][CH2:16]O.O>C1(C)C=CC=CC=1.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>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([CH:15]=[CH2:16])=[N:3][CH:4]=1
Reactant: CCO
Reactant: Cc1ccc(Br)nc1
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: Cc1ccccc1
Solvent: O
Product: C=Cc1ccc(C)cn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 75.6 %

Procedure:
To a stirred mixture of 2-bromo-5-methyl-pyridine (1.7 g, 10 mmol), 2,4,6-trivinyl-cyclotriboroxanein (1.20 g, 5 mmol) and Na2CO3 (3.73 g, 35.2 mmol) in toluene (15 mL)/EtOH (10 mL)/H2O (5 mL) was added Pd(PPh3)4 (300 mg, 0.25 mmol) under N2. The mixture was stirred at 100° C. overnight. The resulting mixture was quenched with water (20 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na2SO4 and concentrated. The residue was purified by chromatography column (PE:EA=50:1) to afford 5-methyl-2-vinyl-pyridine (900 mg, 75.6%) as a yellow oil.
Reaction SMILES: C[CH2:2][N:3](C(C)C)[CH:4](C)C.[F:10][C:11]1[CH:12]=[C:13]([N:18]2[CH2:22][CH2:21][CH2:20][CH:19]2[C:23]2[CH:24]=[C:25]([C:40](O)=[O:41])[CH:26]=[C:27]3[C:32]=2[O:31][C:30]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[CH:29][C:28]3=[O:39])[CH:14]=[C:15]([F:17])[CH:16]=1.[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.CNC>CN(C=O)C>[F:17][C:15]1[CH:14]=[C:13]([N:18]2[CH2:22][CH2:21][CH2:20][CH:19]2[C:23]2[CH:24]=[C:25]([C:40]([N:3]([CH3:4])[CH3:2])=[O:41])[CH:26]=[C:27]3[C:32]=2[O:31][C:30]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[CH:29][C:28]3=[O:39])[CH:12]=[C:11]([F:10])[CH:16]=1
Reactant: O=C(O)c1cc(C2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: CNC
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc(C2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1
Reaction time: 8 h
Yield: 68.4 %

Procedure:
DIPEA (0.046 mL, 0.26 mmol) was added to a suspension of 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (60 mg, 0.13 mmol) in DMF (1 mL) followed by TSTU (43.5 mg, 0.14 mmol) at room temperature under nitrogen and stirred overnight. Dimethylamine (2N in THF) (0.131 mL, 0.26 mmol) was then added and the mixture was stirred for another hour. The reaction mixture was purified by preparative HPLC. The fractions were evaporated to dryness, the residue was taken up in a minimum of DCM, diluted with petroleum ether, stirred for 3 h, collected by filtration and dried to afford 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (43 mg, 68%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:16][CH:17]([OH:28])[CH2:18][NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[Br:15][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH2:16][C:17](=[O:28])[CH2:18][NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=3)[C:5]3[C:13]([C:12]=2[CH:11]=1)=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=3
Reactant: COc1cccc(NCC(O)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)c1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1cccc(NCC(=O)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)c1
Reaction time: 0.5 h

Procedure:
Trietheylamine (1.65 ml, 11.8 mmol) was added to a stirring solution of 1-(3,6-dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol (1.02 g, 2.02 mmol) in DMSO (21 ml). The solution was stirred for 30 minutes before addition of sulfur trioxide pyridine complex (0.659 g, 4.14 mmol). After stirring overnight, additional triethylamine (1.0 ml, 7.17 mmol) was added, followed by sulfur trioxide pyridine complex (0.663 mg, 4.17 mmol) an hour later. After stirring for 1 h, the orange solution was diluted with ˜150 ml ethyl acetate and washed several times with water and then brine.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1)(=O)=O.[P:16]([O-:21])([O:19][CH3:20])[O:17][CH3:18].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:13][C:9]1[CH:8]=[C:7]([P:16](=[O:21])([O:19][CH3:20])[O:17][CH3:18])[CH:12]=[CH:11][CH:10]=1
Reactant: COP([O-])OC
Reactant: O=S(=O)(Oc1cccc(Cl)c1)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COP(=O)(OC)c1cccc(Cl)c1
Temperature: 160 °C

Procedure:
This reaction was performed using a PersonalChemistry™ microwave instrument set at normal absorbance, fixed hold time and 30 sec pre-stirring. A 10-mL reaction vial was charged with 3-chlorophenyl trifluoromethanesulfonate (0.60 g, 2.30 mmol), dimethyl phosphite (0.42 mL, 4.58 mmol) and triethylamine (0.64 mL, 4.59 mmol) in toluene (4 mL). Nitrogen was bubbled through the stirred solution for 5 min, the tetrakis(triphenylphosphine)palladium(0) (0.1 g) was added, the solution was covered with a blanket of nitrogen and sealed. The reaction mixture was heated 11 min at 160° C., then cooled to room temperature and diluted with ethyl acetate. The yellow solution washed successively with water (3×) and brine. The organic solution was dried over sodium sulfate, filtered and the solvent was removed by rotary evaporation under reduced pressure. Pure dimethyl (3-chlorophenyl)phosphonate was obtained as a colorless oil (0.27 g, 57%) by chromatography over silica gel using ethyl acetate-hexane (gradient: 5% ethyl acetate to 100%). 1H NMR (300 MHz, CDCl3) δ 7.77 (br d, J=13.7 Hz, 1H), 7.68 (ddt, J=13.0, 7.5, 1.4 Hz, 1H), 7.53 (dquint., J=8.0, 1.1 Hz, 1H), 7.38-7.45 (m, 1H), 3.79 (s, 3H), 3.75 (s, 3H) ppm; MS [M+H]+ 221, [2M+H]+ 441
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[C:10]([CH:12]=O)[N:11]=1)=[O:5].[CH3:29][NH2:30].S([CH2:41][N+:42]#[C-:43])(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CCO.CC(O)=O>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[C:10]([C:12]2[N:30]([CH3:29])[CH:41]=[N:42][CH:43]=2)[N:11]=1)=[O:5]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CN
Reactant: O=Cc1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC(=O)O
Product: Cn1cncc1-c1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 54 %

Procedure:
Into a solution of Compound 67 (206 mg, 0.5 mmol) and MeNH2 (2.0 M in MeOH, 1.25 mL) in 10 mL of EtOH was added HOAc (0.15 mL). The solution was heated under reflux for 2 hours, cooled to room temperature. The solution was treated with tosylmethyl isocyanide (0.75 mmol) and K2CO3 (2 mmol). The mixture was stirred under reflux for 2 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and 1 N NaOH aq. solution. The organic phase was washed with water, dried (Na2SO4) and concentrated. The residue was purified by column chromatography on silica gel (eluted with MeOH in CH2Cl2) to give Compound 80 (125 mg, 54%) as a yellow solid.