Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:12][C@H:11]([CH2:13]OS(C)(=O)=O)[C@H:10]([CH2:19]OS(C)(=O)=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S-2:25].[Na+].[Na+]>CS(C)=O>[C:1]1([CH2:7][N:8]2[CH2:9][CH:10]3[CH2:19][S:25][CH2:13][CH:11]3[CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)OC[C@@H]1CN(Cc2ccccc2)C[C@@H]1COS(C)(=O)=O
Reactant: [S-2]
Agent: [Na+]
Solvent: CS(C)=O
Product: c1ccc(CN2CC3CSCC3C2)cc1
Temperature: 120 °C
Yield: 78.4 %

Procedure:
To a stirred solution of cis-1-(phenylmethyl)-3,4-di(methylsulfonyloxy)methylpyrrolidine (9.2 g, mmol), in dry DMSO (48 mL) was added anhydrous sodium sulfide (5.7 g, 73.3 mmol). The dark reaction mixture was heated at 120° C. for 18 h. The cooled reaction mixture was poured into ice H2O (150 mL). The resulting mixture was washed with ether (3×200 mL). The combined organics were dried (MgSO4), filtered and concentrated. The resulting residue was purified by flash chromatography using ethyl acetate as the eluent to afford 4.2 g (19.1 mmol, 78%) of the desired product as a thick yellow oil. HRMS (EI) calcd for C13H17NS 219.1082, found 219.1080. Anal. calcd for C13H17NS: C, 71.19; H, 7.81; N, 6.39. Found: C, 70.82; H, 7.83; N, 6.35.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([O:11][C:12]1[CH:13]=[C:14]([CH2:20][CH2:21][CH2:22][CH:23]2OCCC[O:24]2)[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1)(=[O:10])=[O:9].Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([O:11][C:12]1[CH:13]=[C:14]([CH2:20][CH2:21][CH2:22][CH:23]=[O:24])[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1)(=[O:9])=[O:10]
Reactant: COc1cc(CCCC2OCCCO2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(CCCC=O)cc(OS(=O)(=O)c2ccccc2Cl)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 16.7 %

Procedure:
A solution of 156 mg (0.38 mmol) 2-[3-[3-(2-chlorophenylsulfonyloxy)-5-methoxyphenyl]propyl]-1,3-dioxane, as prepared in the preceding step, in 2 mL of tetrahydrofuran was treated with 4.5 μL of 10% aqueous hydrochloric acid. The reaction mixture was stirred at 60° C. for 1 h. The reaction mixture was diluted with water, extracted into dichloromethane, dried (MgSO4), and purified by flash chromatography (dichloromethane) to give 23.4 mg of the title compound as the minor product of the reaction. 1H-NMR (300 MHz, CDCl3) δ 9.70 (t, 1 H, J=2 Hz), 7.93 (dd, 1 H, J=1.5,8Hz), 7.52-7.9 (m, 2 H), 6.57 (t, 1 H), 6.52 (t, 1 H, J=2 Hz), 6.49 (t, 1 H, J=2 Hz), 3.69 (s, 3 H), 2.52 (t, 2 H, J=7 Hz), 2.33 (dt, 2 H, J=1.5, 7 Hz), 1.80 (pentet, 2 H, J=7 Hz).
Reaction SMILES: [N:1]#[N:2].[C:3]1([CH2:9][C:10]([C@@:12]2([N:20]3[C:30]4[N:29]=[C:27]([NH2:28])[NH:26][C:24](=[O:25])[C:23]=4[N:22]=[CH:21]3)[O:19][C@H:16]([CH2:17][OH:18])[C@@H:14]([OH:15])[CH2:13]2)=[O:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:31][O:32][C:33]1[CH:54]=[CH:53][C:36]([C:37](Cl)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)=[CH:35][CH:34]=1>N1C=CC=CC=1>[N:1]#[N:2].[C:3]1([CH2:9][C:10]([C@@:12]2([N:20]3[C:30]4[N:29]=[C:27]([NH2:28])[NH:26][C:24](=[O:25])[C:23]=4[N:22]=[CH:21]3)[O:19][C@H:16]([CH2:17][O:18][C:37]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)([C:38]3[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=3)[C:36]3[CH:35]=[CH:34][C:33]([O:32][CH3:31])=[CH:54][CH:53]=3)[C@@H:14]([OH:15])[CH2:13]2)=[O:11])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: Nc1nc2c(ncn2[C@@]2(C(=O)Cc3ccccc3)C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Agent: N#N
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2O[C@@](C(=O)Cc3ccccc3)(n3cnc4c(=O)[nH]c(N)nc43)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 5 °C
Reaction time: 20 h
Yield: 55.9 %

Procedure:
N2 -(Phenylacetyl)-2'-deoxyguanosine (2a) (23.12 g, 60 mmoles) was dried by coevaporation with dry pyridine (2×100 ml), dissolved in 600 ml of dry pyridine and ice cooled. To this solution, 4,4'-dimethoxytrityl chloride (25.5 g, 72 mmoles) was added. The reaction mixture was stirred at 5° C. for 20 hours. After removing the pyridine under reduced pressure, the resulting residue was taken up in 600 ml of methylene chloride, washed successively with 2×400 ml of 5% NaHCO3 and 1×400 ml of water. The organic layer was dried over anhydrous sodium sulfate and concentrated to near dryness. The product was purified on a silica gel column (6×50 cm) by gradient elution with 1L 0-6% methylene chloride-methanol. The desired fractions were collected, concentrated to about 100 ml and added dropwise to 1.5L cooled hexane (0° C.) to precipitate the product. The precipitated product was filtered, washed with hexane and air dried to yield 24 g (58%) of tritylated product (3a), as confirmed by spectroscopic and elemental analysis.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH2:13][CH2:14][CH2:15][CH2:16]O)=[CH:8][CH:7]=1>>[Cl:3][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[C:9]1[CH:10]=[CH:11][C:6]([F:5])=[CH:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: OCCCCC(c1ccc(F)cc1)c1cccnc1
Product: Fc1ccc(C(CCCCCl)c2cccnc2)cc1
Reaction time: 2 h
Yield: 100 %

Procedure:
64 Parts of thionyl chloride were added portionwise to 4 parts of ε-(4-fluorophenyl)-3-pyridinepentanol. Upon complete addition, stirring was continued for 2 hours at reflux temperature. The reaction mixture was evaporated and the residue was taken up in water. The whole was treated with sodium carbonate. The product was extracted twice with methylbenzene. The combined extracts were washed with water, dried, filtered and evaporated, yielding 3.7 parts (100%) of 3-[5-chloro-1-(4-fluorophenyl)pentyl]pyridine as a residue (int. 57).
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9](=O)[CH3:10])[C:5](=[O:7])[CH3:6])[CH:2]=[CH2:3].C([O-])(=O)C.[Na+].Cl.[CH3:18][NH:19][OH:20]>O1CCOCC1.O>[C:5]([N:4]1[CH2:1][C:2]2([CH3:3])[CH:9]([CH2:10][O:20][N:19]2[CH3:18])[CH2:8]1)(=[O:7])[CH3:6]
Reactant: C=CCN(CC(C)=O)C(C)=O
Reactant: CNO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)N1CC2CON(C)C2(C)C1

Procedure:
15.5 g (0.1 mol) of N-allyl-N-(2-oxopropyl)-acetamide are dissolved in 100 ml of dioxane, and 9 g of anhydrous sodium acetate and 9 g (0. 108 mol) of N-methylhydroxylamine hydrochloride in 10 ml of water are added. The mixture is heated under reflux overnight and cooled and the salts are filtered off with suction and washed with dioxane. The filtrate is concentrated, the residue is taken up in 100 ml of water and K2CO3 is added. The mixture is extracted with CHCl3, the extract is dried over K2CO3 and concentrated and the residue is distilled.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[O:11][C:7]1([CH2:10][CH2:9][CH2:8]1)[CH2:6][CH:5]2[NH:15][C:16](=[O:27])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-])=O.[NH4+].[Cl-]>C(O)C.O.[Fe]>[NH2:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][C:16]([NH:15][CH:5]1[C:4]2[C:12](=[CH:13][CH:14]=[C:2]([Cl:1])[CH:3]=2)[O:11][C:7]2([CH2:10][CH2:9][CH2:8]2)[CH2:6]1)=[O:27]
Reactant: O=C(Cc1ccccc1[N+](=O)[O-])NC1CC2(CCC2)Oc2ccc(Cl)cc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccccc1CC(=O)NC1CC2(CCC2)Oc2ccc(Cl)cc21
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To a well stirred solution of step 1 intermediate (200 mg, 0.512 mmol) in ethanol (5 ml) was added NH4Cl (276 mg, 5.102 mmol) in water (3 ml) at room temperature. The reaction mixture was stirred for 15 min at the same temperature and then heated to 80° C. for 15 min. Iron (86 mg, 1.552 mmol) was added at that same temperature. The reaction mixture was refluxed further for 2 h. The residue obtained after the evaporation of the solvent was extracted with chloroform (2×50 ml). This chloroform layer was passed through celite. The layers were separated. Organic layers were washed with water (2×30 ml), brine (30 ml) and dried over Na2SO4. Solvent was evaporated to give 150 mg of the product.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[NH:15][N:16]=[C:17]([CH3:19])[N:18]=1)[N:7]=3.O1CCCCC1[O:28][CH2:29][CH2:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1>>[CH3:19][C:17]1[N:18]=[C:14]([C:8]2[N:7]=[C:6]3[C:5]4[CH:20]=[CH:21][C:2]([C:34]5[CH:33]=[N:32][N:31]([CH2:30][CH2:29][OH:28])[CH:35]=5)=[CH:3][C:4]=4[O:13][CH2:12][CH2:11][N:10]3[CH:9]=2)[NH:15][N:16]=1
Reactant: Cc1n[nH]c(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n1
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Product: Cc1n[nH]c(-c2cn3c(n2)-c2ccc(-c4cnn(CCO)c4)cc2OCC3)n1

Procedure:
8-Bromo-2-(5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene was reacted with 1-[2-(Tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole under microwave conditions to give 254. MS(ESI+) 378.2
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16](O)[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:23])=O>C1(C)C=CC=CC=1>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]([Cl:23])[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc2c(c1)CCCC2O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)c1ccc2c(c1)CCCC2Cl
Yield: 86.3 %

Procedure:
6-Benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-ol (0.65 g, 2.26 mmol) was dissoved in 50 mL toluene, and 1 mL of thionyl chloride was added. The reaction was refluxed for one hour, and then cooled. Solvent was removed under reduced pressure to yield 6-benzenesulfonyl-1-chloro-1,2,3,4-tetrahydro-naphthalene (0.6 g, 86.3%) as a crude oil. MS: 308 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][N:6]1[CH:10]=[N:9][C:8]([NH2:11])=[N:7]1)[CH3:2].[Cl:13][C:14]1[S:18][C:17]([C:19](O)=[O:20])=[CH:16][CH:15]=1>>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][N:6]1[CH:10]=[N:9][C:8]([NH:11][C:19]([C:17]2[S:18][C:14]([Cl:13])=[CH:15][CH:16]=2)=[O:20])=[N:7]1)[CH3:2]
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: CCOC(=O)Cn1cnc(N)n1
Product: CCOC(=O)Cn1cnc(NC(=O)c2ccc(Cl)s2)n1

Procedure:
61.2 Using general method A, (3-amino-[1,2,4]triazol-1-yl)-acetic acid ethyl ester was coupled with 5-chlorothiophene-2-carboxylic acid to give {3-[(5-chloro-thiophene-2-carbonyl)-amino]-[1,2,4]triazol-1-yl}-acetic acid ethyl ester. Off-white solid. MS 315.1 ([M+H]+)
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH:8][C:9]2[C:10](=[CH:14][C:15]([Br:18])=[CH:16][CH:17]=2)[C:11](O)=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].O=P(Cl)(Cl)[Cl:21].[NH4+].[OH-]>>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:10]([C:11]([Cl:21])=[C:6]2[CH:5]=[N:4]1)=[CH:14][C:15]([Br:18])=[CH:16][CH:17]=3)[CH3:2]
Reactant: CCn1nccc1Nc1ccc(Br)cc1C(=O)O
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: CCn1ncc2c(Cl)c3cc(Br)ccc3nc21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A mixture of N-(1-ethylpyrazol-5-yl)-5-bromoanthranilic acid (12.6 g) and POCl3 (30 ml) was refluxed overnight. The reaction mixture was poured into ice-water (500 ml), stirred for 20 minutes, and then NH4OH was added until a pH of 8-10 was obtained. The mixture was stirred for 0.5 hours and then the solid which formed was collected by filtration. The solid was dissolved in CH2Cl2, dried over MgSO4 and purified by column chromatography on silica gel eluting with 30% hexane/ethyl acetate to afford 6.5 g of 1-ethyl-4-chloro-6-bromo-1H-pyrazolo[3,4-b]quinoline, m.p. 117°-118° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[C:9]1(=O)[O:14][C:12](=[O:13])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12.C(OC(=O)C)(=O)C>C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:12](=[O:13])[C:11]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]3[C:9]2=[O:14])[CH:3]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1ccnc(N)c1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cc1ccnc(N2C(=O)c3ccccc3C2=O)c1
Reaction time: 12 h
Yield: 42.5 %

Procedure:
To a stirring solution of 4-methyl-2-aminopyridine (50 g, 460 mmol) in acetic acid (1 L) was added phthalic anhydride (68 g, 460 mmol) and the reaction was heated to reflux. After 12 h, acetic anhydride (43 mL, 460 mmol) was added and the solution continued to stir at reflux for an additional 48 h. The solvent was then removed in vacuo and the solid residue was suspended in toluene and concentrated in vacuo twice. The solid was then suspended in ethyl acetate with vigorous stirring and filtered. After repeating this ethyl acetate washing procedure the solid was dried overnight in vacuo to give 46.6 g (42%) of a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[C:17]1([CH2:23][CH2:24][CH2:25][OH:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[O:26][CH2:25][CH2:24][CH2:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCCCc1ccccc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: Nc1nc(OCCCc2ccccc2)c(Br)c(-c2ccco2)n1

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, 3-phenyl-1-propanol and DBU in dioxane. ES-MS m/e (%): 376 (M{81Br}+H+, 98), 374 (M{79Br}+H+, 100), 258 ([M{81Br}+H-BnCH═CH2]+, 55), 256 ([M{81Br}+H-BnCH ═CH2]+, 50).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][C:15]=2[O:24][CH3:25])=[C:4]([CH3:26])[N:3]=1.[CH2:27](O)[CH2:28][OH:29].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:27][CH2:28][OH:29])=[O:22])=[CH:16][C:15]=2[O:24][CH3:25])=[C:4]([CH3:26])[N:3]=1
Reactant: CCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1OC
Reactant: OCCO
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: CCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)OCCO)cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product from step (vi) (100 mg), ethane-1,2-diol (0.031 ml) and Hunig's Base (0.146 ml) were combined in DMF (5 mL) and HATU (106 mg) was added and stirred at rt for 1 h. The reaction mixture was purified by RPHPLC to give the title compound as a solid, 6 mg.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[N:24]([C:27]1[CH:35]=[CH:34][C:30]2[O:31][CH2:32][O:33][C:29]=2[CH:28]=1)=[C:25]=[O:26]>>[O:31]1[C:30]2[CH:34]=[CH:35][C:27]([N:24]3[C:4](=[O:5])[C:6]4[CH:7]=[N:8][C:9]5[C:10]([O:22][CH3:23])=[CH:11][CH:12]=[CH:13][C:14]=5[C:15]=4[N:16]([CH:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[C:25]3=[O:26])=[CH:28][C:29]=2[O:33][CH2:32]1
Reactant: O=C=Nc1ccc2c(c1)OCO2
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Product: COc1cccc2c1ncc1c(=O)n(-c3ccc4c(c3)OCO4)c(=O)n(C3CCCC3)c12
Yield: 76.5 %

Procedure:
3-Benzo[1,3]dioxol-5-yl-1-cyclopentyl-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (33 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1 mmol) and 5-isocyanato-benzo[1,3]dioxole (0.5 mmol) following general procedure C. LCMS: m/z 432 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.O=[C:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1.FC(F)(F)C(O)=O.[BH4-].[Na+].[OH-].[Na+]>>[Cl:8][C:3]1[C:2]([NH:1][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Nc1cccnc1Cl
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CCC(Nc2cccnc2Cl)CC1
Temperature: 26 °C
Reaction time: 0.08 h

Procedure:
To a 2 L three-neck Morton-type flask equipped with a mechanical agitator and temperature probe was charged 3-amino-2-chloropyridine and ethyl 4-oxo-1-piperidinecarboxylate followed by IPAC. The mixture became homogeneous after 5 min agitation (16° C.). Trifluoroacetic acid was charged to the mixture over 30 s, causing an increase in temperature to 26° C. (no cooling used). After 15 min age, a caplet of NaBH4 (0.95 g, 0.025 mol) was added. The temperature was observed to increase to 28° C. over a 30 min period and the caplet dissolved completely within this time. This method of NaBH4 addition was repeated, allowing each caplet to dissolve before adding the next, until a total of eight caplets had been added over 7 h. At this time, LC analysis indicated >95% conversion of the 3-amino-2-chloropyridine. A solution of 10 wt % aqueous NaOH was added to the mixture at 30-40° C. (no cooling) over 10 min. When the pH of the mixture was 12-14, the phases were allowed to separate. The separated aqueous phase was 450 mL and LC assay indicated this contained 0.5 g, <1.0% of product. The organic phase washed with brine then the separated organic phase was assayed. The separated brine wash was 275 mL and LC assay indicated this contained negligible product. The organic phase was 690 mL and LC assay indicated this contained 87.5 g, 97% AY of reductively alkylated product and 2.1 g, 5% of starting amine. The yellow organic phase was concentrated (45° C. bath temperature) to approximately one-third original volume. Fresh IPAC was added and this process was repeated until the water content was 110 μg/mL by KF titration. The solution was concentrated to a volume of 170 mL then THF (230 mL) was added. This solution was used directly for the subsequent step.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH2:10]1[O:13][C@H:11]1[CH3:12]>C(O)C>[OH:13][CH:11]([CH3:12])[CH2:10][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: C[C@H]1CO1
Reactant: c1ccc2c(c1)CCN2
Solvent: CCO
Product: CC(O)CN1CCc2ccccc21
Temperature: 25 °C
Yield: 62.9 %

Procedure:
A mixture of 2,3-dihydro-1H-indole (5.74 g, 48.2 mmol), and (S)-propylene oxide (2.8 g, 48.2 mmol) in ethanol (200 mL) is heated at reflux for 18 hours. The resulting mixture is cooled to room temperature, and evaporated to give a crude oil. The material is purified by flash chromatography (25% ethyl acetate/hexanes) to give 5.37 g (63%) of 2,3-dihydro-1-(2-hydroxypropyl)indole.
Reaction SMILES: [N:1]1(C2CCCCCCC2)[CH2:8]CCCCCN1.Cl[C:18]1[N:23]=[C:22]([CH:24]2[CH2:26][CH2:25]2)[CH:21]=[CH:20][N:19]=1.[C-]#N.[Na+]>CS(C)=O.O>[CH:24]1([C:22]2[CH:21]=[CH:20][N:19]=[C:18]([C:8]#[N:1])[N:23]=2)[CH2:26][CH2:25]1
Reactant: Clc1nccc(C2CC2)n1
Reactant: C1CCCC(N2CCCCCCN2)CCC1
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1nccc(C2CC2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 803.7 %

Procedure:
To a solution of diazabicyclooctane (0.013 g, 0.12 mmol) in dimethylsulfoxide and water was added a solution of 2-chloro-4-cyclopropylpyrimidine (0.2 g, 1.2 mmol) in dimethylsulfoxide followed by sodium cyanide (0.066 g, 1.3 mmol). The reaction mixture was stirred at room temperature for 48 h. The mixture was then poured into water and extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure. The crude compound was purified via flash chromatography (10% ethyl acetate in petroleum ether) to afford 4-cyclopropylpyrimidine-2-carbonitrile (0.14 g, 77%). MS (ES+APCI) (M+H) 146.1; LCMS retention time 3.054 min (Method J).
Reaction SMILES: F[B-](F)(F)F.C(N(C(C)C)[CH:10]=[N+:11]([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])(C)C.CC(C)([O-])C.[K+].[C:27]([O:31][C:32]([N:34]1[C:38](=[O:39])[CH2:37][CH2:36][C@H:35]1[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[CH:43][CH:42]=1)=[O:33])([CH3:30])([CH3:29])[CH3:28].C(OC(C)C)(=O)C>C1COCC1>[C:27]([O:31][C:32]([N:34]1[C@H:35]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)=[CH:45][CH:46]=2)[CH2:36]/[C:37](=[CH:10]\[N:11]([CH:12]([CH3:13])[CH3:14])[CH:15]([CH3:16])[CH3:17])/[C:38]1=[O:39])=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1Cc1ccc(-c2ccccc2)cc1
Reactant: CC(C)N(C=[N+](C(C)C)C(C)C)C(C)C
Agent: CC(C)(C)[O-]
Agent: F[B-](F)(F)F
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)C
Product: CC(C)N(/C=C1\C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O)C(C)C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
N,N,N′,N′-tetraisopropylformamidinium tetrafluoroborate (2.13 g, prepared according to Example 11) is added to a 1 M solution of potassium-tert-butoxide in THF (5.69 ml). The resulting mixture is then stirred for 1 h at 50° C. (S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (8-a, R1=Boc) (500 mg) is then added and the mixture stirred at 60° C. for 1 h. The mixture is then cooled to room temperature and diluted by addition of 10 ml isopropyl acetate. The mixture is then filtered through silica and concentrated in vacuo to afford (R)-5-biphenyl-4-ylmethyl-3-[1-diisopropylamino-meth-(E)-ylidene]-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (7-a, R1=Boc, R6=iPr, R7=iPr). Spectroscopic data as for Example 19, Method 1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([NH:17][CH3:18])=[O:16])=[CH:13][CH:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[CH3:31][O:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[C:37]([O:41][CH3:42])[C:38]=1[O:39][CH3:40].C([O-])([O-])=O.[Na+].[Na+].O>CC#N.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>[CH3:18][NH:17][C:15](=[O:16])[C:14]1[CH:19]=[CH:20][C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:35]4[CH:36]=[C:37]([O:41][CH3:42])[C:38]([O:39][CH3:40])=[C:33]([O:32][CH3:31])[CH:34]=4)[CH:3]=3)[NH:8][CH:9]=2)=[CH:12][CH:13]=1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: CNC(=O)c1ccc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(Br)cc23)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CNC(=O)c1ccc(-c2c[nH]c3ncc(-c4cc(OC)c(OC)c(OC)c4)cc23)cc1
Yield: 46.5 %

Procedure:
4-[5-Bromo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-N-methyl-benzamide (Intermediate CE, 100 mg, 0.206 mmol), 3,4,5-trimethoxyphenylboronic acid (53 mg, 0.248 mmol) and dichlorobis(triphenylphosphine)palladium (II) (9 mg, 0.012 mmol) were combined in CH3CN (2 ml) and 1 M Na2CO3 (2 ml) and reacted in a microwave reactor for 20 min at 150° C. Water was added, the aqueous phase was extracted with DCM and the organic phase was dried and evaporated. Purification by silica gel chromatography using 0-8% MeOH:DCM yielded 40 mg (47%) of the title compound. 1H NMR (CDCl3, 300 MHz): δ 12.09 (s, 1H), 8.59 (d, J=1.2 Hz, 1H), 8.48 (d, J=1.2 Hz, 1H), 8.43 (q, J=2.7 Hz, 1H), 8.04 (s, 1H), 7.94 (d, J=4.0, 2H), 7.91 (d, J=4.0 Hz, 2H), 7.00 (s, 2H), 3.89 (s, 6H), 3.70 (s, 3H), 2.80, (d, J=4.5 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]=[CH:10][C:11]1[N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:19](=[O:27])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:35][CH2:36][N:37]([CH2:40][CH3:41])[CH2:38][CH3:39].O>CN(C=O)C>[CH2:36]([N:37]([CH2:40][CH3:41])[CH2:38][CH2:39][O:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]=[CH:10][C:11]1[N:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:19](=[O:27])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)[CH3:35]
Reactant: CCN(CC)CCCl
Reactant: O=c1c2ccccc2nc(C=Cc2cccc(O)c2O)n1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1c(O)cccc1C=Cc1nc2ccccc2c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 1.3 %

Procedure:
To a solution of 75 (0.85 g, 0.023 mol) and K2CO3 (0.45 g, 0.003 mol) in DMF (5 mL) was added (2-chloro-ethyl)-diethyl-amine (0.37 g, 0.025 mol). The reaction mixture was stirred at RT for 10 hours, poured into water. The precipitate formed was filtered off, washed with water and purified by column chromatography on silica gel using EtOAc/hexane 1:4 as eluent to yield 76 (0.14 g, 15%). M. Wt. 455. LCMS [M+H]+=456.