Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li:1].C1C2C(=CC=CC=2)C=CC=1.Cl[P:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:21][C:22]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[C:23]=1[C:24](Cl)=[O:25]>O1CCCC1>[CH3:21][C:22]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[C:23]=1[C:24]([PH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:25].[Li:1]
Reactant: ClP(Cl)c1ccccc1
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Agent: [Li]
Solvent: C1CCOC1
Solvent: c1ccc2ccccc2c1
Product: Cc1cc(C)c(C(=O)Pc2ccccc2)c(C)c1
Temperature: 22.5 °C

Procedure:
Under argon and with the exclusion of moisture, 14.0 g of lithium (2.0 mol) are introduced into 250 ml of tetrahydrofuran at room temperature. Following the addition of 1.25 g of naphthalene, 44.8 g (0.25 mol) of dichlorophenylphosphine are added dropwise with stirring at 20-25° C. and, after stirring for 4 h, the black solution is filtered into a three-necked round flask through a frit (G2 porosity) with the exclusion of moisture and under argon as a protective gas. 47.2 g (0.258 mol) of 2,4,6-trimethylbenzoyl chloride are added dropwise at room temperature over the course of 30 minutes with stirring and cooling. Stirring for 2 hours gives the title compound as a red solution in tetrahydrofuran.
Reaction SMILES: [CH3:1][C:2]([C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[C:20]3[C:21]4([CH2:24][O:25][C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:23][CH2:22]4)=[CH:12][CH:13]=1)=[O:6])([CH3:4])[NH2:3].Cl[C:27](Cl)([O:29]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH3:4][C:2]1([CH3:1])[NH:3][C:27](=[O:29])[N:7]([C:8]2[CH:9]=[N:10][C:11]([O:14][C:15]3[C:20]4[C:21]5([CH2:24][O:25][C:19]=4[CH:18]=[CH:17][CH:16]=3)[CH2:23][CH2:22]5)=[CH:12][CH:13]=2)[C:5]1=[O:6]
Reactant: CC(C)(N)C(=O)Nc1ccc(Oc2cccc3c2C2(CC2)CO3)nc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC1(C)NC(=O)N(c2ccc(Oc3cccc4c3C3(CC3)CO4)nc2)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 139.9 %

Procedure:
To a solution of 2-methyl-N1-[6-(spiro[1-benzofuran-3,1′-cyclopropan]-4-yloxy)-3-pyridinyl]alaninamide (Reference Intermediate 219, 34 mg) in dry dichloromethane (6 mL) TEA (0.070 mL, 0.501 mmol) was added and the mixture was cooled to 0° C. A solution of triphosgene (13.38 mg, 0.045 mmol) in dry dichloromethane (2 mL) was slowly added and the reaction mixture was stirred for 1 hour at the same temperature. The reaction was quenched with water (3 ml) and two phases were separated. The organic layer was dried over sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column SNAP and cyclohexane/ethyl acetate 7:3 to cyclohexane/ethyl acetate 3:7 as eluents affording the title as a white solid (23 mg).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:13][N:12]2[C@H:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][C@H:15]3[C:10]3[C:11]2=[C:6]([CH:7]=[CH:8][CH:9]=3)[NH:5]1.I[CH3:26]>CCCCCC.CN(C)C=O>[CH3:26][N:5]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C@@H:15]4[CH2:16][N:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][CH2:19][C@@H:14]4[N:12]([C:11]=23)[CH2:13][C:4]1=[O:3]
Reactant: CCOC(=O)N1CC[C@H]2[C@@H](C1)c1cccc3c1N2CC(=O)N3
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCOC(=O)N1CC[C@H]2[C@@H](C1)c1cccc3c1N2CC(=O)N3C
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
Sodium hydride (900 mg of 60% dispersion in oil; 22.5 mmol) was washed with hexane, and suspended in anhydrous dimethylformamide (5 mL). The suspension was added to a stirred solution of ethyl (6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (6.02 g, 20 mmol) in anhydrous dimethylformamide (50 mL) under nitrogen. After gas evolution had subsided, the mixture was cooled in ice-water bath and treated with iodomethane (3.55 g., 25 mmol). The mixture was stirred at room temperature for 1 h and then concentrated. The residue was treated with water and extracted with dichloromethane (2×) and the extract was washed with brine, dried over magnesium sulfate and evaporated to dryness to yield 5.48 g (87%) of ethyl (6bR,10aS)-3-methyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate as a tan solid, m.p. 149–151° C. (dec.). [M+H] calc. 316; found 316. 1H NMR (CDCl3, 300 MHz) δ 1.28 (t, J=7.3 Hz, 3H), 1.85 to 1.93 (m,1H), 2.65 to 2.82 (m, 1H),3.08 to 3.25 (m, 1H), 3.25 to 3.40 (m, 1H), 3.30–3.50 (m, 1H), 3.34 (s, 3H), 3.42 (d, J=14.3 Hz, 1H), 3.85 to 4.0 (m,1H), 4.02 (d, J=14.3 Hz, 1H, 4.15 (q, J=7.2 Hz, 4H), 6.76 (d, J=8.1 Hz, 1H), 6.83 (t, J=7.3 Hz, 1H), 6.90 (d, J=7.3 Hz, 1H). MS (CI): 316 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:13]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1CCCc2cc(OCc3ccccc3)ccc21
Yield: 80 %

Procedure:
6-Hydroxy-1-tetralone (10 g, 61.65 mmol), benzyl bromide (8.1 ml, 67.82 mmol) and K2CO3 (21.3 g, 154 mmol) in acetone (40 ml) were heated under reflux 2.5 hr. Following filtration and evaporation of the solvent the crude material was acidified to pHl with 1N HCl and partioned between H2O (150 ml) and EtOAc (150 ml). The aqueous phase was further extracted with EtOAc (100 ml) and the extracts dried (Na2SO4) filtered and evaporated to afford 6-benzyloxy-1-tetralone as an orange solid (12.37 g, 49.3 mmol, 80%) Mp. 97-100° C., MS m/e=252.1 (M+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[Cl-].[S:19]1[C:23]([C@:24]23[CH2:32][NH2+:31][CH2:30][C@H:29]2[CH2:28][S:27][C:26]([NH:33][C:34](=[O:41])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[N:25]3)=[CH:22][CH:21]=[N:20]1.O>CN1CCCC1=O>[F:1][C:2]1[CH:3]=[N:4][C:5]([N:31]2[CH2:30][C@@H:29]3[C@@:24]([C:23]4[S:19][N:20]=[CH:21][CH:22]=4)([N:25]=[C:26]([NH:33][C:34](=[O:41])[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[S:27][CH2:28]3)[CH2:32]2)=[N:6][CH:7]=1
Reactant: Fc1cnc(Cl)nc1
Reactant: O=C(NC1=N[C@@]2(c3ccns3)C[NH2+]C[C@H]2CS1)c1ccccc1
Agent: [Cl-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=C(NC1=N[C@@]2(c3ccns3)CN(c3ncc(F)cn3)C[C@H]2CS1)c1ccccc1
Temperature: 100 °C
Yield: 0.1 %

Procedure:
5-Fluoro-2-chloropyrimidine (58 mL, 608.3 mol), and diisopropylethylamine (227 mL 1.30 mol, 227.3 mL) is added to N-[(4aR,7aR)-7a-isothiazol-5-yl-4a,5,6,7-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazin-6-ium-2-yl]benzamide chloride (174.2 g, 434.5 mol), in N-methylpyrrolidone (1.4 L) at 22° C. and stirred. The reaction is heated at 100° C. for 4 hours and then cooled to room temperature. The crude mixture is added to water (14 L) and then stirred 1 hour. A white solid is collected by filtration and dried under vacuum to constant weight. The crude product is purified by silica gel chromatography, eluting with ethyl acetate: methylene chloride (3/1) to give the title compound (139 g, 72%). ES/MS (m/e): 441.0 (M+H).
Reaction SMILES: C(C1C(SC2C=CC([N+]([O-])=O)=CC=2)=NC=C(C[Br:10])C=1)#N.[CH2:21]([P:25]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH3:24].CCOCC>O1CCCC1>[Br-:10].[CH2:30]([PH+:25]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:26][CH2:27][CH2:28][CH3:29])[CH2:31][CH2:32][CH3:33]
Reactant: CCCCP(CCCC)CCCC
Reactant: N#Cc1cc(CBr)cnc1Sc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCC[PH+](CCCC)CCCC
Product: [Br-]

Procedure:
Alternatively, 3-cyano-2-(4-nitrophenylthio)-5-bromomethylpyridine is allowed to react in tetrahydrofuran with tri-(n-butyl)phosphine for ten hours. Following the addition of ether, the solid which forms is collected by filtration and washed with 1:1 tetrahydrofuran:ether to yield 8 3-cyano-2-(4-nitrophenylthio)pyridin-5-ylmethyl]-tri-(n-butyl)phosphonium bromide as a white solid; mp 175°-176° C.; NMR (CDCl3, 80 MHz) d 0.85-2.63(m, 27H), 4.76(d, 2H, J=15.4 Hz), 7.74(d, 2H, J=9.0 Hz), 8.26(d, 2H, J=9.0 Hz), 8.55 (brs, 1H), 8.79 (brs, 1H); IR (KBr) 2950, 2860, 2220, 1595, 1575, 1515, 1390, 1340, 1075 and 845 cm-1 ; HRMS 471.2116(M+ -HBr), Calc'd. for C25H34N3O2PS471.2109.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C:26]([NH:28][C:29]#[N:30])=[O:27])=[CH:21][CH:20]=3)[C:11]3S[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.O[O:32][S:33]([O-:35])=O.[K+].C1COCC1>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([CH2:25][C:26]([NH:28][C:29]#[N:30])=[O:27])=[CH:23][CH:24]=3)[C:11]3[S:33](=[O:35])(=[O:32])[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=S([O-])OO
Reactant: N#CNC(=O)Cc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2SCCC3)cc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: N#CNC(=O)Cc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2S(=O)(=O)CCC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 18-mL vial was charged with 2-[4-[[2-(3-Chlorophenyl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl]amino]phenyl]-N-cyano-acetamide (19 mg, 0.044 mmol, 1 eq.), oxone (55 mg, 0.18 mmol, 4 eq.), THF (3 ml) and water (3 ml). The clear solution was stirred at room temperature overnight. The volatile material was removed under reduced pressure and the residue was treated with sodium bicarbonate solution. Solid was collected by filtration and washed with water. After drying, the title compound was obtained as a white solid (11 mg, 53% yield). MW=467.93. 1H NMR (400 MHz, methanol-d4) δ 8.34 (s, 1H), 8.25 (d, J=7.6 Hz, 1H), 7.60 (d, J=8.0 Hz, 2H), 7.49 (m, 2H), 7.39 (d, J=8.0 Hz, 2H), 3.61 (t, J=4.8 Hz, 2H), 3.56 (s, 2H), 3.13 (t, J=6.4 Hz, 2H), 2.54 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH3:47])=[CH:41][CH:40]=3)[CH:32]=2)[NH:11][CH:10]1[CH2:48][O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:57](=O)([O-])[O-].[K+].[K+].IC>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38][C:39]3[CH:40]=[CH:41][C:42]([O:45][CH2:46][CH3:47])=[CH:43][CH:44]=3)[CH:32]=2)[N:11]([CH3:57])[CH:10]1[CH2:48][O:49][CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1ccc(Cc2cc(C3NC(COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CI
Product: CCOc1ccc(Cc2cc(C3[C@H](OCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)C(COCc4ccccc4)N3C)ccc2Cl)cc1
Reaction time: 8 h
Yield: 57 %

Procedure:
Compound from step D (50 mg, 0.065 mmol) was dissolved in acetonitrile (1 mL) and treated with potassium carbonate (18 mg, 0.13 mmol) for 30 minutes To this mixture iodomethane (20 uL, 0.32 mmol) was added and stirred overnight. The reaction mixture was diluted with ethyl acetate (10 mL), washed with water, brine, dried (sodium sulfate), and concentrated under vacuum. Chromatography on silica gel (50 to 100% acetonitrile containing 0.1% ammonium acetate/water gradient) provided (3R,4R,5S)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-methylpiperidine (29 mg, 56%). MH+782.1.
Reaction SMILES: [C:1]1([CH2:7]N2C3C=CC=CC=3N=N2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1([CH:27]=NC2C=CC=CC=2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>CO>[C:1]1([C:7]#[C:27][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(Cn2nnc3ccccc32)cc1
Reactant: C(=Nc1ccccc1)c1cccc2ccccc12
Solvent: CO
Product: C(#Cc1cccc2ccccc12)c1ccccc1
Yield: 88 %

Procedure:
In a procedure similar to that of Example 16 using [phenylmethyl]-1H-benzotriazole (10 mmol) and N-([1-naphthalenyl]methylene)benzenamine (10 mmol): 88% yield: mp 51°-53° C. (MeOH) (lit1 oil); 1H NMR (300 MHz, CDCl3) δ7.39-7.69 (m, 8H), 7.77-7.90 (m, 3H), 8.46 (br d, 2.7H, 1H); IR (CDCl3) 3060 (s), 2245 (eyne), 1596, 1581, 1508, 1491 (s), 1442, 1398, 1333, 1215, 1070, 1017 cm1. MS (EI) m/e 228 (M+, 100).
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[I:7].[OH-].[K+].Br[CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1>C1COCC1>[I:1][C:2]1[N:3]=[CH:4][N:5]([CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[C:6]=1[I:7]
Reactant: BrCc1ccc2ccccc2c1
Reactant: Ic1nc[nH]c1I
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Ic1ncn(Cc2ccc3ccccc3c2)c1I

Procedure:
4,5-diiodoimidazole (5.0 mmol) and KOH (5.0 mmol) were placed in a round bottom flask with 50 mL THF. The mixture was brought to reflux and stirred 0.5 h until KOH was consumed. 2-bromomethylnapthalene (5.0 mmol) was added and the solution was stirred at reflux for 17 hours. KBr was removed by vacuum filtration and the filtrate was collected. The volatiles were removed by rotary evaporation to give 4,5-diiodo-1-(naphthalen-2-ylmethyl)-1H-imidazole as a off white solid. 4,5-diiodo-1-(naphthalen-2-ylmethyl)-1H-imidazole was dissolved in acetonitrile in a round bottom flask. The solution was brought to reflux and excess iodomethane was added. The reaction was stirred at reflux for overnight after which time it was cooled. The resulting yellow precipitate was collected by filtration and analyzed. 1H NMR (300 MHz, d6-DMSO): δ 3.88 (s), 5.64 (s), 7.47-7.60 (m), 7.89-8.02 (m), 9.57 (s) ppm.
Reaction SMILES: Cl[CH:2]([Cl:9])[C:3]([CH3:8])([CH3:7])[C:4](Cl)=[O:5].C[O:11][P:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C[Cl:26]>C1(C)C=CC=CC=1>[C:13]1([P:12](=[O:11])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:4](=[O:5])[C:3]([CH2:2][Cl:9])([CH2:8][Cl:26])[CH3:7])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCl
Reactant: COP(c1ccccc1)c1ccccc1
Reactant: CC(C)(C(=O)Cl)C(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(CCl)(CCl)C(=O)P(=O)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
3.8 g (0.02 mol) of dichloropivaloyl chloride are introduced into 20 ml of toluene and heated to 80° C. 4.3 g (0.02 mol) of methoxydiphenylphosphine are added dropwise in the course of about 5 minutes to this solution, methyl chloride escaping. After stirring for 1 hour at 80° C., the slightly yellow solution is cooled to room temperature and evaporated in a rotary evaporator. After purification by means of chromatography (solvent: hexane/ethyl acetate 3:1), this gives 1.6 g, i.e. 22.8% of theory, of the abovementioned compound as a yellow resin.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#N)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.[OH-:23].[K+].[OH2:25]>C(O)CO.CO>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:25])=[O:23])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1
Reactant: [OH-]
Reactant: O
Reactant: N#Cc1ccc(-c2ccc(OCCCCCCO)cc2)cc1
Agent: [K+]
Solvent: CO
Solvent: OCCO
Product: O=C(O)c1ccc(-c2ccc(OCCCCCCO)cc2)cc1
Yield: 93.4 %

Procedure:
To a solution of 8 (13.0 g, 4.4 mmol) in ethylene glycol (370 ml) was added KOH (37.07 g, 66.06 mmol). After refluxing for 2 h, the reaction mixture was poured into 1.6 L water for acidification to a pH less than 4. The precipitate from acidification was boiled in methanol to remove water and ethylene glycol. The solid residue collected by filtration was further purified by boiling in methylene chloride. The solid product was further washed with hot methylene chloride to yield 9 (12.94 g, 93.4%). 1H NMR spectral data (400 MHz, DMSO-d6): δ 1.30-1.50 (m, 6H, —CH2—), 1.74 (m, 2H, —CH2—), δ 3.40 (t, 2H, —CH2OAr), δ 4.01 (t, 2H, HOCH2—), δ 7.05 (d, 2H, aromatic rings), δ 7.67 (d, 2 H, aromatic rings), δ 7.74 (d, 2H, aromatic rings), δ 7.98 (d, 2H, aromatic rings).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:13][C:14]([N:16]2[CH2:21][C@H:20]([CH3:22])[N:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:18][C@H:17]2[CH3:31])=[O:15])=[C:6]([CH:11]=1)[O:7][CH2:8][C:9]#[N:10].[Cl-].[NH4+].[N-:34]=[N+:35]=[N-:36].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:13][C:14]([N:16]2[CH2:21][C@H:20]([CH3:22])[N:19]([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)[CH2:18][C@H:17]2[CH3:31])=[O:15])=[C:6]([O:7][CH2:8][C:9]2[N:34]=[N:35][NH:36][N:10]=2)[CH:11]=1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1OCC#N
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1OCc1nn[nH]n1
Temperature: 100 °C
Reaction time: 12 h
Yield: 14.7 %

Procedure:
To a solution of (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenoxy)-acetonitrile (0.11 g, 0.25 mmol) in dimethylformamide (0.50 mL) was added ammonium chloride (0.058 g, 1.1 mmol) and sodium azide (0.055 g, 0.85 mmol). The resulting mixture was stirred at 100° C. for 12 hours. The reaction was cooled and diluted with ethyl acetate and washed with water. The organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. Trituration with diethyl ether and methylene chloride gave the title compound (0.018 g, LRMS 489.4, 491.5).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[C:9]([CH:11]=O)[NH:8][C:7]=12.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[BH4-].[Na+]>CO>[ClH:1].[CH2:13]([NH:20][CH2:11][C:9]1[NH:8][C:7]2=[C:2]([Cl:1])[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCc1ccccc1
Reactant: O=Cc1cc2ccnc(Cl)c2[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cl
Product: Clc1nccc2cc(CNCc3ccccc3)[nH]c12
Reaction time: 2 h
Yield: 122.8 %

Procedure:
7-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxaldehyde (Example 138) (102 mg, 0.565 mmol) was dissolved in methanol (2.5 mL). Benzylamine (70 μL, 0.62 mmol) was added. After 2 h, sodium borohydride (35 mg, 0.90 mmol) was added. After an additional 2 h, the reaction mixture was quenched by addition of 59% aqueous sodium bicarbonate. The reaction mixture was extracted with diethyl ether, dried (magnesium sulfate), and evaporated to dryness (124 mg, 81% crude). The crude material was dissolved in acetonitrile and treated with hydrochloric acid (0.46 mL, 1 M in diethyl ether) to give N-benzyl-N-[(7-chloro-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl]amine hydrochloride (107 mg, 0.347 mmol, 61%) as an off-white powder: mp 201-204° C.; 1H NMR (300 MHz, CD3OD) δ4.35 (2H, s), 4.52 (2H, s), 6.87 (1H, s), 7.45-7.60 (5H, m), 7.60 (1H, d, J=5.6 Hz), 7.94 (1H, d, J=5.6 Hz); ESI MS m/z 272 [C15H14ClN3+H]+; HPLC (H2O/CH3CN 90:10 to 0:100 over 20 min, hold for 15 min, 0.05% TFA added to solvents) >99%, tR=11.1 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:4]([C:16](=O)[C:17]([CH3:20])([CH3:19])[CH3:18])[CH:3]=1.Cl.[F:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][NH2:31])=[CH:26][CH:25]=1.CC([O-])=O.[Na+]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:4]([C:16](=[N:31][O:30][C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)[C:17]([CH3:20])([CH3:19])[CH3:18])[CH:3]=1
Reactant: NOc1ccc(F)cc1
Reactant: CC(C)(C)C(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)C(=NOc1ccc(F)cc1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Yield: 10.8 %

Procedure:
A solution of N-[4-chloro-2-(2,2-dimethylpropionyl)phenyl]trifluoromethanesulfonamide 29C (280 mg, 0.82 mmol), O-(4-fluorophenyl)hydroxylamine hydrochloride (200 mg, 1.22 mmol) and anhydrous NaOAc (100 mg, 1.22 mmol) in EtOH (20 mL) was stirred for 48 hours at RT. The reaction mixture was concentrated under vacuum and the residue purified by column chromatography (eluting with CH2Cl2/PE, 1:4 to 2:3) to afford N-{4-chloro-2-[1-(4-fluorophenoxyimino)2,2-dimethylpropyl]phenyl}trifluoromethanesulfonamide 198 (40 mg, 11%), as an orange oil. 1H n.m.r. (200 MHz, CDCl3) δ 7.52, d, J=8.8 Hz, 1H; 7.42, dd, J=2.2 and 8.8 Hz, 1H; 7.19, d, J=2.2 Hz, 1H; 7.00, m, 4H; 6.49, br s, 1H; 1.32, s, 9H. HRMS (M+) 452.0576.
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1)=O)C.[NH2:15][C:16]1[CH2:17][C:18]([C:28]([N:30]([CH2:34][C:35]([NH2:37])=[O:36])[CH2:31][CH2:32][CH3:33])=[O:29])=[CH:19][C:20]2[CH:26]=[CH:25][C:24](Br)=[CH:23][C:21]=2[N:22]=1.BrC1C=CC2=C(C=1)N=C(N[C:67](=[O:73])[O:68][C:69]([CH3:72])([CH3:71])[CH3:70])CC(C(=O)N(CCCO[Si](C(C)(C)C)(C)C)CCC)=C2>>[NH2:15][C:16]1[CH2:17][C:18]([C:28](=[O:29])[N:30]([CH2:34][C:35]([NH2:37])=[O:36])[CH2:31][CH2:32][CH3:33])=[CH:19][C:20]2[CH:26]=[CH:25][C:24]([C:9]3[CH:8]=[CH:7][C:6]([CH2:4][C:67]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:73])=[CH:11][CH:10]=3)=[CH:23][C:21]=2[N:22]=1
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Reactant: CCCN(CC(N)=O)C(=O)C1=Cc2ccc(Br)cc2N=C(N)C1
Reactant: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(Br)cc2N=C(NC(=O)OC(C)(C)C)C1
Product: CCCN(CC(N)=O)C(=O)C1=Cc2ccc(-c3ccc(CC(=O)OC(C)(C)C)cc3)cc2N=C(N)C1
Yield: 32 %

Procedure:
tert-Butyl 2-(4-((1E,4E)-2-amino-4-((2-amino-2-oxoethyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)phenyl)acetate (32%) was prepared as described below in Steps 1 and 2, except for substituting isobutyl tert-butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate for 4-(ethoxycarbonyl)phenylboronic acid and (1E,4E)-2-amino-N-(2-amino-2-oxoethyl)-8-bromo-N-propyl-3H-benzo[b]azepine-4-carboxamide for tert-butyl (1E,4E)-8-bromo-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-2-ylcarbamate.
Reaction SMILES: [ClH:1].[CH2:2]([N:9]1[C:14](=[O:15])[C:13]2[CH2:16][NH:17][CH2:18][CH2:19][C:12]=2[NH:11][C:10]1=[O:20])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:21]=O.Cl>C(O)=O>[ClH:1].[CH2:2]([N:9]1[C:14](=[O:15])[C:13]2[CH2:16][N:17]([CH3:21])[CH2:18][CH2:19][C:12]=2[NH:11][C:10]1=[O:20])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=c1[nH]c2c(c(=O)n1Cc1ccccc1)CNCC2
Reactant: C=O
Agent: Cl
Solvent: O=CO
Product: CN1CCc2[nH]c(=O)n(Cc3ccccc3)c(=O)c2C1

Procedure:
6.5 g of 3-benzy1-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]-pyrimidine-2,4-dione hydrochloride were added at 0° C. to a mixture of 5.5 ml of 90% formic acid and 4 ml of 37% formaldehyde, with stirring. After heating for 8 h at the reflux temperature, 26.5 ml of i N hydrochloric acid were added at room temperature and the mixture was then concentrated under reduced pressure. After recrystallization from isopropanol/water, 3-benzyl-6-methyl-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]pyrimidine-2,4-dione hydrochloride was obtained from the residue.