Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:13])[CH2:10][CH2:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrN1C(=[O:20])CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH2:1]([C:8]1[C:9](=[O:13])[CH2:10][CH:11]([OH:20])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1CCC=C1Cc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1CC(O)C=C1Cc1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 2-benzylcyclopent-2-en-1-one and N-bromosuccinimide in dry carbon tetrachloride (150 ml) is refluxed for 1 hour, cooled and filtered. The filtrate is concentrated under reduced pressure to approx. 100 ml, and mixed with a stirred suspension of silver acetate (5 g) in acetic acid (150 ml). The resulting mixture is heated to 50° C. for 30 minutes and then stirred at room temperature overnight. The mixture is filtered, poured onto H2O (50 ml) and extracted with methylene chloride (150 ml×3). The combined extracts are washed with water ag. sodium bicarbonate, ag. sodium chloride, dried and concentrated under reduced pressure. (b.pt. is 128°-132° at 0.05 mmHg). The crude acetate is added to a solution of KOH (1.1 g) in 10% aqueous MeOH (100 ml) and stirred at room temperature for 40 minutes, poured onto dil.HCl and extracted with Et20 (×3). The combined extracts are washed with water dried, concentrated under reduced pressure and finally distilled. The ketone has b.pt 150°-154° C. at 0.04 mmHg and nD 1.5562.
Reaction SMILES: [CH3:1][C@@:2]12[C@:10]([OH:18])([CH2:11][C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:19][CH2:20][C:21]3[C:26]([F:27])=[C:25]([C:28]#[N:29])[CH:24]=[CH:23][C:22]=3[C@H:5]1[CH2:4][CH2:3]2.ClC1C=C(C=CC=1)C(OO)=[O:35]>ClCCl>[CH3:1][C@@:2]12[C@:10]([OH:18])([CH2:11][C:12]3[CH:13]=[CH:14][N+:15]([O-:35])=[CH:16][CH:17]=3)[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:19][CH2:20][C:21]3[C:26]([F:27])=[C:25]([C:28]#[N:29])[CH:24]=[CH:23][C:22]=3[C@H:5]1[CH2:4][CH2:3]2
Reactant: C[C@]12CC[C@@H]3c4ccc(C#N)c(F)c4CC[C@H]3[C@@H]1CC[C@@]2(O)Cc1ccncc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C[C@]12CC[C@@H]3c4ccc(C#N)c(F)c4CC[C@H]3[C@@H]1CC[C@@]2(O)Cc1cc[n+]([O-])cc1
Temperature: 22 °C
Reaction time: 16 h
Yield: 74.9 %

Procedure:
To a solution of EM-5855 (86 mg, 0.22 mmol) in anhydrous dichloromethane (5 mL) at 0° C. was added 3-chloroperoxybenzoic acid (54 mg, 0.22 mmol). The mixture was stirred for 16 h at 22° C. and evaporated to dryness. The crude compound was purified by flash chromatography (silica gel, 0-10% methanol in chloroform) to give 67 mg (75%) of EM-5854. 1H NMR (400 MHz, CDCl3) δ: 0.94 (s, 3H, Me), 2.57 (d, Jgem=13.5 Hz, 1H, —CH2-Pyr), 2.68 (m, 1H, H-6), 2.93 (d, Jgem=13.3 Hz, 2H, —CH2-Pyr, H-6), 7.17 (d, J=8.3 Hz, 1H, Ar), 7.27 (d, J=6.0 Hz, 2H, Pyr), 7.36 (t, J=7.7 Hz., 1H, Ar), 8.01 (d, J=6.8 Hz, 2H, Pyr).
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1OC)[CH2:6][N:7]=[CH:8][C:9]1[S:17][C:12]2[N:13]=[CH:14][N:15]=[CH:16][C:11]=2[CH:10]=1.C(N)C1C=CC=CC=1>>[CH2:6]([N:7]=[CH:8][C:9]1[S:17][C:12]2[N:13]=[CH:14][N:15]=[CH:16][C:11]=2[CH:10]=1)[C:5]1[CH:4]=[CH:3][CH:20]=[CH:19][CH:18]=1
Reactant: COc1ccc(CN=Cc2cc3cncnc3s2)cc1OC
Solvent: NCc1ccccc1
Product: C(=NCc1ccccc1)c1cc2cncnc2s1

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 14 but using benzylamine in place of 3,4-dimethoxybenzylamine. Pale yellow solid (69 mg, 100%), which was used directly without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](O)=O>C(Cl)(Cl)Cl>[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: O=C(O)c1ccccn1
Reactant: Nc1ccccc1S
Solvent: ClC(Cl)Cl
Product: c1ccc(-c2nc3ccccc3s2)nc1

Procedure:
To a solution of polyphosphoric acid ethyl ester (PPE) 360 g in 600 ml of CHCl3 is added o-aminothiophenol 36.9 g, 0.30 mole and picolinic acid 55.5 g, 0.45 mole. The resulting solution is heated at reflux for 1 hour. The solvent is removed in vacuo, and the residue poured onto 1500 cc of ice-water. The pH of the aqueous mixture is adjusted to 10, and it is then extracted three times with 500 cc portions of CHCl3. The extracts are dried (MgSO4); filtered; and concentrated to dryness. Recrystallization from acetonitrile yields 47.4 g of the title A compound in the form of white needles, m.p. 133°-134°.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4]([CH:6]([CH3:15])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])[CH3:5].[Br:16]Br>C(O)(=O)C>[CH3:1][CH2:2][CH2:3][CH:4]([C:6]([Br:16])([CH3:15])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])[CH3:5]
Reactant: BrBr
Reactant: CCCC(C)C(C)C(=O)c1ccccc1
Solvent: CC(=O)O
Product: CCCC(C)C(C)(Br)C(=O)c1ccccc1
Temperature: 0 °C
Yield: 70.6 %

Procedure:
To a solution of the ketone 3 (5.03 g, 0.025 mol) in 15 ml of glacial acetic acid, Br2 (3.94 g, 0.025 mol) was added dropwise, with stirring at 0° C. After the addition was complete the ice bath was removed and the solution was stirred for 2 h at 23° C. The reaction mixture was quenched by the addition of water and after cooling it was extracted with ether. After drying and concentration under vacuum, the residue was purified by flash chromatography, eluting with hexanes, to afford 5.0 g (72%) of compound 4. 1H NMR (100 MHz, CDCl3) δ 0.8 (t, 3H), 1.4 (m, 6H), 1.8 (d, J=6.5 Hz, 3H), 2.7 (t, J=6.4 Hz, 2H), 5.25 (q, 1H), 7.25 (d, J=8.0 Hz, 2H), 7.9 (d, J=8.2 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][CH3:14])[N:12]=1)([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.CCCCCC.[CH3:27][S:28]SC>C1COCC1>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[S:9][C:10]([S:28][CH3:27])=[C:11]([CH2:13][CH3:14])[N:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1csc(NC(=O)OC(C)(C)C)n1
Reactant: CSSC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCc1nc(NC(=O)OC(C)(C)C)sc1SC
Temperature: 25 °C

Procedure:
The above prepared (4-ethyl-thiazol-2-yl)-carbamic acid tert-butyl ester (1.12 g, 4.90 mmol) was dissolved in 12 mL of abs. THF and treated at −78° C. with a solution of nBuLi in hexane (6.53 mL, 1.5M, 2 eq.). The reaction mixture was kept for 15 Min. at −78° C. and then allowed to reach RT. After recooling to −78° C., methyldisulfanylmethane (0.870 mL, 2 eq.) was added and the mixture kept for 30 Min. at this temperature and then slowly warmed to RT. Pouring onto crashed ice/NH4Cl, twofold extraction with ethyl acetate washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/ethyl acetate=85/15), afforded 1.067 g of the title product as off-white solid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][C:7](=[O:18])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[O:16][CH3:17])=[O:4].[N-:19]=[N+:20]=[N-:21].[Na+].[I-].[K+]>CC(C)=O>[N:19]([CH2:2][C:3]([NH:5][CH2:6][C:7](=[O:18])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[O:16][CH3:17])=[O:4])=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(OC)c(C(=O)CNC(=O)CCl)c1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(OC)c(C(=O)CNC(=O)CN=[N+]=[N-])c1
Temperature: 60 °C
Yield: 91 %

Procedure:
In a four neck round bottomed flask, 45 gm (0.165 mole) of 2-Chloro-N-(β-oxo-2,5-Dimethoxy phenethyl)-acetamide prepared according to step (b), 27 g (0.415 mole) sodium azide and 8.3 g (0.049 mole) potassium iodide and 900 ml of acetone is charged. The solution is refluxed at 60° C. for 5 hours. After completion of the reaction the reaction mass cooled and filtered to remove inorganics. Acetone is distilled off under atmospheric pressure. Water is added and the resulting yellow lumps are filtered. (Yield: 91%). The solid is recrystallized from methanol. The following physical properties are measured.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:7]=[C:6]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:5]=1[CH:22]=[O:23]>CN(C)C=O.O>[Cl:3][C:4]1[N:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:7]=[C:6]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:5]=1[CH2:22][OH:23]
Reactant: O=Cc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OCc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl
Yield: 95 %

Procedure:
2.8 g of sodium borohydride are added to a suspension of 46.4 g of 5-chloro-3-p-chlorophenyl-1-phenyl-pyrazole-4-carboxaldehyde in 700 ml of dimethylformamide and 100 ml of water, the temperature possibly rising to 35°. After 30 minutes purification is carried out with active charcoal, precipitation is carried out with 700 ml of water and the precipitate is well washed. 5-Chloro-3-p-chlorophenyl-4-hydroxymethyl-1-phenyl-pyrazole is obtained with a 95 % yield; F 152.5°-153.5° (from acetone).
Reaction SMILES: Cl.CN.[CH2:4]([N:6](CC)CC)C.[Br:11][C:12]1[CH:13]=[CH:14][C:15]([O:22][CH3:23])=[C:16]([S:18](Cl)(=[O:20])=[O:19])[CH:17]=1>C(Cl)Cl>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([O:22][CH3:23])=[C:16]([S:18]([NH:6][CH3:4])(=[O:20])=[O:19])[CH:17]=1
Reactant: CCN(CC)CC
Reactant: COc1ccc(Br)cc1S(=O)(=O)Cl
Agent: CN
Agent: Cl
Solvent: ClCCl
Product: CNS(=O)(=O)c1cc(Br)ccc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.5 %

Procedure:
To a stirred ice cold mixture of methylamine hydrochloride (231.1 mg, 3.5 mmol), triethylamine (1.26 mL, 8.755 mmol) in DCM was added a solution of 5-bromo-2-methoxybenzene-1-sulfonyl chloride (500 mg, 1.751 mmol) in DCM at 0° C. This was stirred at RT for three hours. This mixture was then poured on to ice cold water and extracted with DCM, dried over sodium sulfate and concentrated to get 400 mg (81.63% yield) of titled compound.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:34](=[O:37])[CH2:35][CH3:36])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:33])[NH:14][C:15]=23)[CH2:31][CH2:32]1
Reactant: CCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-fluorophenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f8) and commercially propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:36][C:37]1[C:38]([N:47]2[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH2:49][CH2:48]2)=[CH:39][C:40]([O:44][CH2:45][CH3:46])=[C:41]([NH2:43])[CH:42]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C(F)(F)F>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:43][C:41]3[CH:42]=[C:37]([CH3:36])[C:38]([N:47]4[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH2:49][CH2:48]4)=[CH:39][C:40]=3[O:44][CH2:45][CH3:46])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: OCC(F)(F)F
Product: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 80 °C
Yield: 30.7 %

Procedure:
To 5-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (200 mg, 0.407 mmol) and (5-methyl-2-(ethyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}phenyl)amine (200 mg, 0.586 mmol) (Example 248, Step B) in trifluoroethanol (10 mL) was added p-toluene sulfonic acid (200 mg, 1.05 mmol), and the vial was sealed and heated to 80° C. overnight. The reaction was then cooled to rt and silica was added. The solvent was removed on a rotovap and the product purified on a 12 g ISCO column. Desired fractions were combined and rotovaped down. The resulting foam was dissolved in DCM and ether was added to provide the title compound (100 mg, 0.125 mmol, 31%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.74 (s, 1H), 9.33 (d, J=7.1 Hz, 1H), 8.32 (s, 1H), 8.23 (d, J=5.3 Hz, 1H), 8.08 (s, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.67 (d, J=8.6 Hz, 1H), 7.53 (s, 1H), 7.43-7.33 (m, 2H), 7.25 (d, J=8.4 Hz, 1H), 7.15 (t, J=8.0 Hz, 2H), 6.92 (t, J=6.9 Hz, 1H), 6.71 (s, 1H), 6.56 (d, J=5.3 Hz, 1H), 4.03 (q, J=6.8 Hz, 2H), 3.95 (s, 3H), 3.36-3.25 (m, 2H), 3.03 (s, 3H), 2.86-2.78 (m, 4H), 2.74 (t, J=6.7 Hz, 2H), 2.63-2.50 (m, 4H), 2.11 (s, 3H), 1.22 (t, J=7.0 Hz, 3H). MS (ESI) m/z=398 [M+2H]+2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][C:6]1[C:7](=[O:18])[O:8][C:9]2[C:14]([C:15]=1[CH3:16])=[CH:13][CH:12]=[C:11]([OH:17])[CH:10]=2.[I-].[N:24]1([C:34](N2C=C[N+](C)=C2)=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][C:6]1[C:7](=[O:18])[O:8][C:9]2[C:14]([C:15]=1[CH3:16])=[CH:13][CH:12]=[C:11]([O:17][C:34]([N:24]1[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][CH2:26][CH2:25]1)=[O:35])[CH:10]=2
Reactant: C[n+]1ccn(C(=O)N2CCCc3ccccc32)c1
Reactant: Cc1c(Cc2ccc(Cl)c(Cl)c2)c(=O)oc2cc(O)ccc12
Agent: [I-]
Product: Cc1c(Cc2ccc(Cl)c(Cl)c2)c(=O)oc2cc(OC(=O)N3CCCc4ccccc43)ccc12

Procedure:
The title compound was prepared from 3-(3,4-dichloro-benzyl)-7-hydroxy-4-methyl-2H-chromen-2-one and 3-(3,4-dihydro-2H-quinoline-1-carbonyl)-1-methyl-3H-imidazol-1-ium iodide. HPLC-MS m/z=494 (M+1), Rt: 5.86 min.
Reaction SMILES: [Na].[CH2:2]([OH:14])[CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][OH:13].C1(S(O[CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][OH:33])(=O)=O)C=CC=CC=1.C1C=CC=CC=1.[Na]>>[CH2:12]([OH:13])[CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][O:14][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][OH:33]
Reactant: O=S(=O)(OCCOCCOCCO)c1ccccc1
Reactant: OCCOCCOCCOCCO
Agent: [Na]
Solvent: c1ccccc1
Product: OCCOCCOCCOCCOCCOCCOCCO

Procedure:
Dissolve one equivalet of sodium in at least 5 equivalents of tetraethylene glycol and then add one equivalent of triethylene glycol monobenzenesulfonate. Heat the resulting solution at 100° to 150° C. until the elimination of sodium benzene sulfontate is substantially complete. Remove the insoluble sulfonate salt by filtration and fractionally distill the resultiing product in vacuo to obtain heptaethylene glycol as the higher boiling fraction.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][N:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][CH2:31][C@@H:3]12.C([N:34](C(C)C)[CH:35]([CH3:37])[CH3:36])C.CC(N)C>CN(C=O)C>[CH:35]([NH:34][C:23](=[O:25])[C:22]1[CH:26]=[CH:27][C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][C:9]3[CH:10]=[N:11][C:5]4[N:4]5[CH2:28][CH2:29][CH2:30][CH2:31][C@H:3]5[C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)[CH2:18][CH2:17]2)=[N:20][CH:21]=1)([CH3:37])[CH3:36]
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)nc1
Reactant: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CC(C)N
Product: CC(C)NC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
(S)-6-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinic acid (75 mg, 0.178 mmol) was taken up in DMF (0.9 mL). To the mixture was added N-ethyl-N-isopropylpropan-2-amine (93 μl, 0.53 mmol), O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (101 mg, 0.266 mmol), and propan-2-amine (11.5 mg, 0.195 mmol). The reaction was stirred at room temperature overnight. The reaction was purified via HPLC (10-80 MeCN/H2O, TFA buffered). The fractions were collected and lyophilized to yield 64.8 mg (65%) of the product as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.84 (s, 1H), 9.93 (br. s., 1H), 8.64 (d, J=2.0 Hz, 1H), 8.02-8.11 (m, 2H), 7.82 (d, J=2.0 Hz, 1H), 7.05 (d, J=2.0 Hz, 1H), 6.96 (d, J=9.1 Hz, 1H), 4.43-4.63 (m, 3H), 4.25 (s, 2H), 4.07 (dd, J=14.1, 6.6 Hz, 1H), 3.93-4.02 (m, 1H), 3.37-3.55 (m, 1H), 2.96-3.25 (m, 4H), 2.68 (td, J=12.9, 2.5 Hz, 1H), 2.02-2.11 (m, 1H), 1.87 (d, J=12.4 Hz, 1H), 1.33-1.72 (m, 4H), 1.14 (d, J=6.8 Hz, 6H). [M+H] calc'd for C25H33N7O2, 464. found, 464.
Reaction SMILES: [CH2:1]([C:3]([C:21]1[CH:35]=[CH:34][C:24]([C:25]([NH:27][CH2:28][CH2:29][S:30]([CH3:33])(=[O:32])=[O:31])=[O:26])=[C:23]([CH3:36])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].C[N+]1([O-])CCOCC1>CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH3:18][C:15]([CH3:16])([CH3:17])[C:14](=[O:19])[CH2:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([C:3]([C:21]2[CH:35]=[CH:34][C:24]([C:25]([NH:27][CH2:28][CH2:29][S:30]([CH3:33])(=[O:32])=[O:31])=[O:26])=[C:23]([CH3:36])[CH:22]=2)([CH2:1][CH3:2])[CH2:4][CH3:5])=[CH:7][C:8]=1[CH3:20]
Reactant: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc(C(=O)NCCS(C)(=O)=O)c(C)c1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc(C(=O)NCCS(C)(=O)=O)c(C)c1
Yield: 76 %

Procedure:
Using a procedure analogous to Example 13C, from 4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethylbutoxy)-3-methylphenyl]propyl}-N-(2-methanesulfonylethyl)-2-methylbenzamide, Example 14, (0.08 g, 0.16 mmol), NMO (27 mg, 0.24 mmol), and TPAP (2.8 mg, 0.08 mmol) are reacted for 1 h to give the title compound (0.06 g, 76%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][N:11]=[CH:10][C:9]=1[N+:13]([O-:15])=[O:14].[CH3:16][C:17]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=O>>[N+:13]([C:9]1[CH:10]=[N:11][N:12]2[C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:17]2([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH3:16])([O-:15])=[O:14]
Reactant: CCCCCCC(C)=O
Reactant: Nc1ccccc1-c1[nH]ncc1[N+](=O)[O-]
Product: CCCCCCC1(C)Nc2ccccc2-c2c([N+](=O)[O-])cnn21
Yield: 81.5 %

Procedure:
5-(o-Aminophenyl)-4-nitropyrazole is reacted with n-hexyl methyl ketone as given in Example 11 to give 1-nitro-5-hexyl-5-methyl-5,6-dihydropyrazolo[1,5-c]quinazoline. M.p.: 86°-88° C. Yield: 81.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][C:8]([O:10]C)=[O:9])=[C:4]([C:14]#[C:15][C:16]2[CH:21]=[C:20]([S:22]([CH2:24][CH2:25][CH3:26])=[O:23])[CH:19]=[CH:18][C:17]=2[CH3:27])[CH:3]=1.[OH-].[Na+].O>CO>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([C:14]#[C:15][C:16]2[CH:21]=[C:20]([S:22]([CH2:24][CH2:25][CH3:26])=[O:23])[CH:19]=[CH:18][C:17]=2[CH3:27])[CH:3]=1
Reactant: CCCS(=O)c1ccc(C)c(C#Cc2cc(Cl)ccc2OCC(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCS(=O)c1ccc(C)c(C#Cc2cc(Cl)ccc2OCC(=O)O)c1
Reaction time: 3 h
Yield: 83.4 %

Procedure:
A solution of methyl (4-chloro-2-{[2-methyl-5-(propylsulfinyl)phenyl]ethynyl}phenoxy)acetate (Intermediate 221, 125 mg; 0.31 mmol) in MeOH (5 ml) was treated with a 1M solution of sodium hydroxide in water (0.93 ml; 0.93 mmol). After stirring for 3 hours, the solvent was removed under reduced pressure, the residue was taken up in AcOEt and extracted with 0.1N HCl. The organic phase was dried on MgSO4 and concentrated to give a residue which was triturated in diethyl ether, to afford the title compound as a pale yellow solid (101 mg, 83%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][OH:15])[CH2:9]1)=O)(C)(C)C.[CH2:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1O)[CH3:17]>>[CH2:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:15][CH2:14][C@H:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1)[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CO)C1
Reactant: CCOc1ccccc1O
Product: CCOc1ccccc1OC[C@@H]1CNCCO1

Procedure:
(S)-2-(2-Ethoxy-phenoxymethyl)-morpholine was synthesized from (S)-2-Hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester and 2-ethoxyphenol according to the following procedure:
Reaction SMILES: [NH2:1][CH:2]1[CH:6]2[N:7]([CH3:15])[CH:8]3[CH:13]([CH:5]2[CH2:4][CH2:3]1)[CH:12]=[C:11]([OH:14])[CH:10]=[CH:9]3.C(N(CC)CC)C.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>C(Cl)Cl>[CH3:15][N:7]1[CH:8]2[CH:13]([CH:12]=[C:11]([OH:14])[CH:10]=[CH:9]2)[CH:5]2[CH2:4][CH2:3][CH:2]([NH:1][C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[CH:6]12
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CN1C2C=CC(O)=CC2C2CCC(N)C21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C2C=CC(O)=CC2C2CCC(NC(=O)OCc3ccccc3)C21
Reaction time: 2 h

Procedure:
To a solution of 3-amino-1,2,3,3a,4,8a-hexahydro-4-methylcyclopent[b]-indol-7-ol (10.7 grams) in methylene chloride (125 ml) was added triethylamine (5.6 grams) followed by the dropwise addition of benzyl chloroformate (10.0 grams) in methylene chloride (25 ml). The mixture as stirred for 2 hours, extracted with water, dried (Na2SO4) an concentrated. The product was purified by chromatography on silica gel, eluting with 2:1 hexane/acetone to provide 1,2,3,3a,4,8a-hexahydro-4-methyl-3-phenylmethyloxycarbonylaminocyclopent[b]indol-7-ol.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[CH3:9][O:10][C:11]1[CH:16]=[C:15]([CH3:17])[NH:14][C:13](=[O:18])[C:12]=1[CH2:19][NH:20][C:21]([C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]([CH:32]([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH3:33])[C:24]=1[CH3:40])=[O:22].CCN(CC)CC>CCO>[CH3:9][O:10][C:11]1[CH:16]=[C:15]([CH3:17])[NH:14][C:13](=[O:18])[C:12]=1[CH2:19][NH:20][C:21]([C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]([CH:32]([CH:34]2[CH2:35][CH2:36][N:37]([C:2]3[N:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[CH2:38][CH2:39]2)[CH3:33])[C:24]=1[CH3:40])=[O:22]
Reactant: COc1cc(C)[nH]c(=O)c1CNC(=O)c1c(C)n(C(C)C2CCNCC2)c2ccccc12
Reactant: Clc1ncccn1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1cc(C)[nH]c(=O)c1CNC(=O)c1c(C)n(C(C)C2CCN(c3ncccn3)CC2)c2ccccc12
Temperature: 100 °C
Yield: 64.6 %

Procedure:
To a re-sealable vial was added 2-chloropyrimidine (185 mg, 1.611 mmol), (R or S)-N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(piperidin-4-yl)ethyl)-1H-indole-3-carboxamide hydrochloride (508 mg, 1.074 mmol) (Compound 326), and EtOH (8 mL). To this solution was added Et3N (449 μl, 3.22 mmol). The vial was sealed and heated to 100° C. overnight. The solution was allowed to cool to room temperature and concentrated in vacuo. The crude residue was purified via silica gel chromatography (hexanes: (3:2 DCM:IPA)) to afford the title compound as a solid (357 mg, 0.694 mmol, 64.6% yield). LCMS 515 (M+1)+; 1H NMR (DMSO-d6, 400 MHz) δ 11.60 (s, 1 H), 8.30 (d, J=4.7 Hz, 2 H), 7.76 (d, J=7.6 Hz, 1 H), 7.73-7.64 (m, 2 H), 7.14-7.01 (m, 2 H), 6.55 (t, J=4.7 Hz, 1 H), 6.15 (s, 1 H), 4.84-4.75 (m, 1 H), 4.57-4.47 (m, 1 H), 4.33 (d, J=4.2 Hz, 2 H), 4.22-4.11 (m, 1 H), 3.84 (s, 3 H), 2.92-2.81 (m, 1 H), 2.63-2.52 (m, 4 H), 2.20 (s, 3H), 2.05-1.94 (m, 1 H), 1.61-1.49 (m, 4 H), 1.34-1.21 (m, 1 H), 1.04-0.91 (m, 1 H), 0.83-0.75 (m, 1 H).