Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[C:23]([CH3:30])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].Cl.[CH3:32][O:33][C:34](=[O:39])[C:35]([NH2:38])([CH3:37])[CH3:36].O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>>[CH3:32][O:33][C:34](=[O:39])[C:35]([NH:38][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:21]([C:3]([CH2:1][CH3:2])([C:6]2[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]3([OH:19])[CH2:15][CH2:16][CH2:17][CH2:18]3)=[C:8]([CH3:20])[CH:7]=2)[CH2:4][CH3:5])=[CH:22][C:23]=1[CH3:30])([CH3:37])[CH3:36]
Reactant: COC(=O)C(C)(C)N
Reactant: CCC(CC)(c1ccc(C#CC2(O)CCCC2)c(C)c1)c1ccc(C(=O)O)c(C)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Product: CCC(CC)(c1ccc(C#CC2(O)CCCC2)c(C)c1)c1ccc(C(=O)NC(C)(C)C(=O)OC)c(C)c1
Yield: 82.1 %

Procedure:
4-{1-Ethyl-1-[4-(1-hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-benzoic acid (389 mg, 0.962 mmol), α-aminoisobutyric acid methyl ester hydrochloride (221 mg, 1.44 mmol), 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (276 mg, 1.44 mmol), 1-hydroxybenzotriazole hydrate (195 mg, 1.44 mmol) and triethylamine (536 μL, 3.85 mmol) are stirred overnight. The reaction is concentrated and partitioned between EtOAc (150 ml) and 1N HCl (50 ml). The aqueous layer is extracted with EtOAc (100 ml). The combined organic layers are washed with, water (50 ml), NaHCO3 (50 ml), brine (50 ml), dried (anhydrous MgSO4), concentrated and chromatographed (12 g SiO2, 15% EtOAc/Hexanes) to yield the title compound (398 mg, 82%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[N:21]1([CH2:26][CH2:27][CH2:28][NH:29][C:30]([C:32]2[C:36](C)=[C:35]([CH:38]=O)[NH:34][C:33]=2[CH3:40])=[O:31])[CH2:25][CH2:24][CH2:23][CH2:22]1>C(O)C.N1CCCCC1>[N:21]1([CH2:26][CH2:27][CH2:28][NH:29][C:30]([C:32]2[CH:36]=[C:35]([CH3:38])[NH:34][C:33]=2[CH:40]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:4]=3)[NH:13][C:12]2=[O:18])=[O:31])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C1Cc2c(cccc2-c2cccc(C(F)(F)F)c2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCCN1CCCC1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)NCCCN2CCCC2)c(C=C2C(=O)Nc3cccc(-c4cccc(C(F)(F)F)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40 %

Procedure:
To a solution of 4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-pyrrolidin-1-yl-propyl)-amide (69.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-methyl-2-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (3-pyrrolidin-1-yl-propyl)-amide as a yellow solid (52.2 mg, 40%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[OH-].[Na+].[F:16][C:17]([F:27])([F:26])[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1>CO.O>[F:16][C:17]([F:26])([F:27])[C:18]1[CH:19]=[CH:20][C:21](/[CH:22]=[CH:12]/[C:11](=[O:13])/[CH:10]=[CH:9]/[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:24][CH:25]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(/C=C/C(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(/C=C/C(=O)/C=C/c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.4 %

Procedure:
(E)-4-(4-Methoxyphenyl)but-3-en-2-one (1 g, 5.7 mmol) was dissolved in MeOH (18 mL) and stirred for 5 min at room temperature. A solution of NaOH (500 mg, 12.5 mmol) in H2O (34 mL) was added and the reaction mixture was stirred for further 1 h. After the dropwise addition of 4-(trifluoromethyl)-benzaldehyde (822 μl, 6.0 mmol), the mixture was stirred overnight at ambient temperature. The resulting yellow precipitate was filtered and dried in vacuo to obtain NW336.2 as a pale yellow solid (1.75 g, 92%). mp: 144-146° C. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.66 (d, 3J=15.9 Hz, 1H, Hvin), 7.64 (d, 3J=15.5 Hz, 1H, Hvin), 7.63 (d, 3J=9.0 Hz, 2H, HAr), 7.58 (d, 3J=8.6 Hz, 2H, HAr), 7.50 (d, 3J=8.8 Hz, 2H, HAr), 7.06 (d, 3J=16.0 Hz, 1H, Hvin), 6.87 (d, 3J=16.0 Hz, 1H, Hvin), 6.86 (d, 3J=8.8 Hz, 2H, HAr), 3.78 (s, 3H, OCH3). 13C NMR (75 MHz, CDCl3) δ (ppm): 188.4 (C), 161.9 (C), 143.9 (CH), 140.8 (CH), 138.4 (q, 4J(C, F)=1.3 Hz, CH), 131.7 (q, 2J(C, F)=32.7 Hz, C), 130.3 (CH), 128.4 (CH), 127.6 (CH), 127.3 (C), 125.9 (q, 3J(C, F)=3.8 Hz, CH), 123.9 (q, 1J(C, F)=272.2 Hz, C), 123.2 (CH), 114.5 (CH), 55.5 (OCH3). MS (FAB) m/z: 333.1 (M+). Anal. calcd for C19H15F3O2: C, 68.67; H, 4.55. Found: C, 68.81; H, 4.63%.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][CH2:11]Cl)=[N:5][N:4]=[N:3]1.SN1NC[C:18](=[O:21])[C:17]2[CH:22]=[CH:23][CH:24]=[CH:25][C:16]=2[NH:15]1.[OH-].[Na+]>CO>[CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][CH2:11][S:7][C:6]2[NH:5][NH:4][C:18](=[O:21])[C:17]3[CH:22]=[CH:23][CH:24]=[CH:25][C:16]=3[N:15]=2)=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1SCCCCCl
Reactant: O=C1CNN(S)Nc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1nnnc1SCCCCSC1=Nc2ccccc2C(=O)NN1
Yield: 136.5 %

Procedure:
1-Methyl-5-(4-chlorobutyl)thio-1,2,3,4-tetrazole (2.00 g) and 2-mercapto-3H,4H-benzotriazepin-5-one (2.2 g) are dissolved in methanol (50 ml), and thereto is added sodium hydroxide (4.8 g), and the mixture is refluxed at 2.5 hours. After the solvent is distilled off, water is added to the residue, and the mixture is extracted with chloroform. The chloroform layer is washed with 5% aqueous sodium hydroxide and saturated aqueous sodium chloride and dried over magnesium sulfate. After chloroform is distilled off, the residue is recrystallized from methanol to give 1-methyl-5-[4-(3H,4H-1,3,4-benzotriazepin-5-on-2-yl)thiobutyl]thio-1,2,3,4-tetrazole (2.4 g) as colorless prisms, m.p. 94°-95° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH:7]=O)=[C:5]([CH3:9])[N:4]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[N:20]=[C:21]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:22][C:23]=3[CH3:24])=[CH:13][CH:12]=2)[N:3]=1.C(OP([CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])(OCC)=O)C.[H-].[Na+].O>CN(C)C=O>[CH3:1][C:2]1[C:6](/[CH:7]=[CH:39]/[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:5]([CH3:9])[N:4]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]3[N:20]=[C:21]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:22][C:23]=3[CH3:24])=[CH:15][CH:16]=2)[N:3]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: Cc1nn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c(C)c1C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1c(C)nn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 70 %

Procedure:
To a solution of 3,5-dimethyl-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-carbaldehyde (900 mg) and ethyl diethylphosphonoacetate (1.10 g) in N,N-dimethylformamide (20 ml), sodium hydride (60%, oily, 200 mg) was added at 0, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated. The obtained crystals were collected by filtration, and ethyl(E)-3-[3,5-dimethyl-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propenoate (740 mg) was obtained. After the mother liquor was concentrated, the residue was subjected to silica gel column chromatography, and 150 mg of crystals were additionally obtained from the fraction eluted with ethyl acetate-hexane (2:3, volume ratio). The total was 890 mg (yield: 87%). This was recrystallized from ethyl acetate-isopropyl ether. Melting point: 98–99° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([CH2:14][CH3:15])=[C:9]([C:12]#[N:13])[C:10]=1I)=[O:5])[CH3:2].[Br:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([CH2:14][CH3:15])=[C:9]([C:12]#[N:13])[C:10]=1[C:20]1[CH:21]=[CH:22][C:17]([Br:16])=[CH:18][CH:19]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(CC)c(C#N)c1I
Reactant: OB(O)c1ccc(Br)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1sc(CC)c(C#N)c1-c1ccc(Br)cc1
Temperature: 25 °C
Yield: 90.3 %

Procedure:
Add 4-cyano-5-ethyl-3-iodo-thiophene-2-carboxylic acid ethyl ester (268.1 g, 0.8 mol) and 4-bromophenyl boronic acid (173.5 g, 0.86 mol), to a solution of bis(tri-o-tolylphosphine)palladium (II) diacetate (7.00 g, 0.008 mole) in acetonitrile(1.9 L) within a 5000 mL, 3-neck round-bottom flask equipped with an overhead stirrer, internal temperature probe, heating mantle, and a glycol-cooled condenser fitted with a nitrogen inlet. Add a solution of sodium carbonate (169.6 g, 1.6 mol) in water (1.3 L) and stir the reactor contents at room temperature while sweeping the headspace with nitrogen for 10 min. the reaction apparatus was then set for a nitrogen by-pass and the reaction mixture was heated to 73° C. Observe that HPLC analysis indicates substantial (>98%) consumption of 4-bromophenyl boronic acid and 4-cyano-5-ethyl-3-iodo-thiophene-2-carboxylic acid ethyl ester (flow rate: 1.5 mL/min; detection: 210 nm; mobile phase: isocratic 65/35 (v/v) acetonitrile/0.1% trifluoroacetic acid in water; column: Zorbax® SB-Phenyl; 4.6 mm×25 cm; 5 microns at 35 C). Cool the mixture to 23° C. and separate the phases. Extract the aqueous phase twice with methyl t-butyl ether (300 mL). Combine the organic phases and concentrate under reduced pressure to an oil. Dissolve the oil in a mixture of heptane (500 mL) and methyl t-butyl ether (500 mL). This results in separation of an immiscible water phase which is separated, extracted with methyl t-butyl ether (100 mL) and discarded. The organic phases are combined and concentrated under reduced pressure to an oil. The oil is dissolved in a mixture of heptane (500 mL) and methyl t-butyl ether (300 mL) and the solution is transferred to a flask set for atmospheric distillation at 83° C. The distillation is continued until distillation at 83° C. and atmospheric pressure stops. The resulting solution is cooled to 30° C. and is seeded with 3-(4-Bromo-phenyl)-4-cyano-5-ethyl-thiophene-2-carboxylic acid ethyl ester, then the mixture is further cooled to 18° C. Filter the resulting suspension and wash the filter cake with heptane (3×100 mL). The resulting cake is air-dried and then transferred to a vacuum oven (40° C.) to afford the title compound (263 g, 90.4% yield). The title compound may be additionally purified as follows if desired.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]3[C:10](=[CH:11][CH:12]=2)[CH:9]=[CH:8][C:7]([CH3:16])=[N:6]3)[N:3]=1.[N+:17]([O-])([OH:19])=[O:18].S(=O)(=O)(O)O>>[N+:17]([C:11]1[CH:12]=[C:13]2[C:4]([N:3]=[C:2]([CH3:1])[CH:15]=[CH:14]2)=[C:5]2[C:10]=1[CH:9]=[CH:8][C:7]([CH3:16])=[N:6]2)([O-:19])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc2ccc3ccc(C)nc3c2n1
Agent: O=S(=O)(O)O
Product: Cc1ccc2cc([N+](=O)[O-])c3ccc(C)nc3c2n1

Procedure:
Specifically, 2,9-dimethyl-1,10-phenanthroline shown by the formula (A) in FIG. 1 is reacted with an acid mixture composed of nitric acid and sulfuric acid to give 5-nitro-2,9-dimethyl-1,10-phenanthroline shown by the formula (B) in FIG. 1. The 5-nitro-2,9-dimethyl-1,10-phenanthroline is then reacted with selenium dioxide to give a dialdehyde compound shown by the formula (C) in FIG. 1. This dialdehyde compound is then oxidized to obtain the compound of the formula (1).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:7][Si:8]([CH3:11])([CH3:10])[CH3:9].[OH-].[Na+]>>[C:1]([NH:5][CH2:7][Si:8]([CH3:11])([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)CCl
Reactant: CC(C)(C)N
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)NC[Si](C)(C)C
Temperature: 200 °C

Procedure:
A mixture of tert-butylamine (18.0 mL, 171 mmol) and (chloromethyl)trimethylsilane (7.00 g, 57.1 mmol) was heated in a thick-walled glass tube at 200° C. overnight. After cooling to ambient temperature, the reaction mixture was poured into 1 N NaOH and extracted three times with diethyl ether. The combined organic extracts were washed with brine, dried (MgSO4), and the volatiles evaporated in vacuo. Distillation (atmospheric pressure; ˜135° C.) of the residual liquid gave the title compound as a colorless liquid.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][C@H:6]1[O:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=2[O:21][CH3:22])[C:10]2[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:9]=2[N:8]([CH2:28][C:29]([CH2:33][OH:34])([CH3:32])[CH2:30][OH:31])[C:7]1=[O:35])C.[OH-].[Na+].O.Cl>C(O)C>[Cl:27][C:24]1[CH:25]=[CH:26][C:9]2[N:8]([CH2:28][C:29]([CH2:33][OH:34])([CH3:32])[CH2:30][OH:31])[C:7](=[O:35])[C@@H:6]([CH2:5][C:4]([OH:36])=[O:3])[O:12][C@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=3[O:21][CH3:22])[C:10]=2[CH:23]=1
Reactant: CCOC(=O)C[C@H]1O[C@H](c2cccc(OC)c2OC)c2cc(Cl)ccc2N(CC(C)(CO)CO)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cccc([C@H]2O[C@H](CC(=O)O)C(=O)N(CC(C)(CO)CO)c3ccc(Cl)cc32)c1OC
Temperature: 60 °C
Reaction time: 1 h
Yield: 40.2 %

Procedure:
To a solution of (3R,5S)-7-chloro-1-(3-hydroxy-2-hydroxymethyl-2-methylpropyl)-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid ethyl ester (1.0 g) in ethanol (10 ml) was added a 1N aqueous solution of sodium hydroxide. The mixture was stirred at 60° C. for one hour. To the reaction mixture was added water, which was neutralized with 1N HCl, followed by subjecting to extraction with ethyl acetate. The extract solution was dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from a mixture of ethyl acetate and hexane to afford 0.38 g of (3R,5S)-7-chloro-1-(3-hydroxy-2-hydroxymethyl-2-methylpropyl)-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid, m.p. 208-210° C.
Reaction SMILES: C(N1C(C2SC3N=CN=C(SC)C=3C=2)=C(C2C=CC=CC=2)N=C1)C.[CH2:25]([N:27]1[C:31]([C:32]2[S:33][C:34]3[N:35]=[CH:36][N:37]=[C:38]([S:41][CH3:42])[C:39]=3[N:40]=2)=[C:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[N:29]=[CH:28]1)[CH3:26].CSC1C2C=C(C=[O:61])SC=2N=CN=1.C(CN)O>>[CH3:42][S:41][C:38]1[C:39]2[N:40]=[C:32]([C:31]3[N:27]([CH2:25][CH2:26][OH:61])[CH:28]=[N:29][C:30]=3[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[S:33][C:34]=2[N:35]=[CH:36][N:37]=1
Reactant: CCn1cnc(-c2ccccc2)c1-c1nc2c(SC)ncnc2s1
Reactant: CSc1ncnc2sc(C=O)cc12
Agent: CCn1cnc(-c2ccccc2)c1-c1cc2c(SC)ncnc2s1
Solvent: NCCO
Product: CSc1ncnc2sc(-c3c(-c4ccccc4)ncn3CCO)nc12

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 70 but using 7-(methylthio)[1,3]thiazolo[5,4-d]pyrimidine-2-carbaldehyde (Intermediate 78) in place of 4-(methylthio)thieno[2,3-d]pyrimidine-6-carbaldehyde (Intermediate 15) and ethanolamine in place of ethylamine. Colourless solid (52 mg, 56%);
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=1)[CH3:9].[CH3:21][N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([OH:26])=O.CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O>C(#N)C>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([N:10]([CH2:8][CH3:9])[C:24]([C@@H:23]2[CH2:27][CH2:28][CH2:29][N:22]2[CH3:21])=[O:26])=[CH:12][C:13]=1[N+:18]([O-:20])=[O:19]
Reactant: CN1CCC[C@H]1C(=O)O
Reactant: CCNc1ccc(N)c([N+](=O)[O-])c1
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCN(C(=O)[C@@H]1CCCN1C)c1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 54.6 %

Procedure:
Triethylamine (1.0 mL, 7.33 mmol) was added to a stirred solution of N1-ethyl-3-nitrobenzene-1,4-diamine (440 mg, 2.43 mmol), N-methyl-L-proline (314 mg, 2.43 mmol) and DEPBT (727 mg, 2.43 mmol) in acetonitrile (15 mL). The mixture was stirred at room temperature and further aliquots of N-methyl-L-proline (314 mg, 2.43 mmol), DEPBT (727 mg, 2.43 mmol), and triethylamine (1.0 mL, 7.33 mmol) were added after 1, 2, and 3 days. After stirring for a further 1 day, the mixture was concentrated and the residue taken up in EA (75 mL). The EA solution was extracted with water, and with 1M sodium carbonate solution (2×). The combined water and 1M sodium carbonate solution extracts were back-extracted with EA (4×) and the combined EA extracts washed with brine, dried over magnesium sulfate, and concentrated to give (S)—N-(4-amino-3-nitrophenyl)-N-ethyl-1-methyl-pyrrolidine-2-carboxamide (388 mg) as an orange/brown oil. This was hydrogenated in ethanol, using 10% palladium on carbon (153 mg) as the catalyst. After stirring overnight under a hydrogen atmosphere (balloon), the mixture was filtered through a pad of diatomaceous earth and the filtrate concentrated to give (S)—N-(3,4-diaminophenyl)-N-ethyl-1-methylpyrrolidine-2-carboxamide (335 mg).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[C:22]([NH:24][CH:25]1[CH2:27][CH2:26]1)=[O:23].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[Cl:18][C:19]1[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=1[N:31]1[CH2:32][CH2:33][N:34]([CH2:2][C:3]2[CH:12]=[N:11][C:10]3[N:9]4[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]4[C:7](=[O:17])[NH:6][C:5]=3[CH:4]=2)[CH2:35][CH2:36]1)[C:22]([NH:24][CH:25]1[CH2:27][CH2:26]1)=[O:23]
Reactant: O=C1Nc2cc(CO)cnc2N2CCCC[C@@H]12
Reactant: O=C(NC1CC1)c1ccc(N2CCNCC2)c(Cl)c1
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: O=C(NC1CC1)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)c(Cl)c1
Temperature: 100 °C
Yield: 85.5 %

Procedure:
(S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one (150 mg, 0.643 mmol), 3-chloro-N-cyclopropyl-4-(piperazin-1-yl)benzamide (216 mg, 0.772 mmol), (cyanomethyl)trimethylphosphonium iodide (250 mg, 1.029 mmol) and N,N-diisopropylethylamine (562 μl, 3.22 mmol) were suspended in Propiononitrile (Volume: 1931 μl) and heated in a closed vial at 100° C. for 4 h. The reaction mixture became a dark brown solution with a precipitate. It was cooled to room temperature and the precipitate was filtered off, washed with MeCN (2 mL) and suspended in MeCN (15 mL) with heating and sonication. It was then cooled to ambient temperature, the precipitate was filtered off, washed with MeCN (2 mL) and dried in vacuum to afford (S)-3-chloro-N-cyclopropyl-4-(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)benzamide (272.4 mg, 0.550 mmol, 86% yield) as a white solid. 1H NMR (DMSO-d6) δ 10.49 (s, 1H), 8.39 (d, J=4.3 Hz, 1H), 7.85 (d, J=2.0 Hz, 1H), 7.75 (dd, J=8.3, 2.0 Hz, 1H), 7.66 (s, 1H), 7.16 (d, J=8.6 Hz, 1H), 6.97 (d, J=1.8 Hz, 1H), 4.50 (d, J=12.9 Hz, 1H), 3.84 (dd, J=11.4, 2.8 Hz, 1H), 3.38 (s, 2H), 3.02 (br. s., 4H), 2.77-2.88 (m, J=0.8 Hz, 1H), 2.60 (td, J=12.6, 2.5 Hz, 1H), 2.49-2.55 (m, J=3.5, 1.8, 1.8 Hz, 4H), 2.04 (br. d, J=12.6 Hz, 1H), 1.86-1.87 (m, OH), 1.84 (br. s., 1H), 1.64 (br. d, J=12.6 Hz, 1H), 1.32-1.57 (m, 3H), 0.61-0.72 (m, 2H), 0.51-0.61 (m, 2H); [M+H] calc'd for C26H31ClN6O2, 495. found, 495.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[N:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([F:32])=[C:18]([C@:20]23[CH2:28][O:27][C@H:26]([CH2:29][F:30])[C@H:25]2[CH2:24][S:23][C:22]([NH2:31])=[N:21]3)[CH:19]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[OH-].[NH4+]>CCOC(C)=O.O>[NH2:31][C:22]1[S:23][CH2:24][C@@H:25]2[C@@H:26]([CH2:29][F:30])[O:27][CH2:28][C@:20]2([C:18]2[CH:19]=[C:14]([NH:13][C:9]([C:6]3[CH:5]=[N:4][C:3]([CH:2]([F:1])[F:12])=[CH:8][N:7]=3)=[O:11])[CH:15]=[CH:16][C:17]=2[F:32])[N:21]=1
Reactant: O=C(O)c1cnc(C(F)F)cn1
Reactant: NC1=N[C@@]2(c3cc(N)ccc3F)CO[C@H](CF)[C@H]2CS1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: NC1=N[C@@]2(c3cc(NC(=O)c4cnc(C(F)F)cn4)ccc3F)CO[C@H](CF)[C@H]2CS1
Temperature: 42.5 °C
Reaction time: 3 h
Yield: 72.4 %

Procedure:
5-(Difluoromethyl)pyrazine-2-carboxylic acid (30.0 g, 1.05 equiv) and (4aS,5S,7aS)-7a-(5-amino-2-fluorophenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine (49.2 g, 1.00 equiv.) were charged to a reactor and EtOAc (443 mL) was added to the mixture to give a suspension. A solution of ®T3P (105 g, 1.10 equiv, 50 wt % in EtOAc) (Archimica, Germany) was added at ambient temperature while controlling the internal temperature below 30° C. The reaction mixture was stirred at 40-45° C.>3 hours and monitored by HPLC. The reaction mixture was cooled to ambient temperature and water (98 mL) was charged. After 10-15 minutes charged 28% ammonium hydroxide (137 mL) while controlling the temperature below 30° C. Additional EtOAc (172 mL) was added and the reaction mixture was stirred for 30 minutes at ambient temperature. The aqueous phase was separated and back-extracted with EtOAc (246 mL). The organic phases were combined and washed with 15% aq. NaCl (98 mL) and water (98 mL). The organic layer was filtered over Celite (0.5 Wt) and concentrated under vacuum to obtain a beige solid (quantitative crude yield) which was recrystallized from 1-propanol to afford N-(3-((4aS,5S,7aS)-2-amino-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-fluorophenyl)-5-(difluoromethyl)pyrazine-2-carboxamide as a tan solid (54.2 g).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N+:3]=1[O-].[CH2:10]([N:12](CC)CC)C.[Si](C#N)(C)(C)C>C(#N)C>[Br:1][C:2]1[N:3]=[C:4]([C:10]#[N:12])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc[n+]([O-])c1Br
Reactant: CCN(CC)CC
Agent: C[Si](C)(C)C#N
Solvent: CC#N
Product: Cc1ccc(C#N)nc1Br
Temperature: 25 °C
Yield: 33.7 %

Procedure:
To a solution of 2-bromo-3-methylpyridine 1-oxide (compound 350.1, 5.65 g, 30.1 mmol, 1.00 equiv) in acetonitrile (50 mL) were added triethylamine (6.10 g, 60.3 mmol, 2.00 equiv) and TMSCN (8.90 g, 3.00 equiv). The resulting solution was heated to reflux and stiffed overnight in an oil bath, then cooled to ambient temperature and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:5) as eluent to yield 2.00 g (34%) of the title compound as a yellow solid.
Reaction SMILES: C(N1CCC(CN2C3C4C=CC=CC=4N=CC=3N=[C:13]2[CH2:25][O:26][CH2:27]C)(O)CC1)(=O)C.[C:29]([N:32]1[CH2:37][CH2:36][C:35]([CH2:45][N:46]2[C:58]3[C:57]4[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=4[N:51]=[CH:50][C:49]=3[N:48]=[C:47]2[CH2:59]OCC)([O:38][CH2:39][CH2:40][S:41]([CH3:44])(=[O:43])=[O:42])[CH2:34][CH2:33]1)(=[O:31])[CH3:30]>>[C:29]([N:32]1[CH2:33][CH2:34][C:35]([CH2:45][N:46]2[C:58]3[C:57]4[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=4[N:51]=[CH:50][C:49]=3[N:48]=[C:47]2[CH2:59][CH2:27][O:26][CH2:25][CH3:13])([O:38][CH2:39][CH2:40][S:41]([CH3:44])(=[O:42])=[O:43])[CH2:36][CH2:37]1)(=[O:31])[CH3:30]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCN(C(C)=O)CC1
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(OCCS(C)(=O)=O)CCN(C(C)=O)CC1
Product: CCOCCc1nc2cnc3ccccc3c2n1CC1(OCCS(C)(=O)=O)CCN(C(C)=O)CC1
Yield: 13 %

Procedure:
1-Acetyl-4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}piperidin-4-ol (1.80 g, 4.68 mmol) was converted into 1-({1-acetyl-4-[2-(methylsulfonyl)ethoxy]piperidin-4-yl}methyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinoline according to the method described in Part A of Example 13. Purification by flash chromatography (silica gel, eluted with 10% methanol/dichloromethane) yielded 1-({1-acetyl-4-[2-(methylsulfonyl)ethoxy]piperidin-4-yl}methyl)-2-(ethoxyethyl)-1H-imidazo[4,5-c]quinoline (0.30 g, 13%) and recovered starting material, 1-acetyl-4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}piperidin-4-ol (1.20 g).