Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.[C:5]([NH:12][C@H:13]([CH2:18][OH:19])[CH2:14][CH:15]([CH3:17])[CH3:16])([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].CCN(CC)CC>C(Cl)Cl>[C:5]([NH:12][C@H:13]([CH:18]=[O:19])[CH2:14][CH:15]([CH3:16])[CH3:17])([O:7][C:8]([CH3:9])([CH3:11])[CH3:10])=[O:6]
Reactant: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
A solution of sulfur trioxide pyridine complex (7.8 g, 49.1 mmol, 3.0 equiv) in a 1:1 mixture of DMSO and CH2Cl2 (100 mL) was added to a solution of BOC-L-Leucinol (3.56 g, 16.4 mmol. 1 equiv) and Et3N (8 mL) in a 1:1 mixture of DMSO and CH2Cl2 (100 mL) at 0° C. The reaction mixture was stirred at 23° C. for 30 min, then poured into ice water (300 mL), and extracted with Et2O (2×200 mL). The combined organic layers were washed with 0.5M HCl (150 mL), half saturated NaHCO3 (150 mL) and H2O (2×150 mL), then dried over Na2SO4, and concentrated to afford crude BOC-L-Leucinal as pale yellow oil (3.48 g, 99%). This material was used without further purification. 1H NMR (CDCl3) δ 0.92-0.94 (m, 6H), 1.44 (s, 9H), 1.59-1.64 (m, 1H), 1.67-1.85 (m, 2H), (4.21 (m, 1H), 5.12 (s, br, 1H), 9.57 (s, 1H).
Reaction SMILES: Cl.C1(=O)[O:8][C:5]([Cl:7])([Cl:6])[C:4](Cl)([Cl:9])[O:3]1>>[C:4]([Cl:9])(=[O:3])[C:5]([Cl:6])=[O:8].[C:5]([Cl:7])([Cl:6])=[O:8]
Reactant: O=C1OC(Cl)(Cl)C(Cl)(Cl)O1
Agent: Cl
Product: O=C(Cl)C(=O)Cl
Product: O=C(Cl)Cl

Procedure:
Broadly stated, the invention is a process for producing oxalyl chloride comprising: contacting ethylene carbonate with chlorine in a reaction vessel at a temperature in the range of about 70° to 100° C.; continuously circulating the above reaction mixture from the reaction vessel through an illuminated reaction zone of reduced cross-sectional area relative to that of the reaction vessel, and back into the reaction vessel to form tetrachloroethylene carbonate and hydrogen chloride; venting the hydrogen chloride from the reaction vessel; decomposing the tetrachloroethylene carbonate by heating tetrachloroethylene carbonate with a catalytic amount of a tertiary amine or amide to form oxalyl chloride and phosgene gas; and separating the phosgene gas from the oxalyl chloride.
Reaction SMILES: [ClH:1].FC(F)(F)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.BrC1C=CC=CC=1[C:27]([F:30])([F:29])[F:28]>>[ClH:1].[Cl:1][C:4]1[CH:9]=[CH:8][C:7]([C:27]([F:30])([F:29])[F:28])=[CH:6][C:5]=1[NH:10][CH2:11][CH:12]1[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]1
Reactant: FC(F)(F)c1ccccc1NCC1CCNCC1
Reactant: FC(F)(F)c1ccccc1Br
Agent: Cl
Product: FC(F)(F)c1ccc(Cl)c(NCC2CCNCC2)c1
Yield: 47 %

Procedure:
The synthesis of intermediate 1s is conducted starting with 1-bromo-2-trifluoromethyl-benzene following the operating mode for the synthesis of 1r (white solid, total yield 47%). TLC silica gel 60 F 254 Merck, CH2Cl2-MeOH—NH4OH: 90:9:1, Rf=0.23.
Reaction SMILES: [C:1]([N:4]1[CH:8]([C:9]([OH:11])=[O:10])[CH2:7][S:6][CH:5]1[C:12]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:13]=1[OH:19])(=[O:3])[CH3:2].S1CCN[CH2:21]1>>[CH3:21][O:10][C:9]([CH:8]1[CH2:7][S:6][CH:5]([C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:13]=2[OH:19])[N:4]1[C:1](=[O:3])[CH3:2])=[O:11]
Reactant: CC(=O)N1C(C(=O)O)CSC1c1cc(O)ccc1O
Reactant: C1CSCN1
Product: COC(=O)C1CSC(c2cc(O)ccc2O)N1C(C)=O

Procedure:
The procedure described above for preparation of 3-acetyl-2-(2,5-dihydroxyphenyl)-1,3-thiazolidine-4-carboxylic acid (3) was followed to prepare 8, except that the methyl ester of the thiazolidine starting material was employed.
Reaction SMILES: [H-].[K+].NCCCN.[CH2:8]([OH:16])[CH2:9][C:10]#[C:11][CH2:12][CH2:13][CH2:14][CH3:15]>CCCCCC>[CH2:8]([OH:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[CH:15]
Reactant: CCCCC#CCCO
Agent: NCCCN
Agent: [H-]
Agent: [K+]
Solvent: CCCCCC
Product: C#CCCCCCCO
Temperature: 25 °C

Procedure:
Potassium hydride, (35%) in mineral oil (27 g, 240 mmol) under an argon atmosphere was washed with hexane and treated dropwise with 1,3-diaminopropane. The mixture was stirred at room temperature until it became homogeneous. The flask was cooled to 0° C. and 3-octyn-1-ol (10 g, 79 mmol, Lancaster Synthesis) was slowly added. The reaction was then stirred at room temperature for 18 hours. The reaction was quenched with H2O (50 mL) and the product was extracted into ether. The organic layer was washed with 10% HCl and brine and dried (MgSO4). Evaporation gave the captioned product as a colorless oil which was used without further purification: 1H NMR (90 MHz, CDCl3) δ3.65 (t, J=5 Hz, 2H, O--CH2), 2.23 (m, 2H, CH2), 2.0 (m, 1H, acetylenic), 1.7-1.2 (m, 8H, (CH2)4); IR (neat) nmax 3350, 2930, 2125 cm-1.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:18][CH2:19][OH:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.F[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:18][CH2:19][O:20][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCCN(Cc1ccccc1)c1nc2ccccc2s1
Reactant: O=Cc1ccc(F)cc1
Product: O=Cc1ccc(OCCN(Cc2ccccc2)c2nc3ccccc3s2)cc1

Procedure:
The title compound was prepared from 2-(N-(2-benzothiazolyl)-N-benzylamino)ethanol (8.25 g) and 4-fluorobenzaldehyde (3.6 g) by an analogous procedure to that described in Preparation 22.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13](=O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:7]=[CH:6]2.Cl.[CH2:22]([N:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)N)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)C.Cl>[CH2:22]([N:29]1[C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[C:13]1[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCCCCCC(=O)c1ccc2cc(OC)ccc2c1
Reactant: NN(Cc1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCO
Product: CCCCCc1c(-c2ccc3cc(OC)ccc3c2)n(Cc2ccccc2)c2ccccc12
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
1-(6-methoxy-naphthalen-2-yl)heptan-1-one (0.176 kg, 0.651 moles) was dissolved in anhydrous ethanol (1.56 L), 1-benzyl-1-phenylhydrazine hydrochloride (BPH, 0.168 kg, 0.716 moles) was added, a 37% aqueous solution of hydrochloric acid (1.2 g, 12.2 mmoles) was added, and the reaction mixture was heated under reflux for 7 hours. Two portions of BPH (8.4 g, 71.6 mmoles each) were added to the mixture at one hour intervals at 70° C. The temperature of the mixture returned to the reflux temperature after the first BPH addition. Heating was terminated, the reaction mixture was diluted with heptane (1.65 L) followed by water (0.62 kg), and the mixture was stirred for 30 minutes while maintaining the temperature at 45° C. The addition of heptane resulted in the precipitation of solids from the homogeneous organic phase, while the addition of water brought the mixture to a biphasic state with layers in an approximate ratio of 1:1. The bottom layer was drained (pH 1) and the upper layer was washed with water (0.26 kg) while stirring the mixture for 30 minutes. The bottom layer was again drained (pH 3) and the upper layer was cooled to 12° C. in the reactor. All operations subsequent to the quenching step were conducted at 45° C. to prevent premature product crystallization. About 10 grams of the chilled solution were withdrawn from the reactor, subjected to low-temperature crystallization, and returned to the chilled solution as a seeding suspension. The mixture was kept at 12° C. for 30 minutes, cooled to −10° C. over two hours, and stirred at that temperature for 30 minutes. The suspension was filtered, the solids were dried in a nitrogen stream on a filter for 30 minutes, and the solids were vacuumed at 50° C./50 mm Hg to yield 221 g (78%) of the title compound as light-yellow prills with 99.45% ar. HPLC purity.
Reaction SMILES: C(C1C=CC([NH:10][C:11]([C:13]2[NH:14][C:15]3[C:20]([CH:21]=2)=[CH:19][C:18]([O:22][CH3:23])=[CH:17][CH:16]=3)=[O:12])=CC=1)(=O)C.CO[C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)N[C:30](C(O)=O)=[CH:29]2.C(C1C=CC(N)=CC=1)(=O)C.[OH:48][NH:49][C:50]([NH:52][NH2:53])=[NH:51].CC1C=CC(S(O)(=O)=O)=CC=1>>[OH:48][NH:49][C:50]([NH:52][N:53]=[C:29]([C:28]1[CH:27]=[CH:26][CH:34]=[CH:33][C:32]=1[C:19]1[C:18]([O:22][CH3:23])=[CH:17][CH:16]=[C:15]2[C:20]=1[CH:21]=[C:13]([C:11]([NH2:10])=[O:12])[NH:14]2)[CH3:30])=[NH:51]
Reactant: N=C(NN)NO
Reactant: COc1ccc2[nH]c(C(=O)Nc3ccc(C(C)=O)cc3)cc2c1
Reactant: COc1ccc2[nH]c(C(=O)O)cc2c1
Agent: CC(=O)c1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COc1ccc2[nH]c(C(N)=O)cc2c1-c1ccccc1C(C)=NNC(=N)NO

Procedure:
5-Methoxy-1H-indole-2-carboxylic acid (4-acetyl-phenyl)-amide, made from 5-Methoxy-1H-indole-2-carboxylic acid and 4-acetyl phenylamine, and N-hydroxy-N′-aminoguanidine PTSA salt, prepared by following method discussed in Tai, et al. (J. Med. Chem. (1983) 26:1326-1329) were combined according to synthetic scheme, to obtain the pure product after purification by reverse phase HPLC: tR 20.5 min (20-60% CH3CN in H2O, 25 min); MS (m/z) 381 (MH+).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:10]=[CH:9][S:8][CH:7]=1.[Cl:11][C:12]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:13]=1[C:14](Cl)=[O:15].Cl>C(Cl)Cl>[Cl:5][C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:14]([C:13]1[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:12]=1[Cl:11])=[O:15]
Reactant: Clc1ccsc1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1cc([N+](=O)[O-])ccc1Cl)c1sccc1Cl
Yield: 44 %

Procedure:
To a mixture of aluminum chloride (1.33 g, 0.0102 mol) and methylene chloride is added 3-chlorothiophene (1.21 g, 0.0102 mol) dropwise. The resultant mixture is stirred 30 minutes and treated with a solution of 2-chloro-5-nitrobenzoyl chloride (2.20 g, 0.0100 mol) in methylene chloride. The resultant mixture is stirred overnight at room temperature, poured into ice, acidified with concentrated hydrochloric acid and extracted twice with methylene chloride. The combined organic layers are washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to a brown oil. Trituration with ether affords the title compound as a brown solid (1.33 g, 44.0%, mp 114-116° C.) which is identified by NMR spectral analysis.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([C@@H:15]([CH3:31])[C:16](N2[C@H]3C4C=CC=CC=4C[C@H]3OC2=O)=[O:17])[NH:13][C:12]1=[O:32])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH2:33].OO.[OH-].[Na+].O>CO.O>[Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([C@@H:15]([CH3:31])[C:16]([OH:17])=[O:33])[NH:13][C:12]1=[O:32])[CH3:10])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: O
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)N1C(=O)O[C@@H]2Cc3ccccc3[C@@H]21
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)O
Yield: 89 %

Procedure:
To a solution of 3-{(2R)-2-[(3S,4R)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidin-4-yl)propionyl}-(3aS-cis)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-2-one (308 mg) dissolved in a methanol-water solvent mixture (2:1, 3 ml), 30% hydrogen peroxide water (0.15 g, 1.35 mmol) was added at room temperature. To the resulting mixture, a 28% aqueous solution of sodium hydroxide (0.12 g, 0.81 mmol) was added dropwise at the same temperature. Stirring was continued until the full consumption of the starting material was confirmed by HPLC. After the completion of the reaction, cool water (10 ml) was added to the reaction mixture. After washing with methylene chloride (5 ml), the pH of the mixture was adjusted to 2 with 35% hydrochloric acid. The crystals so precipitated were collected by filtration, washed with water and then dried, whereby 160 mg (β:α=96:4) of the colorless title compound was obtained (yield: 89%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([N:9]2[C:14]([CH3:16])([CH3:15])[CH2:13][CH:12]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:11][C:10]2([CH3:25])[CH3:24])[N:3]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>O>[O:29]1[CH2:30][CH2:31][N:26]([C:2]2[N:7]=[C:6]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[N:5]=[C:4]([N:9]3[C:14]([CH3:16])([CH3:15])[CH2:13][CH:12]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:11][C:10]3([CH3:25])[CH3:24])[N:3]=2)[CH2:27][CH2:28]1
Reactant: C1COCCN1
Reactant: CCCCCCOC1CC(C)(C)N(c2nc(Cl)nc(Cl)n2)C(C)(C)C1
Solvent: O
Product: CCCCCCOC1CC(C)(C)N(c2nc(N3CCOCC3)nc(N3CCOCC3)n2)C(C)(C)C1

Procedure:
9.7 g of the product from Example 10 are heated under reflux for 3 hours with 50 ml of morpholine. The orange reaction mixture is poured into water. The crude product precipitating during this is dissolved in ethyl acetate and purified chromatographically on an SiO2 column. The purified product is a viscous material.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[CH2:10]([O:12][C:13](=[O:17])[C:14]#[C:15][CH3:16])[CH3:11].N12CCCN=C1CCCCC2>O1CCCC1>[CH2:10]([O:12][C:13](=[O:17])[CH:14]=[C:15]([O:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH3:16])[CH3:11]
Reactant: CC#CC(=O)OCC
Reactant: COc1ccc(O)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOC(=O)C=C(C)Oc1ccc(OC)cc1
Temperature: 130 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
A mixture of 4-methoxy-phenol (1.10 g, 8.91 mmol) and ethyl-2-butynoate (2.0 g, 17.8 mmol) in tetrahydrofuran (13.7 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (1.33 mL, 8.91 mmol). The reaction was then heated at 130° C. for 1.5 h. At this time, the reaction was cooled to 25° C. and was stirred at 25° C. overnight. At this time, the reaction was concentrated in vacuo. The residue was dissolved in dichloromethane (40 mL) and was washed with a 2N aqueous hydrochloric acid solution (1×100 mL), a 1N aqueous sodium hydroxide solution (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL). The organics were then dried over sodium sulfate, filtered, rinsed with dichloromethane and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 10-20% ethyl acetate/hexanes) afforded 3-(4-methoxy-phenoxy)-but-2-enoic acid ethyl ester (0.99 g, 47%) as a clear oil: HR-ES-MS m/z calculated for C13H16O4 [M+H]+ 237.1122, observed 237.1121; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.11 (t, J=7.0 Hz, 3H), 2.41 (s, 3H), 3.76 (s, 3H), 3.98 (q, J=7.0 Hz, 2H), 4.63 (s, 1H), 6.99 (d, J=9.1 Hz, 2H), 7.05 (d, J=9.1 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[C:11]([Cl:18])[CH:12]=[CH:13][CH:14]=2)[CH:9]=1)[C:5]([OH:7])=O.ClCl.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.[NH2:43][CH:44]1[C:55](=[O:56])[N:46]2[C:47]([C:52]([OH:54])=[O:53])=[C:48]([CH3:51])[CH2:49][S:50][C@H:45]12.C[Si](N([Si](C)(C)C)C(=O)C(F)(F)F)(C)C>ClCCl.CO>[CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[C:11]([Cl:18])[CH:12]=[CH:13][CH:14]=2)[CH:9]=1)[C:5]([NH:43][CH:44]1[C:55](=[O:56])[N:46]2[C:47]([C:52]([OH:54])=[O:53])=[C:48]([CH3:51])[CH2:49][S:50][C@H:45]12)=[O:7]
Reactant: CON=C(C(=O)O)c1ccc2cccc(Cl)c2c1
Reactant: CC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: C[Si](C)(C)N(C(=O)C(F)(F)F)[Si](C)(C)C
Agent: ClCl
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C)CS[C@H]12)c1ccc2cccc(Cl)c2c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Four hundred twenty milligrams of α-methoxyimino-α-(8-chloro-2-naphthyl)acetic acid were converted to the acid chloride by reaction with excess chlorine and 500 mg of triphenyl phosphite in 20 ml of dichloromethane. The reaction mixture was added in one portion to a stirred solution of 350 mg of 7-amino-3-methyl-3-cephem-4-carboxylic acid in 5 ml of dichloromethane containing 2 ml of bis(trimethylsilyl)trifluoroacetamide. The reaction mixture was stirred at 25° C. for six hours and then diluted by addition of 20 ml of methanol. The solvent was removed by evaporation under reduced pressure to provide 7-[α-methoxyimino-α-(8-chloro-2-naphthyl)acetamido]-3-methyl-3-cephem-4-carboxylic acid. The product thus formed is dissolved in formic acid containing zinc metal dust to give, following isolation and purification, 7-(8-chloro-2-naphthyl)glycylamido-3-methyl-3-cephem-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:12]([NH2:14])[CH3:13]>>[CH2:12]([NH:14][C:4](=[O:5])[C:3]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:2]=1[Cl:1])[CH3:13]
Reactant: O=C(Cl)c1cc(Cl)ccc1Cl
Reactant: CCN
Product: CCNC(=O)c1cc(Cl)ccc1Cl
Yield: 84.5 %

Procedure:
2,5-Dichlorobenzoyl chloride (51 mmol) and 70% aq EtNH2 (130 mmol) were combined according to General Method E1 to afford 9.4 g of N-ethyl-2,5-dichlorobenzamide as a beige solid, an 85% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][N:25]=1>CC#N>[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6](=[O:15])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:29])=[CH:26][N:25]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.7 %

Procedure:
To solution of (2-amino-phenyl)-carbamic acid tert-butyl ester (22) (Seto, C. T.; Mathias, J. P.; Whitesides, G. M.; J. Amer. Chem. Soc., (1993), 115, 1321-1329.) (1.56 g, 7.49 mmol) in MeCN (40 mL) is added triethylamine (2.60 mL, 18.7 mmol) and 6-chloronicotinic acid (1.42 g 8.99 mmol). The mixture is stirred for 18 h at r.t. Upon completion of the reaction, the solvent is removed in vacuo and the residue is partitioned between EtOAc and an NH4Cl solution. The organic phase is collected and the aqueous layer is then extracted with EtOAc; the combined organic layers are washed with brine, dried over MgSO4 and evaporated. The residue is purified by flash chromatography using EtOAc/Hexane (a gradient of 20:80 to 50:50) as an eluent, to afford the title compound 94 (2.39 g, 92% yield). 1H NMR (DMSO-d6) δ(ppm): 10.01 (s, 1H), 8.96 (d, J=2.0 Hz, 1H), 8.71 (s, 1H), 8.35 (dd, J=8.4, 2.4 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.22 (td, J=7.8, 1.4 Hz, 1H), 7.13 (t, J=7.6 Hz, 1H), 1.44 (s, 9H). LRMS (ESI): (calc) 347.10 (found) 370.1 (M+Na+).
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][C:18]([C:20]4[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=4)[CH:23]=O)=[CH:19][C:14]3=[N:13][CH:12]=2)[CH:8]=[C:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:6]=1)([CH3:3])[CH3:2].[CH2:34]([NH2:36])[CH3:35].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(Cl)Cl>[CH2:34]([NH:36][CH2:23][C:22]1[CH:21]=[C:20]([C:18]2[CH:17]=[CH:16][N:15]3[C:11]([C:9]4[CH:8]=[C:7]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:6]=[C:5]([NH:4][CH:1]([CH3:2])[CH3:3])[CH:10]=4)=[CH:12][N:13]=[C:14]3[CH:19]=2)[CH:27]=[CH:26][CH:25]=1)[CH3:35]
Reactant: CCN
Reactant: CC(C)Nc1cc(-c2cnc3cc(-c4cccc(C=O)c4)ccn23)cc(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CCNCc1cccc(-c2ccn3c(-c4cc(NC(C)C)nc(-c5ccccc5)c4)cnc3c2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-[3-(2-isopropylamino-6-phenyl-pyridin-4-yl)-imidazo[1,2-a]pyridin-7-yl]-benzaldehyde (Ex. 1.186) (1 eq, 0.055 mmol, 30 mg) in MeOH (2 ml) is added ethyl amine (10 eq, 0.55, 0.27 ml) and acetic acid (2 eq, 0.11 mmol, 6.59 mg) and the reaction mixture is stirred at room temperature for 30 min. After this time sodium triacetoxyborohydride (5 eq, 0.27 mmol, 58.2 mg) is added to the reaction mixture and is stirred for a further 2 h. The reaction is diluted with CH2Cl2 and the organic phase is washed with NaHCO3. The aqueous layer is further extracted with EtOAc. The combined organic layers are washed with brine, dried over MgSO4, filtered and the solvent removed in vacuo. The reaction mixture is purified by flash column chromatography eluting with 8:2 DCM/MeOH to yield {4-[7-(3-ethylaminomethyl-phenyl)-imidazo[1,2-a]pyridin-3-yl]-6-phenyl-pyridin-2-yl}-isopropyl-amine as a light yellow solid; [M+H]+=462
Reaction SMILES: [CH2:1]=O.N[C:4]1[CH:5]=[C:6]([CH:19]=[C:20]([O:22][CH2:23][CH2:24][C:25]2[S:29][CH:28]=[N:27][C:26]=2[CH3:30])[CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][N:11]=1)=[O:8].[C:31]([BH3-])#[N:32].[Na+]>CO>[CH3:1][N:32]([CH3:31])[C:4]1[CH:5]=[C:6]([CH:19]=[C:20]([O:22][CH2:23][CH2:24][C:25]2[S:29][CH:28]=[N:27][C:26]=2[CH3:30])[CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][N:11]=1)=[O:8]
Reactant: Cc1ncsc1CCOc1cc(N)cc(C(=O)Nc2ccc(C(=O)O)cn2)c1
Reactant: C=O
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1ncsc1CCOc1cc(C(=O)Nc2ccc(C(=O)O)cn2)cc(N(C)C)c1
Reaction time: 40 h
Yield: 19 %

Procedure:
Formaldehyde (37% wt. in water) (0.021 ml, 0.75 mM) was added to a solution of 2-[3-amino-5-(4-methyl-thiazol-5-yl) ethoxy benzoyl]amino-5-pyridine carboxylic acid (0.10 g 0.25 mM) and 4A molecular sieves (0.25 g) in methanol (15 ml), under an inert atmosphere at room temperature. After 1 hr sodium cyanoborohydride (0.019 g, 0.3 mM) was added and the reaction mixture stirred for 40 hrs. The reaction mixture was filtered, concentrated in vacuo, 2M NaOH added to pH=11–12 then acidified with 2M HCl to precipitate a solid. The solid was filtered, washed with water, dried and purified on silica gel (5% to 12% MeOH/DCM) to give the title compound as a pale yellow solid (0.020 g, 19%); 1H NMR δ (d6-DMSO): 2.36 (s, 3H), 2.95 (m, 2H), 4.19 (dd, 2H), 6.39 (s, 1H), 6.92 (m, 2H), 6.99 (s, 1H), 8.27 (s, 2H), 8.83 (s, 1H), 8.88 (s, 1H), 11.02 (bs, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[NH2:12].Cl.[N:14]1([CH2:19][C:20](O)=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[NH:12][C:20](=[O:21])[CH2:19][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COc1cc([N+](=O)[O-])ccc1N
Reactant: O=C(O)CN1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc([N+](=O)[O-])ccc1NC(=O)CN1CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.3 %

Procedure:
Dissolve 2-methoxy-4-nitro-phenylamine (1.0 g, 5.95 mmol), pyrrolidin-1-yl-acetic acid hydrochloride (0.99 g, 5.95 mmol) and N,N-diisopropylethylamine (1.08 mL, 6.55 mmol) in N,N-dimethylformamide (20 mL) and add O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (2.49 g, 6.55 mmol). Stir the mixture at room temperature for 16 h. Dilute the mixture with water (50 mL) and extract with dichloromethane (3×25 mL). Dry the combined organics (Na2SO4), filter, and concentrate in vacuo. Purify by chromatography (0% to 4% MeOH/CH2Cl2) to afford 0.77 g (46%) of the title compound. MS/ES m/z 280.0 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][NH:5][CH:4]=1)#[N:2].[C:14](OC(=O)C)(=[O:16])[CH3:15]>O>[C:14]([N:5]1[CH:6]=[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:3]([C:1]#[N:2])=[CH:4]1)(=[O:16])[CH3:15]
Reactant: N#Cc1c[nH]cc1-c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)n1cc(C#N)c(-c2ccccc2)c1

Procedure:
4 g of 3-cyano-4-phenylpyrrole (Compound No. 8) was added to 20 ml of acetic anhydride and heated for 4 hours in oil-bath of 140°-150° C. After cooling, the resulting reaction mixture was poured into about ten-times volume of cold water to decompose excess acetic anhydride. The resulting precipitate was filtrated, washed with water and dried to obtain 4.5 g of crystal. The crystal was recrystallized from methyl alcohol to obtain 3 g of the desired product.