Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH:8][C:9]2[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11](O)=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].O=P(Cl)(Cl)[Cl:20]>>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:10]([C:11]([Cl:20])=[C:6]2[CH:5]=[N:4]1)=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCn1nccc1Nc1ccccc1C(=O)O
Product: CCn1ncc2c(Cl)c3ccccc3nc21
Temperature: 0 °C
Yield: 68.3 %

Procedure:
A mixture of N-(1-ethylpyrazol-5-yl)anthranilic acid (278 g, 1.2 mol) and POCl3 (550 g, 3.6 mol) was refluxed for 3 hours. The reaction mixture was cooled and then was poured into ice/water (3-4 L) . A solid formed which was collected by filtration and washed with water. The filtrate was extracted with CH2Cl2 (1 L) and the CH2Cl2 layer was evaporated to about 50 ml and both this solution and the previously isolated solid were purified by column chromatography on silica gel eluting with CH2Cl2 to afford 190 g (68%) of 1-ethyl-4-chloro-1H-pyrazolo[3,4-b]quinoline.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([NH2:19])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:12])[CH3:11].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[CH3:11][C:10]([NH:19][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(N)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(NC(=O)c1ccccc1)c1ccccc1
Yield: 97.6 %

Procedure:
In a similar manner to Step 1 of Example 16, benzoyl chloride (10.0 g, 71.1 mmol) was dissolved in dichloromethane (200 mL), and the solution was treated with cumylamine (11.3 mL, 78.3 mmol), triethylamine (14.9 mL, 107 mmol) and DMAP (870 mg, 7.11 mmol), followed by purification by slurry using diisopropylether to obtain N-(1-methyl-1-phenylethyl)benzamide (16.6 g, yield 98%).
Reaction SMILES: O1CCCCC1[O:7][CH:8]([C:14]([O-:16])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10].Cl.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24]Cl)[CH:19]=1.[CH3:26][CH2:27]O>>[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][C:8]([OH:7])([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:14]([O:16][CH2:26][CH3:27])=[O:15])[CH:19]=1
Reactant: CCOC(=O)C(OC1CCCCO1)C(=O)[O-]
Reactant: ClCc1cccnc1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C(O)(Cc1cccnc1)C(=O)OCC
Reaction time: 1 h

Procedure:
4.3 g of ethyl 2-(2-tetrahydropyranyloxy)-1,3-propanedioate are added to 11 ml of a Na ethoxide solution (prepared from 0.72 g of Na) under stirring, shielding from humidity, keeping the temperature at 0° to 5° C. After 1 h, a solution of 2.4 g of 3-pyridylmethyl chloride hydrochloride in 8 ml of EtOH is dropped therein. The reaction mixture, which turns suddenly red, is kept under stirring at r.t. for 24 hours more. EtOH is evaporated off and the residue is partitioned between AcOEt and a 20% solution of monobasic potassium phosphate in water. The organic phase is separated, evaporated to dryness and the residue (about 4 g) is dissolved with 16 ml of 2N HCl, keeping r.t. for 4 hours; ethyl tartronate is removed by extraction with AcOEt. From the aqueous phases after alkalization to pH 8-8.5, subsequent extraction with AcOEt, the usual work up of the organic extract and subsequent chromatography on silica gel, 1.8 g of ethyl 3-(pyrid-3-yl)-2-hydroxy-2-ethoxycarbonyl-propanoate are obtained, oil, I.R.: 3500, 3000, 1740, 1590 cm-1, TLC (SiO2 : one spot Rf : 0.24 eluent AcOEt), H-NMR(CDCl3) δ (TMS): 1.2-1.3 t, 3.3 s , 4.15-4.3 q, 7.1-7.2 q, 7.6-7.65 m, 8.4-8.5 m.
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].[CH3:12][N:13]([CH2:15][C:16]1[N:17]([C:21]2[CH:22]=[C:23]([NH:31][C:32](=[O:51])[C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[C:35](C#CC4N5C=CN=CC5=NC=4)[CH:34]=3)[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=2)[CH:18]=[CH:19][N:20]=1)[CH3:14].CCN(C(C)C)C(C)C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:14][N:13]([CH2:15][C:16]1[N:17]([C:21]2[CH:22]=[C:23]([NH:31][C:32](=[O:51])[C:33]3[CH:34]=[CH:35][C:36]([CH3:39])=[C:37]([C:2]#[C:1][C:3]4[N:7]5[CH:8]=[CH:9][CH:10]=[CH:11][C:6]5=[N:5][CH:4]=4)[CH:38]=3)[CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=2)[CH:18]=[CH:19][N:20]=1)[CH3:12]
Reactant: C#Cc1cnc2ccccn12
Reactant: Cc1ccc(C(=O)Nc2cc(-n3ccnc3CN(C)C)cc(C(F)(F)F)c2)cc1C#Cc1cnc2cnccn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2cc(-n3ccnc3CN(C)C)cc(C(F)(F)F)c2)cc1C#Cc1cnc2ccccn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-ethynylimidazo[1,2-a]pyridine (0.032 g, 0.22 mmol) in anhydrous DMF (1.26 mL) was added N-(3-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide (prepared as in Example 3), Pd(PPh3)4 (0.013 g, 0.011 mmol), Cul (0.0032 mg, 0.0165 mmol) and DIPEA (0.064 mL, 0.44 mmol). The solution was degassed with argon for 15 minutes then stirred overnight at rt. The solvent was removed and the resultant residue was chromatographed over silica gel eluting initially with EtOAc and then with methanol/methylene chloride (5:95) to furnish the desired product: (0.07 g, 59%) MS (M+H)+ 542.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6](O)=[CH:5][CH:4]=1)[CH3:2].[CH2:10]([O:12][CH:13]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:11].N(C(N1CCCCC1)=O)=NC(N1CCC[CH2:33][CH2:32]1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:10]([O:12][CH:13]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:2][CH2:1][C:3]2[CH:8]=[CH:7][C:6]([CH2:32][CH3:33])=[CH:5][CH:4]=2)=[CH:24][CH:25]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:11]
Reactant: CCc1ccc(O)cc1
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Reactant: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccc(OCCc2ccc(CC)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.1 %

Procedure:
4-Ethyl-phenyl alcohol (0.45 g, 3 mmol) and ethyl 2-ethoxy-3-(4-hydroxyphenyl)propanoate (0.86 g, 3.6 mmol) were mixed in dichloromethane (15 ml). 1,1′-(Azodicarbonyl)dipiperidine (0.91 g, 3.6 mmol) and triphenylphosphine (0.95 g, 3.6 mmol) were then added respectively. The mixture was stirred at room temperature overnight and filtered. The filtrate was evaporated to dry in vacuum. Column chromatography of the residue on silica gel using ethyl acetate/heptane (gradient 10:90 to 50:50) as eluant gave 0.49 g desired product, yield 44%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9](=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:35][S:36][CH2:37][CH2:38]O.CCOC(/N=N/C(OCC)=O)=O>O>[CH3:35][S:36][CH2:37][CH2:38][O:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9](=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[N:6][CH:7]=1
Reactant: CSCCO
Reactant: CCCCCC(=O)Nc1ncc(O)cn1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: CCCCCC(=O)Nc1ncc(OCCSC)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
N-(5-Hydroxypyrimidin-2-yl)hexanamide (8.18 g, 39 mmol) and triphenylphosphine (20.5 g, 78 mmol) were mixed, and dried under reduced pressure, and then the atmosphere was substituted with argon. These substances were dissolved by heating in anhydrous N,N-dimethylformamide (80 mL), and the solution was cooled to room temperature, and then added with 2-methylthioethanol (5.40 g, 58.6 mmol). The reaction mixture was added with DEAD (2.2 M solution in toluene, 26.6 mL, 58.6 mmol) on an ice bath, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added with water (300 mL), and the mixture was stirred for 15 minutes, and then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, the resulting residue was dissolved in saturated ammonia in methanol (60 mL), and the solution was left at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1→hexane:acetone=2:1), the eluate was concentrated under reduced pressure, and the resulting residue was dissolved in chloroform by heating. The crystals obtained by ice cooling of the solution were removed, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from chloroform-hexane to obtain N-{5-[2-(methylthio)ethoxy]pyrimidin-2-yl}hexanamide (6.80 g, 61%) as a pale dark brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20](O)=[O:21])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[NH2:23][N:24]1[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([NH:23][N:24]3[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26][CH2:25]3)=[O:21])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: NN1CCC(O)CC1
Product: O=C(NN1CCC(O)CC1)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chlorophenyl)-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAN 1018782-82-5) and 1-amino-4-piperidinol (CAN 79414-82-7) as starting materials; LC-MS (UV peak area/ESI) 97.7%, 430.1150 (M+H)+.
Reaction SMILES: N[C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=2)=[CH:4][N:3]=1.C(=O)(O)O.[NH2:22][C:23]([NH2:25])=[NH:24]>CN(C)C(=O)C>[NH2:24][C:23]1[N:25]=[C:8]([NH2:9])[C:7]2[C:2](=[N:3][CH:4]=[C:5]([C:10]3[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=3)[N:6]=2)[N:22]=1
Reactant: N=C(N)N
Reactant: N#Cc1nc(-c2cc(Cl)cc(Cl)c2)cnc1N
Agent: O=C(O)O
Solvent: CC(=O)N(C)C
Product: Nc1nc(N)c2nc(-c3cc(Cl)cc(Cl)c3)cnc2n1

Procedure:
This compound is prepared in a manner analogous to that of Step B of Example 4, using 0.8 gram (0.003 mole) of 2-amino-3-cyano-5-(3,5-dichlorophenyl)pyrazine and 1.3 grams (0.007 mole) of guanidine carbonate in 10 mL of N,N-dimethylacetamide, yielding 2,4-diamino-6-(3,5-dichlorophenyl)pteridine.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[CH:17]1[C:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=2[CH:20]=[CH:19][C:18]=1[NH2:27]>>[CH:17]1[C:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=2[CH:20]=[CH:19][C:18]=1[NH:27][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3
Reactant: Nc1ccc2c(c1)CCCC2
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Product: O=c1[nH]c2ncccc2c2cc(Nc3ccc4c(c3)CCCC4)ccc12
Yield: 65.2 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 231 using 6 (50 mg, 0.22 mmol) and 5,6,7,8-tetrahydro-2-naphthylamine (96 mg; 0.65 mmol) to provide 248 (49 mg, 27% yield) as a brown solid. LC-MS (M+H (parent)=343, obsd.=343).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=4)[CH:15]=[CH:16][CH:17]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:32](Cl)(=[O:34])[CH3:33].C(N(CC)CC)C>O1CCCC1>[C:32]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:27])[CH3:28])[CH:21]=4)[CH:15]=[CH:16][CH:17]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1)(=[O:34])[CH3:33]
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(N)sc4c3)c2)c1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)c4cccc(C(C)(C)C#N)c4)c3)cc2s1
Yield: 46.2 %

Procedure:
Using N-{3-[(2-amino-1,3-benzothiazol-6-yl)oxy]phenyl}-3-(1-cyano-1-methylethyl)benzamide (100 mg, 0.23 mmol) produced in Example A12(iv), tetrahydrofuran (20 mL), acetyl chloride (0.12 mL, 1.69 mmol) and triethylamine (1.0 mL, 7.18 mmol) as starting materials, and in the same manner as in Example A38, the title compound (50 mg, 46%) was obtained as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5]2.[CH3:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([C:29]4[CH:28]=[CH:27][CH:26]=[C:25]([CH3:24])[CH:30]=4)=[CH:10][CH:9]=3)[CH:5]=[C:6]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2n1Cc1ccc(C)cc1
Reactant: Cc1cccc(B(O)O)c1
Product: CCOC(=O)c1cc2cc(-c3cccc(C)c3)ccc2n1Cc1ccc(C)cc1

Procedure:
The title compound was prepared from ethyl 5-bromo-1-(4-methylbenzyl)-1H-indole-2-Carboxylate (step 1 of Example 1) and 3-methylphenylboronic acid in substantially the same manner, as described in step 2 of Example 1. The product was obtained as a solid. Mass spectrum (ESI, [M+H]+) m/z 384. 1H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.63 (d, 1H, J=7.70 Hz), 7.60 (d, 1H, J=8.47 Hz), 7.48 (s, 1H), 7.44 (d, 1H, J=7.95 Hz), 7.39 (s, 1H), 7.33 (t, 1H, J=7.63 Hz), 7.14 (d, 1H, J=7.49 Hz), 7.07 (d, 2H, J=7.94 Hz), 6.93 (d, 2H, J=7.94 Hz), 5.82 (s, 2H), 4.29 (q, 2H, J=7.17 Hz), 2.37 (s, 3H), 2.21 (s, 3H), and 1.30 ppm (t, 3H, J=7.18 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)([CH2:13][CH2:14][OH:15])[CH2:9]1)=[O:7].ClCCl.N1C=CC=CC=1.[C:40](OC(=O)C)(=[O:42])[CH3:41]>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)([CH2:13][CH2:14][O:15][C:40](=[O:42])[CH3:41])[CH2:9]1)=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(C(=O)N2CCC(CCO)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCC(CCOC(C)=O)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reaction time: 2 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine (4.5 g 9.9 mmol) and dichloromethane/pyridine (70 mL, 6/1). Add acetic anhydride (1.04 mL, 11.0 mmol) and 4-dimethylaminopyridine (50 mg, 0.41 mmol). After 2 hours, concentrate the reaction mixture in vacuo to obtain a residue. Dissolve the residue in ethyl acetate and extract with 1M hydrochloric acid solution (2×200 mL), saturated sodium bicarbonate solutions and saturated sodium chloride solution. Dry the organic layer over MgSO4, filters and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with ethyl acetate to give 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-acetoxyethyl)pyrrolidine: Rf =0.38 (silica gel, ethyl acetate). Elemental Analysis calculated for C24H27Cl2NO6 : C 58.07; H 5.48; N 2.82; Found: C 57.67; H 5.46; N 2.84.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH:8]=[CH:9][N:10]([C:11]([C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:20])=[O:12])[C:6]=2[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:30])[CH3:29].C(OCC)(=O)C>O1CCCC1>[Cl:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=1[C:11]([N:10]1[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:28](=[O:30])[CH3:29])[C:7]=2[CH:8]=[CH:9]1)=[O:12]
Reactant: CC(=O)Cl
Reactant: Nc1nccc2c1ccn2C(=O)c1c(Cl)cccc1Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nccc2c1ccn2C(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
To an ice-cooled solution of (4-amino-1H-pyrrolo[3,2-c]pyridin-1-yl)(2,6-dichlorophenyl) methanone (50 mg, 0.16 mmol) and triethylamine (0.05 ml, 0.32 mmol) in tetrahydrofuran (5 mL) was added acetyl chloride (0.01 ml, 0.15 mmol) drop wise and stirred at room temperature for about 1 hour. Ethyl acetate was added and washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate and concentrated. The residue was taken up in methanol (5 mL), potassium carbonate (50 mg) was added and stirred for 10 minutes. The solvent was removed on a rotary evaporator at 20° C. and the residue was dissolved in dichloromethane, washed with water and brine, dried and concentrated to afford the crude product. Purification by silica gel column chromatography using ethyl acetate and dichloromethane gradient as eluent yielded N-[1-(2,6-dichlorobenzoyl)-1H-pyrrolo[3,2-c]pyridin-4-yl]acetamide (45 mg, 81%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:6]=[CH:7][CH:8]=1)#[CH:2].Br[C:20]1[CH:21]=[N:22][CH:23]=[C:24]([CH:37]=1)[C:25]([N:27]=[S@@:28]([CH3:36])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].CCN(CC)CC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CCOC(C)=O>[CH3:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:10]([NH:9][C:5]1[CH:4]=[C:3]([C:1]#[C:2][C:20]2[CH:21]=[N:22][CH:23]=[C:24]([CH:37]=2)[C:25]([N:27]=[S@@:28]([CH3:36])(=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH:8]=[CH:7][CH:6]=1)=[O:18]
Reactant: C[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Reactant: C#Cc1cccc(NC(=O)c2ccccc2C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=[S@@](C)(=O)c3ccccc3)c2)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 83.1 %

Procedure:
In a 4 mL vial, N-(3-ethynylphenyl)-2-methylbenzamide (0.104 g, 0.443 mmol) and (S)-5-bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (0.100 g, 0.295 mmol) were added and dissolved into EtOAc (2 mL) The mixture was then degassed for ˜20 min after which NEt3 (0.141 mL, 1.035 mmol) was added followed by Pd(PPh3)2Cl2 (21.0 mg, 0.030 mmol) and CuI (2.9 mg, 0.016 mmol). The reaction mixture was allowed to stir at 50° C. for 4 hours after which the reaction mixture was partitioned between EtOAc (4 mL) and water (4 mL). The organic extracts were combined, dried over anhydrous Na2SO4 and concentrated. The residue as purified by chromatography (silica gel, gradient elution 25% EtOAc/Hexanes EtOAc). The product containing fractions were concentrated to give the title compound as a solid (121 mg, 83%).
Reaction SMILES: [H][H].[C]=O.[CH3:5][CH:6]=[CH:7][CH2:8][CH2:9][CH3:10].[CH:11](=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]C>[Rh].O>[CH3:5][CH:6]=[CH:7][CH2:8][CH2:9][CH3:10].[CH2:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCC=O
Reactant: [H][H]
Agent: [Rh]
Agent: CC=CCCC
Agent: [C]=O
Solvent: O
Product: C=CCCCC
Temperature: 100 °C
Reaction time: 3 h

Procedure:
20 parts by volume of the rhodium catalyst solution prepared as described in Example B are mixed with 800 parts by volume of polyethylene glycol 400 having a water content of 2% and are introduced into an autoclave whose gas space is then filled with an equimolar mixture of hydrogen and carbon monoxide under a total pressure of 80 bar. The solution is heated while stirring to 100° C., this temperature is held for another three hours while continuing to stir and while maintaining the pressure of 80 bar and 800 parts by volume of 2-hexene are then added while maintaining these reaction conditions, the reaction mixture is stirred for another two hours at 100° C. and 80 bar and, after cooling and venting the autoclave, the reaction mixture obtained is transferred to a phase separator in which the aldehyde phase having a heptanal content of 96% is separated off. As a result of the partial isomerization of 2-hexene to 1-hexene, this gives a mixture of 1-heptanal and 2-heptanal in a mixing ratio of 0.83. The yield of heptanal mixture is 96% of theory.
Reaction SMILES: [CH2:1]([OH:12])[C@H:2]([C@H:4]([C@@H:6]([C@@H:8]([CH2:10][OH:11])[OH:9])[OH:7])[OH:5])[OH:3].CO[C:15](OC)([CH3:17])[CH3:16].C(=O)(O)[O-].[Na+].O1C[CH2:28][CH2:27][CH2:26]1>CN(C)C=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:16][C:15]1([CH3:17])[O:9][C@@H:8]([C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]2[O:3][C:27]([CH3:28])([CH3:26])[O:12][CH2:1]2)[CH2:10][O:11]1
Reactant: C1CCOC1
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H]([C@@H](O)[C@H](O)[C@H]2COC(C)(C)O2)O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.3 %

Procedure:
To a stirring suspension of D-Mannitol (1.82 g, 10.0 mmol) in tetrahydrofuran (21 mL) and dimethylformamide (9 mL) was added p-toluenesulfonic acid monohydrate (0.02 g, 0.1 mmol,) at ambient temperature, followed by 2,2-dimethoxypropane (2.8 mL, 0.023 mol). The reaction mixture was stirred for 18 hours at room temperature, then additional 2,2-dimethoxypropane (0.3 mL, 2.4 mmol) was added. The suspension was heated to 40° C. to 45° C., and stirred for 2 hours. Sodium bicarbonate (1.8 g, 0.016 mol) was added to neutralize the acid and the mixture was stirred for 30 minutes. The excess Na2CO3 was filtered and washed with tetrahydrofuran (5 mL). The filtrate was concentrated. To the remaining light yellow oil was added toluene (15 mL) and the mixture was stirred at 3° C. to 5° C. until a light-yellow gelatinous solid formed. The solid was filtered and washed with hexane (2×5 mL). The product was dried in a vacuum oven for 18 hours to give 1,2:5,6-di-O-isopropylidene-D-mannitol (1.24 g, 47.3%) as an off-white solid, mp 110-113° C. Step B: Preparation of (S)-(+)-(2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].O=S(Cl)Cl.[NH3:16]>ClCCCl.CN(C=O)C>[F:1][C:2]1[N:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:16])=[O:5]
Reactant: O=C(O)c1ccc(F)nc1F
Reactant: N
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: NC(=O)c1ccc(F)nc1F
Temperature: 0 °C
Yield: 77136.1 %

Procedure:
A solution 2,6-difluoronicotinic acid (7.4 g, 0.046 mmol) and SOCl2 (20 mL) in 1,2-dichloroethane (60 mL) containing DMF (1 drop) is heated under reflux for 4 h, then concentrated to dryness under reduced pressure. The residue is dissolved in Et2O (100 mL), cooled to 0° C., and treated dropwise with concentrated ammonia (10.0 mL, 0.17 mmol). After 10 min the solution is washed with aqueous NaHCO3 and worked up to give 2,6-difluoronicotinamide (5.61 g, 76%). 1H NMR (CDCl3) δ 8.70 (1H, dd, J=9.6, 8.3 Hz), 7.00 (1H, ddd, J=8.3, 2.9, 1.1 Hz), 6.71, 6.55 (1H, 1H, 2 brs).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2]CC.Cl[C:7]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([CH3:18])[N:10]=[C:9]2[N:19]([CH3:22])[CH:20]=[N:21][C:8]=12.[CH2:23](N1C2=NC(C)=C(C(OCC)=O)C(Cl)=C2N=C1)CCC>CC(O)C>[CH2:16]([O:15][C:13]([C:12]1[C:7]([O:5][CH:1]([CH3:2])[CH3:23])=[C:8]2[N:21]=[CH:20][N:19]([CH3:22])[C:9]2=[N:10][C:11]=1[CH3:18])=[O:14])[CH3:17]
Reactant: CCOC(=O)c1c(C)nc2c(ncn2C)c1Cl
Reactant: CCCCO
Reactant: CCCCn1cnc2c(Cl)c(C(=O)OCC)c(C)nc21
Solvent: CC(C)O
Product: CCOC(=O)c1c(C)nc2c(ncn2C)c1OC(C)C
Yield: 67 %

Procedure:
When n-butyl alcohol is replaced by propane-2-ol and 7-chloro-3,5-dimethyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid, ethyl ester is processed as described for 3-butyl-7-chloro-5-methyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid, ethyl ester in Example 5, 3,5-dimethyl-7-(1-methylethoxy)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid ethyl ester is obtained. Yield 67%, b.p. 170°-175°/0.01. The free acid is obtained as described in Example 9. The potassium salt is obtained by substituting potassium hydroxide for sodium hydroxide in that example.