Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([O:9][C:10]([NH:12][CH:13]1[CH2:18][CH2:17][N:16]([S:19]([C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[C:24]([F:31])[CH:23]=2)(=[O:21])=[O:20])[CH2:15][CH2:14]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].N1C=CC=CC=1.[CH2:38]([NH2:46])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[C:5]([O:9][C:10](=[O:11])[NH:12][CH:13]1[CH2:14][CH2:15][N:16]([S:19]([C:22]2[CH:30]=[CH:29][C:25]([C:26](=[O:28])[NH:46][CH2:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[C:24]([F:31])[CH:23]=2)(=[O:20])=[O:21])[CH2:17][CH2:18]1)([CH3:7])([CH3:8])[CH3:6]
Reactant: NCCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(C(=O)O)c(F)c2)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(C(=O)NCCc3ccccc3)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
Thionyl chloride (0.16 g, 2.2 mmol) was added dropwise to a stirred solution of 4-(4-tert-butoxycarbonylamino-piperidine-1-sulfonyl)-2-fluoro-benzoic acid (0.3 g, 0.75 mmol) and pyridine (0.36 ml, 4.5 mmol) in DCM (10 ml). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 4 hours, after this time phenethylamine (0.19 ml, 1.5 mmol) was added in one portion and stirring was continued for a further 12 hours. The mixture was then diluted with DCM (10 ml) before being washed sequentially with HCl (1M solution, 10 ml) and NaOH (1M solution, 10 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated to give the title compound (0.38 g, 74%) as a white foam which was taken on without further purification. Tr=2.16 min m/z (ES+) (M+Na+) 528.
Reaction SMILES: [NH2:1][CH:2]1[CH:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:10]2[CH:9]=[C:8]([CH2:20][CH2:21][CH2:22][NH:23][S:24]([CH2:27][CH:28]3[CH2:30][CH2:29]3)(=[O:26])=[O:25])[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[C:31](O)(=O)[CH3:32].[CH:35](=O)[CH3:36].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][CH:11]2[C:10]3[CH:9]=[C:8]([CH2:20][CH2:21][CH2:22][NH:23][S:24]([CH2:27][CH:28]4[CH2:29][CH2:30]4)(=[O:26])=[O:25])[CH:7]=[CH:6][C:5]=3[CH2:4][CH2:3][CH:2]2[N:1]([CH2:31][CH3:32])[CH2:35][CH3:36])=[CH:14][CH:15]=1
Reactant: CC(=O)O
Reactant: NC1CCc2ccc(CCCNS(=O)(=O)CC3CC3)cc2C1Cc1ccc(Cl)cc1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCN(CC)C1CCc2ccc(CCCNS(=O)(=O)CC3CC3)cc2C1Cc1ccc(Cl)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-(3-(7-Amino-8-(4-chlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl)propyl)-1-cyclopropylmethanesulfonamide (49 mg, 0.11 mmol) was dissolved in dichloromethane (2 mL). Acetic acid (7 μL, 0.11 mmol) was added followed by acetaldehyde (18 μL, 0.322 mmol) in dichloromethane (2 mL) and sodium triacetoxyborohydride (34 mg, 0.16 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with dichloromethane (20 mL) and washed with water (2×10 mL). The organic layer was dried (MgSO4) and the solvent was evaporated in vacuo. The crude product was purified by flash chromatography (silica gel, dichloromethane, methanol). The amine was dissolved in dichloromethane (3 mL) and excess hydrochloric acid in ethanol was added. The solvents were evaporated and the product dried in vacuo. Yield: 22 mg (0.041 mmol, 38%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH3:18][O:19][CH2:20][CH2:21][C:22]1[C:27]([C:28](O)=[O:29])=[CH:26][N:25]=[C:24]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[N:23]=1.COC(=O)CC(=O)CCOC>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][NH:16][C:28]([C:27]2[C:22]([CH2:21][CH2:20][O:19][CH3:18])=[N:23][C:24]([C:31]3[CH:32]=[CH:33][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:36]=3)=[N:25][CH:26]=2)=[O:29])=[CH:13][CH:14]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: COCCc1nc(-c2ccc(C(F)(F)F)cc2)ncc1C(=O)O
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CN)cc1
Agent: COCCC(=O)CC(=O)OC
Product: CCOC(=O)C(C)(C)Oc1ccc(CNC(=O)c2cnc(-c3ccc(C(F)(F)F)cc3)nc2CCOC)cc1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-(4-aminomethyl-phenoxy)-2-methyl-propionic acid ethyl ester [PCT Int. Appl. (2002), WO 2002/096895A1] was reacted with 4-(2-methoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid (prepared from 5-methoxy-3-oxo-pentanoic acid methyl ester, in analogy to the procedures described in examples 27C] and 27D] followed by saponification in analogy to the procedure described in example 53B]) to give 2-[4-({[4-(2-methoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-methyl)-phenoxy]-2-methyl-propionic acid ethyl-ester, which was subsequently saponified to yield the title compound as light yellow solid.
Reaction SMILES: C(O[CH:4]=[C:5]1[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7][C:6]1=[O:17])C.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][C:29]2[S:30][CH:31]=[CH:32][N:33]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[O:17]=[C:6]1[C:5](=[CH:4][NH:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([NH:28][C:29]3[S:30][CH:31]=[CH:32][N:33]=3)(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7]1
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Reactant: Nc1ccc(S(=O)(=O)Nc2nccs2)cc1
Product: O=C1Nc2ccc3ncsc3c2C1=CNc1ccc(S(=O)(=O)Nc2nccs2)cc1
Yield: 33 %

Procedure:
The title compound was prepared in 33% yield from 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one and 4-amino-N-(thiazol-2-yl)-benzenesulfonamide according to Procedure J: 1H NMR (DMSO-d6): δ 12.7 (s, 1H), 11.2 (d, 1H), 10.9 (s, 1H), 9.3 (s, 1H), 8.1 (d, 1H), 7.8 (t, 3H), 7.6 (d, 2H), 7.3 (d, 1H), 7.2 (d, 1H), 6.8 (d, 1H); APCI−MS m/z 456 (M+H)+ and 454 (M−H)−.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])#[N:4].[H][H].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([S:22][CH3:23])[N:17]=1>CS(C)=O>[C:9]([O:8][C:6](=[O:7])[CH:5]([C:3]#[N:4])[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([S:22][CH3:23])[N:17]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)CC#N
Reactant: CSc1nccc(Cl)n1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CSc1nccc(C(C#N)C(=O)OC(C)(C)C)n1
Temperature: 80 °C

Procedure:
To a suspension of sodium hydride (7.15 g, 179 mmol, 60% in oil) in DMSO (100 mL) was added tert-butyl cyanoacetate (24.8 g, 170 mmol) at 23° C. After the evolution of hydrogen ceased, 4-chloro-2-methylthiopyrimidine (13.7 g, 85 mmol) was added. The reaction was heated at 80° C. for 16 h. The reaction mixture was then cooled to room temperature and quenched with ice-cooled saturated ammonium chloride (300 mL). The solid was filtered and washed with water (2×200 mL). 300 mL of hexane was added to the solid and the suspension was heated at 60° C. for 1 h and then cooled to room temperature. The solid was filtered and washed with hexane to afford the title compound; 1H NMR 400 MHz (CDCl3) δ 7.82 (d, 1H), 6.74 (d, 1H), 2.63 (s, 3H), 2.61 (s, 1H), 1.52 (s, 9H); MS m/z: 266.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:6][CH:5]([C:7]([OH:9])=[O:8])[CH2:4][O:3]1.[Ca:11]>>[CH3:1][C:2]1([CH3:10])[O:6][CH:5]([C:7]([O-:9])=[O:8])[CH2:4][O:3]1.[Ca+2:11].[CH3:1][C:2]1([CH3:10])[O:6][CH:5]([C:7]([O-:9])=[O:8])[CH2:4][O:3]1
Reactant: CC1(C)OCC(C(=O)O)O1
Reactant: [Ca]
Product: CC1(C)OCC(C(=O)[O-])O1
Product: [Ca+2]

Procedure:
In the second mother liquor there was left 54 g of 2,2-dimethyl-1,3-dioxolane-4-carboxylic acid (14% e.e. in R-form) as a mixture of its calcium and sodium salts.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[CH:5]=[CH:4]1.[CH3:12][Si:13]([CH3:20])([CH3:19])[CH2:14][CH2:15][O:16][CH2:17]Cl.O>CN(C)C=O.CS(C)=O.CN(C)C=O>[CH3:12][Si:13]([CH3:20])([CH3:19])[CH2:14][CH2:15][O:16][CH2:17][N:3]1[C:11]2=[N:10][CH:9]=[CH:8][CH:7]=[C:6]2[CH:5]=[CH:4]1
Reactant: c1cnc2[nH]ccc2c1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2cccnc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100.8 %

Procedure:
A solution of sodium hydride (1.44 g, 60 mmol) in dimethyl formamide/dimethyl sulfoxide (5:1, 120 mL) cooled to 0° C. was treated with a solution of 7-azaindole (4.72 g, 40 mmol) in dimethyl formamide dropwise. The mixture was then stirred at 0° C. for 15 min, then room temperature for 30 min and then recooled to 0° C. After this time, 2-(trimethylsilyl)ethoxymethyl chloride (10.62 mL, 60 mmol) was added dropwise. The mixture was then stirred for 30 min at 0° C. and then warmed to room temperature and stirred for 2 h. The mixture was then poured into water (200 mL) slowly. The aqueous layer was extracted with diethyl ether (2×50 mL). The combined organic layers were then dried over magnesium sulfate, filtered and the filterate concentrated in vacuo. The orange oil was then purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 33% ethyl acetate/hexanes) to afford 1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (10.02 g, 99%) as a pale yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[CH3:19][C:20]([CH3:25])=[CH:21][C:22](Cl)=[O:23].O>C(Cl)(Cl)Cl>[CH3:19][C:20]([CH3:25])=[CH:21][C:22]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1)=[O:23]
Reactant: CCCCCC(C(=O)OCC)c1ccc(N)cc1
Reactant: CC(C)=CC(=O)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCCC(C(=O)OCC)c1ccc(NC(=O)C=C(C)C)cc1
Temperature: 25 °C

Procedure:
10.4 g of (RS)-ethyl 2-(4-aminophenyl)-heptanoate dissolved in 100 ml of chloroform was treated dropwise with 4.64 ml of 3,3-dimethylacryloyl chloride. The mixture was heated to reflux for 6 hours. After cooling to room temperature, 100 ml of water were added. The phases were separated and the aqueous phase was extracted with two portions of 50 ml of chloroform. The combined organic extracts were washed with two portions of 100 ml of saturated aqueous sodium bicarbonate solution and one portion of 100 ml of saturated aqueous sodium chloride solution. The organic phase was dried over MgSO4 and concentrated in vacuo. The product was used without purification. 1H NMR (CDCl3): 7.48 (br. d, J=8.4 Hz, 2H), 7.39 (br. s, 1H), 7.24 (d, J=8.5 Hz, 2H), 5.71 (br. s, 1H), 4.20-4.00 (m, 2H), 3.48 (t, J=7.7 Hz, 1H), 2.21 (br. s, 3H), 2.15-1.95 (m, 1H), 1.87 (s, 3H), 1.80-1.65 (m, 1H), 1.35-1.15 (m, 6H), 1.20 (t, J=7.1 Hz, 3H), 0.85 (t, J=6.7 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.Cl.Cl.[NH2:32][CH2:33][CH2:34][CH2:35][S:36][C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([NH:32][CH2:33][CH2:34][CH2:35][S:36][C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1)=[O:9]
Reactant: O=C(O)c1cnccn1
Reactant: NCCCSc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Product: O=C(NCCCSc1ccncc1)c1cnccn1
Yield: 34 %

Procedure:
To a solution of 1.00 g (8.06 mmol) of 2-pyrazinecarboxylic acid and 1.21 g (10.5 mmol) of N-hydroxysuccinimide in 70 ml of methylene-chloride, 1.85 g (9.67 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) was added with stirring under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Further, 1.94 g (8.06 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate and water, and dried. The solvent was distilled off and the residue was purified by column chromatography (eluent: ethyl acetate) to give 0.751 g of the desired compound (34.0% yield, colorless powder).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][S:7]([C:10]2[CH:11]=[C:12]([C:15]([C:17]3[C:18](Cl)=[N:19][CH:20]=[CH:21][CH:22]=3)=O)[NH:13][CH:14]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.O.[NH2:27][NH2:28].O>C(O)C>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][S:7]([C:10]2[CH:11]=[C:12]([C:15]3[C:17]4[C:18](=[N:19][CH:20]=[CH:21][CH:22]=4)[NH:28][N:27]=3)[NH:13][CH:14]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(c1cc(S(=O)(=O)Cc2ccc(Cl)cc2)c[nH]1)c1cccnc1Cl
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=S(=O)(Cc1ccc(Cl)cc1)c1c[nH]c(-c2n[nH]c3ncccc23)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 94.3 %

Procedure:
{4-[(4-chlorobenzyl)sulfonyl]-1H-pyrrol-2-yl}(2-chloropyridin-3-yl)methanone (280 mg, 0.711 mmol) and 359 mg of hydrazine monohydrate (7.11 mmol) were mixed in 4 mL of ethanol. The mixture was stirred at 80° C. overnight (16 hour) and then cooled down to room temperature. Water was added and filtered. Washed with additional water and methanol to collect the product, dried to afford 250 mg (95% yield) of the title compound.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:17]([C:19]4[C:27]5[C:22](=[CH:23][C:24]([C:28]6[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=6)=[CH:25][CH:26]=5)[NH:21][CH:20]=4)=[O:18])=[C:12]3[CH2:11][S:10]2)[CH:4]=1.[C:35]([O:39][CH3:40])(=[O:38])[CH:36]=[CH2:37]>CN(C=O)C.[Cl-].[Na+].O>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:17]([C:19]4[C:27]5[C:22](=[CH:23][C:24]([C:28]6[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=6)=[CH:25][CH:26]=5)[N:21]([CH2:37][CH2:36][C:35]([O:39][CH3:40])=[O:38])[CH:20]=4)=[O:18])=[C:12]3[CH2:11][S:10]2)[CH:4]=1
Reactant: O=C(c1ccn2c1CSC2c1cccnc1)c1c[nH]c2cc(-c3ccc(F)cc3)ccc12
Reactant: C=CC(=O)OC
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCn1cc(C(=O)c2ccn3c2CSC3c2cccnc2)c2ccc(-c3ccc(F)cc3)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.7 %

Procedure:
Sodium hydride (95%, 37.4 mg, 1.48 mmol) was added to a solution of 3-(pyridin-3-yl)-7-[6-(4-fluorophenyl)indol-3-ylcarbonyl]-1H,3H-pyrrolo[1,2-c]thiazole (0.50 g, 1.14 mmol), prepared according to the method of Example 28, in DMF (30 mL). The reaction mixture was stirred for 30 min. at ambient temperature, and then methyl acrylate (0.40 mL, 4.56 mmol) was added. The reaction mixture was poured into brine and extracted three times with ethyl acetate. The combined organic layers where dried over MgSO4, filtered, and concentrated in vacuo. 3-(Pyridin-3-yl)-7-[1-(2-carbomethoxyethyl)-6-(4-fluorophenyl)indol-3-ylcarbonyl]-1H,3H-pyrrolo[1,2-c]thiazole (190 mg, 32%) was obtained by flash chromatography on silica gel (5 g, 40%, then 60%, then 80% ethyl acetate, hexanes). 1H NMR (CDCl3, 300 MHz) δ2.93 (t, 2 H, J=6, 8 Hz), 3.68 (s, 3H), 4.53 (dd, 3H, J=6, 11 Hz), 4.7 (dd, 1H, J=2, 15 Hz), 6.38 (d, 1H, J=3 Hz), 6.43 (s, 1H), 6.78 (d, 1H, J=3 Hz), 7.15 (t, 2H, J=9, 10 Hz), 7.35 (dd, 1H, J=5, 8 Hz), 7.5 (dd, 2H, J=3, 10 Hz), 7.6-7.1 (m, 3H), 7.95 (s, 1H), 8.45 (dd, 1H, J=1, 9 Hz), 8.6-8.68 (m, 2H). MS (DCI/MH3) m/e 526 (M+H)+.
Reaction SMILES: [C:1]([OH:21])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][C@@H:12]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[OH:13].C(N(CC)CC)C.[N+:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1)([O-:31])=[O:30].O>CC(C)=O>[C:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH:12]([O:13][C:36](=[O:37])[C:35]1[CH:34]=[CH:33][C:32]([N+:29]([O-:31])=[O:30])=[CH:40][CH:39]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])([OH:21])=[O:20]
Reactant: CCCCCC[C@@H](O)C/C=C\CCCCCCCC(=O)O
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCCCCCC(CC=CCCCCCCCC(=O)O)OC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.3 %

Procedure:
To a mixture of ricinoleic acid (1600 g), triethylamine (1100 mL) in acetone (6 L) at 0-5° C., was added 4-nitro benzoyl chloride (1200 g). It was stirred at room temperature for 16 hours. After the reaction was completed then the total reaction mass was poured onto cold water (12 L) and extracted with ethyl acetate (6 liter) and combined total organic layers and washed with 15% NaHCO3 solution (IL) and 15% NaCl solution (1.0 L) followed by water washing (1.0 L), then dry the organic layer with sodium sulphate and distilled up the solvent under reduced pressure completely till thick oily mass is obtained. Resulting crude was purified by column chromatography by using hexane: ethyl acetate (9:1) to yield pure 4-nitro-benzoic acid 11-carboxy-1-hexyl-undec-3-enyl ester product as light yellow thick syrup (750 g). The resulting compound was characterized by 1H NMR (DMSO-d6) δ 0.85 (t, 3H, CH3), 1.12-1.6 (m, 22H, 11×CH2), 1.91 (m, 2H, CH2), 2.2-2.32 (m, 4H, 2×CH2), 3.5 (m, 1H, CH) 5.52 (m, 1H, CH), 5.65 (m, 1H, CH), 8.25-8.35 (m, 4H, Ar).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]2=[N:8][C:9]([C:11]([O:13]C)=[O:12])=[CH:10][N:5]2[C:4]=1[CH3:15])[CH3:2]>[OH-].[Na+]>[CH2:1]([C:3]1[S:7][C:6]2=[N:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][N:5]2[C:4]=1[CH3:15])[CH3:2]
Reactant: CCc1sc2nc(C(=O)OC)cn2c1C
Agent: [Na+]
Agent: [OH-]
Product: CCc1sc2nc(C(=O)O)cn2c1C
Yield: 85.3 %

Procedure:
1.5 g of 2-ethyl-3-methyl-6-carbomethoxy-imidazo-(2,1-b)thiazole(obtained as described in Example 45) are refluxed for 2 hours in 5 ml of 10% NaOH. The solution obtained is treated in the same manner as described in Example 49 to yield 1.2 g of 2-ethyl-3-methyl-imidazo-(2,1-b)thiazole-6-carboxylic acid m.p. 243°-245° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][C:20]2[N:21]=[C:22]3[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][N:23]3[CH:29]=2)[CH:12]=[CH:13][C:14]=1[N+:15]([O-])=O)C1C=CC=CC=1.[H][H]>CO.O1CCCC1.[Pd]>[NH2:15][C:14]1[CH:13]=[CH:12][C:11]([CH2:18][CH2:19][C:20]2[N:21]=[C:22]3[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][N:23]3[CH:29]=2)=[CH:10][C:9]=1[OH:8]
Reactant: [H][H]
Reactant: Cc1ccn2cc(C=Cc3ccc([N+](=O)[O-])c(OCc4ccccc4)c3)nc2c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccn2cc(CCc3ccc(N)c(O)c3)nc2c1

Procedure:
A solution of 2-[2-(3-benzyloxy-4-nitrophenyl)vinyl]-7-methylimidazo[1,2-a]pyridine in a mixture of methanol (300 ml) and tetrahydrofuran (300 ml) was hydrogenated over 10% palladium on carbon (5.0 g) under atmospheric pressure of hydrogen gas at ambient temperature. The catalyst was removed by filtration and the filtrate was evaporated in vacuo. The residue was triturated with diethyl ether to give a precipitate which was collected by filtration and dried to give 2-[2-(4-amino-3-hydroxyphenyl)ethyl]-7-methylimidazo[1,2-a]pyridine (20.67 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:35]=[CH:34][C:12]([CH2:13][C@@H:14]([NH:19][C:20](=[O:33])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:15][CH2:16][C:17]#[N:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:36]=[N+:37]=[N-:38].[Na+].N(CC)CC.Cl>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:35]=[CH:34][C:12]([CH2:13][C@@H:14]([NH:19][C:20](=[O:33])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:15][CH2:16][C:17]2[NH:38][N:37]=[N:36][N:18]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCC[C@@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)CCCCCCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCNCC
Product: O=C(CCCCCCc1ccccc1)N[C@@H](CCc1nnn[nH]1)Cc1ccc(OCc2ccccc2)cc1
Yield: 219.9 %

Procedure:
A mixture of (65) (74 mg, 0.16 mmol), NaN3 (103 mg, 1.58 mmol) and Et2NH.HCl (173 mg, 1.58 mmol) in toluene (1.5 mL) was heated at reflux for 48 h. The organic phase was decanted, and the remaining gum washed several times with CH2Cl2. The washings were filtered (Celite™), and the organic phases combined. Evaporation of the solvent under reduced pressure afforded a brown gum (180 mg) which was chromatographed on a C-18 reverse phase column to provide (66) (29 mg, 36%). 1H NMR (500 MHz, d4-MeOH) δ 7.43-7.07 (m, 12H), 6.9 (d, 2H, J=8.6 Hz), 4.99 (s, 2H), 4.15-4.04 (m, 1H), 3.03-2.86 (m, 2H), 2.79 (dd, 1H, J=5.7, 13 Hz), 2.65 (dd, 1H, J=8.7, 13 Hz), 2.54 (t, 2H, J=7.6 Hz), 2.12-2.00 (m, 3H), 1.90-1.78 (m, 1H), 1.50-1.36 (m, 2H), 1.33-1.10 (m, 4H). 13C NMR (125 MHz, d4-MeOH) δ 176.2, 158.9, 156.2, 143.9, 138.8, 131.9, 131.3, 129.5, 129.4, 129.3, 128.8, 128.5, 126.6, 115.8, 71.0, 51.5, 41.1, 37.2, 36.8, 33.5, 32.5, 30.0 (two superimposed), 27.0, 21.3. ESMS 512 (M+H)+.
Reaction SMILES: [CH2:1]([N:3](CC)CC)C.[C:8]([O:12][C:13](=[O:31])[C:14]1[C:19]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:22]=2[Cl:28])=[C:18]([Cl:29])[C:17](Cl)=[N:16][CH:15]=1)([CH3:11])([CH3:10])[CH3:9].CCO[C:35]([CH3:37])=[O:36]>C(#N)C>[C:8]([O:12][C:13](=[O:31])[C:14]1[C:19]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:22]=2[Cl:28])=[C:18]([Cl:29])[C:17]([NH:3][CH2:1][CH:35]([OH:36])[CH3:37])=[N:16][CH:15]=1)([CH3:9])([CH3:10])[CH3:11]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)c1cnc(Cl)c(Cl)c1Nc1ccc(Br)cc1Cl
Reactant: CCN(CC)CC
Solvent: CC#N
Product: CC(O)CNc1ncc(C(=O)OC(C)(C)C)c(Nc2ccc(Br)cc2Cl)c1Cl
Temperature: 25 °C
Yield: 75 %

Procedure:
I-Amino-propan-2-ol (2.44 g, 30.3 mmol) and triethylamine (0.42 mL, 3.03 mmol) were added to a solution of 4-(4-bromo-2-chlorophenylamino)-5,6-dichloronicotinic acid tert-butyl ester (1.37 g, 3.03 mmol) in acetonitrile (30 mL). The reaction was heated to reflux. After 23 hours the reaction was cooled to room temperature and diluted with EtOAc, washed with saturated NaHCO3, water, brine, dried over Na2SO4 and concentrated to a white solid. Purification by flash column chromatography (20:1 dichloromethane/methanol) provided the desired product as a white solid (1.11 g, 75%). MS APCI (+) m/z 492, 494 (M+, Cl, Br pattern) detected.
Reaction SMILES: Br[C:2]1[C:7]2[NH:8][C:9]3[CH:10]=[C:11]([Cl:15])[CH:12]=[CH:13][C:14]=3[C:6]=2[C:5](=[O:16])[NH:4][CH:3]=1.[CH3:17][N:18](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[Cl:15][C:11]1[CH:12]=[CH:13][C:14]2[C:6]3[C:5](=[O:16])[NH:4][CH:3]=[C:2]([C:17]#[N:18])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: O=c1[nH]cc(Br)c2[nH]c3cc(Cl)ccc3c12
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1c[nH]c(=O)c2c1[nH]c1cc(Cl)ccc12
Temperature: 90 °C
Reaction time: 24 h

Procedure:
4-Bromo-7-chloro-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one (35.55 g, 119 mmol), zinc cyanide (9.82 g, 84 mmol), and Pd(PPh3)4 (13.81 g, 11.95 mmol) were combined and stored under vacuum for 20 min before DMF (300 mL, presparged with nitrogen for 1 h) was transferred to the mixture via cannula. The reaction mixture was heated to 90° C. overnight. Additional Pd(PPh3)4 (13.0 g, 11.2 mmol) was added to the mixture, and the resultant mixture was heated to 90° C. for 20 h, cooled to room temperature, and left to stir for 1 d. The reaction mixture was filtered, and washed with DMF. The filtrate was treated with water (15 mL), aged at room temperature for 3 h, treated with additional water (70 mL), and the resultant slurry was left overnight. The mixture was treated with additional water (70 mL), filtered, washed with water, and dried under vacuum. The solid was suspended in EtOAc, aged, filtered, washed with EtOAc, and dried under vacuum to give the title compound. 1H NMR (600 MHz, CD3SOCD3) δ 12.66 (s, 1H); 12.19 (s, 1H); 8.31 (s, 1H); 8.06 (d, 1H); 7.55 (s, 1H); 7.30 (d, 1H). LRMS (APCI) calc'd for (C12H6ClN3O) [M+H]+, 244.0. found 244.0.