Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1C=CC=CC=1.N1CCCCC1>O>[C:7]([C:6]1[CH:11]=[CH:12][C:3]([CH:1]=[CH:14][C:15]([OH:17])=[O:16])=[CH:4][CH:5]=1)([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Solvent: O
Product: COC(=O)c1ccc(C=CC(=O)O)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
To a 3-L three-necked round-bottom flask equipped with an overhead stirrer, condenser, and a nitrogen/thermocouple unit was added methyl p-formylbenzoate (82.08 g, 0.50 mole), malonic acid (104.06 g, 1.00 mole), and pyridine (200 mL). Stirring was started followed by heating to 50° C. for 75 minutes. By this time, a sizable amount of solids had formed and to this mixture was added piperidine (7.5 mL, 0.076 mole) and the temperature raised to 80° C. After another one hour at 80° C., the temperature was raised to 115° C. After another 2.5 hours at this temperature, heating was stopped and the mixture allowed to cool before pouring into water (2 L). To the aqueous mixture was carefully added concentrated HCI (250-300 mL) until the mixture became acidic. The mixture was filtered, and the solids washed with fresh water (1 L) before being suction dried. A yield of 96.83 g (93.9 percent) of white solids was obtained. Proton nmr (DMSO-d6) delta: 7.95 (2H, d); 7.80 (2H, d); 7.60 (1H, d); 6.62 (1H, d); 3.82 (3H, s).
Reaction SMILES: [I-].[CH:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:4])[CH3:3].[Br:24][C:25]1[CH:37]=[CH:36][C:28]([CH:29]=[CH:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:27][CH:26]=1>>[Br:24][C:25]1[CH:26]=[CH:27][C:28]([C@H:29]2[C@H:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:2]2([CH3:4])[CH3:3])=[CH:36][CH:37]=1
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C=Cc1ccc(Br)cc1
Agent: [I-]
Product: CCOC(=O)[C@H]1[C@H](c2ccc(Br)cc2)C1(C)C
Yield: 54 %

Procedure:
Isopropyltriphenylphosphonium iodide (8.65 g, 20.0 mmol) and ethyl 4-bromo-cinnamate (5.10 g, 20.0 mmol) were reacted as described under General Procedure B to furnish the title compound (3.21 g, 54%) as a colourless oil. 1H NMR (300 MHz, CDCl3) δ 7.40 (d, J=8.3 Hz, 2H), 7.03 (d, J=8.3 Hz, 2H), 4.18 (q, J=7.1 Hz, 2H), 2.62 (d, J=5.5 Hz, 1H), 1.91 (d, J=5.5 Hz, 1H), 1.36 (s, 3H), 1.30 (t, J=7.1 Hz, 3H), 0.91 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:11](Cl)(=O)C(Cl)=O.CO.C(N(CC)CC)C>ClCCl.CN(C)C=O>[CH3:11][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[CH3:1]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccccc1C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccccc1C

Procedure:
A solution of 2-methyl-benzoic acid (1.36 g, 10 mmol) in dichloromethane (10 mL) was treated with oxalyl chloride (6 mL, 12 mmol) and dimethylformamide (several drops) followed by treatment with methanol (10 mL) and triethylamine (2.78 mL, 20 mmol). Workup afforded 2-methyl-benzoic acid methyl ester. The material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[CH3:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:29])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([NH:39][CH2:38][C:37]4[CH:40]=[CH:41][C:34]([O:33][CH3:32])=[CH:35][CH:36]=4)=[O:24])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: COc1ccc(CN)cc1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: COc1ccc(CNC(=O)c2ccc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3C(F)(F)F)CCN4)cc2)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-methoxybenzylamine as in General Procedure 10 to give the title compound. LCMS: m/z=566.97 (M+H+); retention time=0.90 minutes.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3]Cl.[CH3:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][NH2:13])=[CH:10][CH:9]=1>O>[F:1][CH:2]([F:5])[CH2:3][NH:13][CH2:12][C:11]1[CH:14]=[CH:15][C:8]([O:7][CH3:6])=[CH:9][CH:10]=1
Reactant: COc1ccc(CN)cc1
Reactant: FC(F)CCl
Solvent: O
Product: COc1ccc(CNCC(F)F)cc1
Yield: 68 %

Procedure:
An amount of 23.15 g (214 mmol) of 2,2-difluoro-1-chloroethane and 10 g (71 mmol) of 4-methoxybenzylamine are heated in an autoclave at an internal temperature of 120° C. for 16 hours. Subsequently, 50 g of water are added and the aqueous phase is separated. The aqueous phase is again extracted with 2,2-difluoro-1-chloroethane and the combined organic phases are distilled as described in Example 1.1. Here also, the 4-methoxybenzylamine hydrochloride present in the aqueous phase can be converted back into free 4-methoxybenzylamine by addition of sodium hydroxide solution. After distillation, 4.93 g of 2,2-difluoro-N-(4-methoxybenzyl)ethanamine are obtained, which corresponds to a yield of 68%, based on reacted 4-methoxybenzylamine.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:36])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13](=[O:35])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[C:24]([OH:31])[C:23]=3[CH2:32][CH2:33][CH3:34])[CH:15]=2)[CH:7]=1>O1CCCC1.O>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][C:16]2[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=2)[C:13]([NH:12][C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=2)[C:5]([OH:36])=[O:4])=[O:35])=[C:23]([CH2:32][CH2:33][CH3:34])[C:24]=1[OH:31])(=[O:30])[CH3:29]
Reactant: CCCc1c(OCc2cccc(C(=O)Nc3cccc(C(=O)OC)c3)c2)ccc(C(C)=O)c1O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1c(OCc2cccc(C(=O)Nc3cccc(C(=O)O)c3)c2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
Add 1N lithium hydroxide (30 mL) to a solution of 3-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-benzoylamino]-benzoic acid methyl ester (4.00 g, 8.67 mmol) in tetrahydrofuran (40 mL). Stir overnight at room temperature and then dilute with water. Acidify the resulting mixture (the salt precipitated) with 1N hydrochloric acid. Concentrate to remove the organic solvents, filter and wash with water several times, then with hexanes. Dry to afford the title compound as a white powder (3.56 g, 92%): 1H NMR (DMSO-d6) δ 0.83 (t, 3H), 1.50 (sextet, 2H), 2.58 (s, 3H), 2.62 (t, 2H), 5.36 (s, 2H), 6.75 (d, 1H), 7.49 (t, 1H), 7.59 (t, 1H), 7.67 (d, 1H), 7.71 (d, 1H), 7.82 (d, 1H), 7.96 (d, 1H), 8.04 (d, 1H), 8.06 (s, 1H), 8.41 (s, 1H), 10.49 (s, 1H), 12.85 (s, 1H), 13.00 (bs, 1H); MS (APCI-neg mode) m/z (rel intensity) 446 (100).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][CH:7]2[C:14](N)=[O:15].[OH-:17].[K+].CO>O>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][CH:7]2[C:14]([OH:15])=[O:17]
Reactant: [OH-]
Reactant: COc1ccc2c(c1OC)CCC2C(N)=O
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1OC)CCC2C(=O)O
Temperature: 25 °C
Yield: 91.2 %

Procedure:
The mixture of 4,5-dimethoxyindane-1-carboxamide (8.4 g, 38.0 mmol), KOH (6.4 g, 114.0 mmol), MeOH (31.0 mL) and water (62 mL) was heated to refluxed for 14 h. The reaction mixture was cooled to room temperature, and MeOH was removed in vacuo. The residue was diluted by 50 mL of water, and the aqueous mixture was extracted with EtOAc (50×2). The aqueous layer was added conc. HCl to adjusted pH ˜1. The solid was filtered, washed by water (100 mL), and dried over P2O5 to afford 4,5-dimethoxyindane-1-carboxylic acid as off-white solid (7.7 g, 92%). M. P.: 128-130° C.
Reaction SMILES: O[C:2]1[C:11]2C(=C(C(F)(F)F)C=CC=2)N=C(C(O)CC)[C:3]=1C(NC1SC=CN=1)=O.[C:28]([OH:41])(=[O:40])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>>[C:28]([O:41][CH2:3][CH2:2][CH3:11])(=[O:40])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCC(O)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Reactant: CCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCC(=O)OCCC

Procedure:
Using the procedure of Example 15, 5 g of 4-hydroxy-2-(1-hydroxypropyl)-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline carboxamide and 2.8 g of lauric acid were reacted to obtain 6 g of 1-(4-hydroxy-3-(2-thiazolylamino)-carbonyl]-8-(trifluoromethyl)-2-quinolinyl]-propyl dodecanoate melting at 158° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:16])=[C:13]([OH:15])[CH:14]=1.Cl>CCO.CCOC(C)=O>[Cl:16][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:2]2[N:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:14][C:13]=1[OH:15]
Reactant: Nc1ccc(Cl)c(O)c1
Reactant: Clc1ncccn1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: Oc1cc(Nc2ncccn2)ccc1Cl
Yield: 36.7 %

Procedure:
2-Chloropyrimidine (1.5 g, 13.3 mmol), 5-amino-2-chlorophenol (318 mg, 2.2 mmol) and 37% HCl solution (1.1 mL, 13.3 mmol) in 10% aqueous EtOH solution (10 mL) was stirred at 90° C. for 24 h. Afterwards, 2-chloropyrimidine (1.5 g, 13.3) was added and after 24 h, the reaction mixture was diluted with AcOEt and washed with 5% aqueous K2CO3 solution and brine. The organic phase was dried over Na2SO4, concentrated and the crude product (179 mg, 36% yield) was used for the next step without additional purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[C:15]3[NH:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9](=[O:17])[N:8]([CH2:18][O:19][CH3:20])[C:7]=2[CH:6]=[C:5](/[CH:21]=[N:22]/[N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:4]=1.C([BH3-])#N.[Na+].CO.Cl>O1CCCC1>[CH3:1][O:2][C:3]1[C:16]2[C:15]3[NH:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9](=[O:17])[N:8]([CH2:18][O:19][CH3:20])[C:7]=2[CH:6]=[C:5]([CH2:21][NH:22][N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[CH:4]=1
Reactant: COCn1c(=O)c2c(c3c(OC)cc(/C=N/N4CCOCC4)cc31)NCCC2
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COCn1c(=O)c2c(c3c(OC)cc(CNN4CCOCC4)cc31)NCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.6 %

Procedure:
The compound (50 mg, 0.12 mmol) prepared in step 2 was dissolved in tetrahydrofuran (2 ml), added with sodium cyanoborohydride (4 mg, 0.06 mmol) and 1.25 N hydrochloric acid methanol solution (5 ml) slowly. The resulting mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure to remove the solvent. The residue was basified with 1 N sodium hydroxide aqueous solution and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and the solvent was concentrated to dryness. The residue was then purified by flash column chromatography (dichloromethane:methanol=20:1) to obtain the title compound (18 mg, yield: 38%, yellow solid).
Reaction SMILES: [CH3:1][N:2]1[CH2:30][CH2:29][C:5]2[N:6]([CH2:14][C:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)O)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.S(Cl)(Cl)=O.[OH-].[Na+]>C(Cl)Cl.CN(C=O)C>[C:23]1([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:14][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:30][CH2:29][C:5]2=3)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Cc1ccc2c(c1)c1c(n2CC(O)(c2ccccc2)c2ccccc2)CCN(C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: Cc1ccc2c(c1)c1c(n2C=C(c2ccccc2)c2ccccc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 15.9 %

Procedure:
A solution of 2-(2,8-Dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1,1-diphenyl-ethanol (100 mg, 0.25 mmol) in DCM (5 mL) and DMF (2 drops) was stirred at 0-10° C. Thionyl chloride (1.55 mL, 21.46 mmol) was added and the reaction mixture was stirred at RT for 2.5 h. The solvent was removed under vacuum to obtain crude yellow solid. 1N NaOH (10 mL) was added to the reaction mixture and the desired compound extracted with EtOAc (20 mL×2). The organic layer was dried over anhydrous sodium sulfate, concentrated under vacuum to obtain the crude product (90 mg) which was purified by column chromatography on silica gel (100-200 mesh) using eluent 0-3% MeOH and DCM to obtain 15 mg product which was converted to HCL salt. 1H NMR (CD3OD, HCl salt) δ (ppm): 7.40 (m, 5H), 7.22-7.16 (m, 6H), 6.98 (m, 3H), 4.62 (d, 1H), 4.30 (m, 1H), 3.62 (m, 1H), 3.36 (m, 1H), 2.98 (s, 3H), 2.80 (m, 2H), 2.40 (s, 3H).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[NH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([Br:30])[C:14]=2[N:16]2[CH2:21][CH2:20][CH2:19][C@@H:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:17]2)[NH:9][CH:8]=1.[Li+].[OH-]>CN1C(=O)CCC1.C(Cl)Cl.O.N1C=CC=CC=1>[Br:30][C:13]1[C:14]([N:16]2[CH2:21][CH2:20][CH2:19][C@@H:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:17]2)=[C:15]2[C:7]([NH:6][C:1](=[O:4])[CH2:2][CH3:3])=[CH:8][NH:9][C:10]2=[N:11][CH:12]=1
Reactant: CCC(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(N)c23)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: c1ccncc1
Product: CCC(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.8 %

Procedure:
DCM (2 mL), pyridine (0.5 mL) and propionyl chloride (0.180 g, 1.95 mmol) were added to (R)-tert-butyl 1-(3-amino-5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (0.200 g, 0.487 mmol; Example 98, Step A) in NMP (3 mL). The reaction was then stirred for 1 hour at room temperature. 3M aqueous LiOH (3 mL) was then added, and the reaction was stirred for 10 minutes. Water (10 mL) and DCM (10 mL) were then added, and the organic fraction was dried, filtered and concentrated to give the crude product. Purification by reverse phase HPLC (5-95% ACN in water) gave the product (R)-tert-butyl 1-(5-bromo-3-propionamido-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (0.120 g, 52.8% yield).
Reaction SMILES: [CH:1]([C:4]1[C:5]([CH2:10][NH:11][CH2:12][C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].[CH3:20][O:21][C:22](=[O:33])[C:23]1[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[CH:25][C:24]=1[CH2:31]Br.CCN(C(C)C)C(C)C>CC#N>[CH3:20][O:21][C:22](=[O:33])[C:23]1[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[CH:25][C:24]=1[CH2:31][N:11]([CH2:10][C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=[CH:7][N:6]=1)[CH2:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: Cc1cccnc1CNCc1ncccc1C(C)C
Reactant: COC(=O)c1cc(C#N)ccc1CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1cc(C#N)ccc1CN(Cc1ncccc1C)Cc1ncccc1C(C)C

Procedure:
Using General Procedure A: Reaction of (3-isopropyl-pyridin-2-ylmethyl)-(3-methyl-pyridin-2-ylmethyl)-amine, 2-bromomethyl-5-cyano-benzoic acid methyl ester, and DIPEA in CH3CN gave 5-Cyano-2-{[(3-isopropyl-pyridin-2-ylmethyl)-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-benzoic acid methyl ester as a yellow oil.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:5]([O:11][C:12]2[CH:25]=[CH:24][C:15]([O:16][CH:17]([CH3:23])[C:18]([O:20]CC)=[O:19])=[CH:14][CH:13]=2)=[N:6][CH:7]=[C:8]([Cl:10])[CH:9]=1>O1CCCC1>[Cl:3][C:4]1[C:5]([O:11][C:12]2[CH:13]=[CH:14][C:15]([O:16][CH:17]([CH3:23])[C:18]([OH:20])=[O:19])=[CH:24][CH:25]=2)=[N:6][CH:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: CCOC(=O)C(C)Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1)C(=O)O
Temperature: 52 °C
Yield: 70 %

Procedure:
10% Sodium hydroxide solution (170 mL, 0.424 mol) is added to a solution of ethyl 2-{p-[(3,5-dichloro-2-pyridyl)oxy]phenoxy}propionate (79.09 g, 0.212 mol) in tetrahydrofuran with stirring. The reaction mixture is heated to 52° C., stirred for 3 hours, concentrated in vacuo and diluted with water. The aqueous solution is washed with methylene chloride, acidified with concentrated sulfuric acid and extracted with ethyl acetate. The combined organic extracts are dried and concentrated in vacuo to give the title product as a white solid (48.7 g) which is identified by 1H NMR spectral analysis.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:4]2[N:3]=1.[C:15]([C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1)#[CH:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:15]([C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:12]([C:11]2[CH:10]=[N:9][N:5]3[C:6]([CH3:8])=[CH:7][C:2]([CH3:1])=[N:3][C:4]=23)=[O:14])=[CH:19][CH:18]=1)#[CH:16]
Reactant: C#Cc1ccc(N)cc1
Reactant: Cc1cc(C)n2ncc(C(=O)O)c2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C#Cc1ccc(NC(=O)c2cnn3c(C)cc(C)nc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.5 %

Procedure:
5,7-Dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (722 mg, 3.78 mmol), 4-ethynylaniline (442 mg, 3.78 mmol), and HATU (1436 mg, 3.78 mmol) were taken up in DMF (10 ml) and then treated with diisopropylethylamine (1.979 ml, 11.33 mmol). The contents stirred at room temperature overnight. The product had precipitated from reaction mixture. The reaction was diluted with water, filtered through a Büchner funnel under house vacuum. The residue was washed with water (×2), then CH2Cl2, diethyl ether, and air dried to obtain N-(4-ethynylphenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide (500 mg, 1.72 mmol, 46% yield). LC-MS: rt (min)=3.65. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.71 (s, 3H), 2.77 (s, 3H), 4.11 (s, 1H), 7.21 (s, 1H), 7.49 (d, J=8.6 Hz, 2H), 7.77 (d, J=8.6 Hz, 2H), 8.65 (s, 1H), 10.31 (s, 1H).
Reaction SMILES: [CH:1]1([CH2:7][C:8]([OH:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:13])=O>>[CH:1]1([CH2:7][C:8]([Cl:13])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CC1CCCCC1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CC1CCCCC1
Temperature: 50 °C
Reaction time: 14.5 h
Yield: 76.6 %

Procedure:
Cyclohexyl-acetic acid (288 ml, 2.04 mol) and thionyl chloride (306 ml, 4.19 mol) were stirred in a 1000 ml flask fitted with reflux condenser, CaCl2 drying tube, thermometer, heating mantle, and magnetic stirrer. The reaction solution was heated to 50° C. with stirring (gas evolution). After 14.5 hours at 50° C., the reaction mixture was further heated to a gentle reflux for 90 min and then cooled to room temperature. Excess thionyl chloride was removed under reduced pressure. The residual liquid was vacuum distilled to afford cyclohexyl-acetyl chloride (250.92 g, 77%) as a pale yellow liquid. bp.: 60° c./5 mm Hg; MS m/z: 161 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)[CH:2]([CH3:4])[CH3:3].[CH:28]1(Br)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.Cl>CN(C=O)C>[CH2:1]([C:5]1[CH:6]=[C:7]([CH:23]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[C:24]([O:26][CH3:27])=[O:25])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)Cc1ccc(OCc2ccc3ccccc3n2)c(CC(C)C)c1
Reactant: BrC1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccc(OCc2ccc3ccccc3n2)c(CC(C)C)c1)C1CCCCC1
Temperature: 0 °C

Procedure:
12 g (0.003 mol) of methyl 2-[3-isobutyl-4-(quinolin-2-yl-methoxy)phenyl]acetate and 6.52 g (0.04 mol)=4.9 ml of cyclohexyl bromide are dissolved in 36 ml of DMF under an argon atmosphere and the solution is cooled to 0° C. 4.88 g (0.04 mol) of potassium tertiary butylate, dissolved in 80 ml of DMF, are added dropwise thereto with stirring. After a reaction time of about 2 hours the temperature is allowed to rise to RT and the mixture is acidified with 2N hydrochloric acid and evaporated to dryness in vacuo. The remaining residue is extracted with 100 ml of dichloromethane and 50 ml of water, the organic phase is separated off, dried with Na2SO4, evaporated to a small volume in vacuo and the remaining residue is separated by column chromatography (silica gel 60, mobile solvent: dichloromethane/ethyl acetate=100/2).
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:33])[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@@H:24]1[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:22])=[O:10])C1C=CC=CC=1>C(OC(=O)C)C.[Pd]>[CH2:31]([O:30][C:28]([C@H:24]1[CH2:25][CH2:26][CH2:27][N:23]1[C:21](=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@@H:11]1[C:9]([OH:10])=[O:8])=[O:33])=[O:29])[CH3:32]
Reactant: CCOC(=O)[C@H]1CCCN1C(=O)CCCCC(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1CCCN1C(=O)CCCCC(=O)N1CCC[C@@H]1C(=O)O
Yield: 95 %

Procedure:
A mixture of 92 mg (0.2 mmol) (R)-1-[6-[(R)-2-ethoxycarbonyl-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylic acid benzyl ester and 30 mg 10% palladium/carbon in 5 ml ethylacetate was hydrogenated over night. Filtration and removal of the solvent yielded 70 mg (R)-1-[6[(R)-2-ethoxycarbonyl-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylic acid as a light yellow oil, MS m/e (%): 369 (M+H+, 100).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:19]([OH:21])=[O:20])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7]C(OCC1C=CC=CC=1Cl)=O.C(N)(C)(C)C.N(C(OC(C)(C)C)=O)[C@H](C(O)=O)CCCCNC(OCC1C=CC=CC=1)=O.C1(NC2CCCCC2)CCCCC1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[NH2:1][C@H:2]([C:19]([OH:21])=[O:20])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1Cl)C(=O)O
Agent: C1CCC(NC2CCCCC2)CC1
Agent: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)(C)N
Product: NCCCC[C@H](N)C(=O)O
Reaction time: 24 h

Procedure:
Relative stability of amino-protecting groups, namely Xys, 2-chlorobenzyloxycarbonyl and Z against trifluoroacetic acid. Boc-Lys(Xys)-OH(41.4 mg, 0.1 m.mol), Boc-Lys(2-Cl-Z)-OH.t-butylamine salt (48.8 mg, 0.1 m.mol) and Boc-Lys(Z)-OH.dicyclohexylamine salt (56.1 mg, 0.1 m.mol) are each dissolved in trifluoroacetic acid (0.5 ml) containing anisole (0.03 ml) and the solutions are allowed to stand at room temperature for 24 hours. The trifluoroacetic acid is distilled off and the residue is made up to 20 ml with cold water. An aliquot of this solution is taken and its lysine content is determined by means of an amino acid analyzer. The yields of lysine (% cleavage of ε-amino-protecting groups) are calculated.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([CH:12]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[NH2:25])[CH2:13]1)=O)C>O1CCCC1>[NH2:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[O:17][CH:14]1[CH2:15][CH2:16][CH:12]([CH2:10][OH:9])[CH2:13]1
Reactant: CCOC(=O)C1CCC(Oc2ccc(Cl)cc2N)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1cc(Cl)ccc1OC1CCC(CO)C1
Reaction time: 0.5 h
Yield: 105.7 %

Procedure:
A solution of lithium aluminum hydride (1 M, 3 mL) was added to a cooled (0° C.) solution of 3-(2-amino-4-chloro-phenoxy)-cyclopentanecarboxylic acid ethyl ester (0.2 g) in tetrahydrofuran (5 mL) and the resulting mixture was stirred for 30 minutes. The reaction mixture was then quenched by addition of a saturated aqueous solution of ammonium chloride and filtered. The filter cake was washed with ethyl acetate and the filtrate was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 180 mg of [3-(2-amino-4-chloro-phenoxy)-cyclopentyl]-methanol without further purifications.