Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([O:18][CH2:19][CH:20]4[CH2:24][CH2:23][CH2:22][NH:21]4)=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[I-].[K+].[CH3:42][O:43][C:44](=[O:49])[CH2:45][CH2:46][CH2:47]Br>C1COCC1.O>[CH3:42][O:43][C:44](=[O:49])[CH2:45][CH2:46][CH2:47][N:21]1[CH2:22][CH2:23][CH2:24][CH:20]1[CH2:19][O:18][C:16]1[C:17]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[C:10]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:11][C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: COC(=O)CCCBr
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCC4CCCN4)c23)cc1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)CCCN1CCCC1COc1ncnc2oc(-c3ccccc3)c(-c3ccc(OC)cc3)c12

Procedure:
Dissolve 100 mg (0.25 mmol) of (+/−)-5-(4-methoxyphenyl)-6-phenyl-4-(pyrrolidin-2-ylmethoxy)furo[2,3-d]-pyrimidine (Example 38A) in 2 ml of THF and successively add 65 μl (0.374 mmol) of DIEA, 4.1 mg (0.025 mmol) of potassium iodide and 45 mg (0.25 mmol) of 4-bromobutyric acid methyl ester. Heat the mixture under reflux for 1 h and then add to water with cooling. Extract three times with ethyl acetate and wash the combined organic phases twice with buffer solution (pH 7) and with saturated sodium chloride solution. Dry the solution over magnesium sulphate and concentrate under reduced pressure. Purify the crude product by preparative RP-HPLC (eluent: acetonitrile/water gradient). 47 mg (37.6% of theory) of the target product are obtained.
Reaction SMILES: CC[O:3][CH2:4][CH2:5][OH:6].[Cl:7][CH2:8][CH2:9][S:10](Cl)=[O:11]>CCOCC>[Cl:7][CH2:8][CH2:9][S:10]([O:6][CH2:5][CH2:4][O:3][S:10]([CH2:9][CH2:8][Cl:7])=[O:11])=[O:11]
Reactant: O=S(Cl)CCCl
Reactant: CCOCCO
Solvent: CCOCC
Product: O=S(CCCl)OCCOS(=O)CCCl
Temperature: 25 °C

Procedure:
Ethyl glycol (6.2) was added dropwise under a nitrogen atmosphere to a stirred solution of 2-chloroethanesulfinyl chloride (14.7 w), prepared as in Example I, in dry ether (40 v). During the addition period the temperature of the reaction was controlled at -20° by external cooling. Upon completion of the addition, the reaction mixture was warmed to ambient temperature and the solvent was removed by distillation in a vacuum. Examination of the residue by gas-liquid chromatography revealed more than one major component. The residue was then redissolved in dry ether (200 v) and further treated with 2-chloroethanesulfinyl chloride (14.7 w) as above. Using the same procedure as above an oily residue was obtained which after purification in a wiped film molecular still yielded a colorless liquid, 2-(chloroethanesulfinyloxy)ethyl 2-chloroethanesulfinate (8.5 w) boiling at 110-115° under reduced pressure (1 × 10-4 torr).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1Cl.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1>[Pd]>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[C:17]1[CH:18]=[CH:19][C:14]([C:13]([F:24])([F:23])[F:12])=[CH:15][CH:16]=1
Reactant: COC(=O)c1cccnc1Cl
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Product: COC(=O)c1cccnc1-c1ccc(C(F)(F)F)cc1

Procedure:
2-(4-Trifluoromethyl-phenyl)-nicotinic acid methyl ester is prepared by palladium [PdCl2 (dppf)] catalyzed coupling of 2-chloronicotinic acid methyl ester (1.45 g, 8.45 mmol) and 4-trifluoromethylbenzeneboronic acid (2.41 g, 12.68 mmol) to give an oil: 1H NMR (CDCl3, 300 MHz): δ 8.80 (1H dd), 8.19 (1H, dd), 7.67 (4H, q), 7.40 (1H, dd), 3.70 (3H, s).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C([O:7][C:8]([C:10]1[C:11]2[S:19][CH:18]=[C:17]([CH2:20][O:21][C:22]3[CH:27]=[C:26]([C:28]4[N:32]([CH2:33][C:34]5[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=5)[C:31]([CH3:42])=[N:30][N:29]=4)[CH:25]=[CH:24][C:23]=3[CH3:43])[C:12]=2[C:13]([NH2:16])=[N:14][CH:15]=1)=O)C>CS(C)=O.O>[OH:2][CH2:1][CH2:3][NH:4][C:8]([C:10]1[C:11]2[S:19][CH:18]=[C:17]([CH2:20][O:21][C:22]3[CH:27]=[C:26]([C:28]4[N:32]([CH2:33][C:34]5[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=5)[C:31]([CH3:42])=[N:30][N:29]=4)[CH:25]=[CH:24][C:23]=3[CH3:43])[C:12]=2[C:13]([NH2:16])=[N:14][CH:15]=1)=[O:7]
Reactant: NCCO
Reactant: CCOC(=O)c1cnc(N)c2c(COc3cc(-c4nnc(C)n4Cc4ccc(OC)cc4)ccc3C)csc12
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(Cn2c(C)nnc2-c2ccc(C)c(OCc3csc4c(C(=O)NCCO)cnc(N)c34)c2)cc1
Temperature: 135 °C

Procedure:
Ethanolamine (1.8 mL; 29.9 mmol) (Aldrich) was added to a solution of 4-amino-3-{5-[4-(4-methoxy-benzyl)-5-methyl-4H-[1,2,4]triazol-3-yl]-2-methyl-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (50 mg; 0.08277 mmole) (from Example 59 supra) in dimethylsulfoxide (0.6 mL). The mixture was heated in a microwave reactor at 135° C. for 2.25 hours. After cooling to room temperature, the reaction mixture was diluted with water, resulting in precipitation of the product as a milky solid which was collected by centrifugation and dried. The crude solid was triturated with hot methanol, cooled slightly, filtered and dried, to give 4-amino-3-{5-[4-(4-methoxy-benzyl)-5-methyl-4H-[1,2,4]triazol-3-yl]-2-methyl-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide in two crops. (Yield 31.2 mg, 51.3%). HRMS (ES+) m/z Calcd for C29H30N6O4S+H [(M+H)+]: 559.2122. Found: 559.2120.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.[NH2:18][C:19]1[CH:31]=[C:30]([C:32]2[CH:40]=[CH:39][C:35]3[O:36][CH2:37][O:38][C:34]=3[CH:33]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])O.[Na+]>C(Cl)Cl>[O:36]1[C:35]2[CH:39]=[CH:40][C:32]([C:30]3[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])=[C:19]([NH:18][C:13](=[O:14])[C:12]4[CH:16]=[CH:17][C:9]([F:8])=[CH:10][CH:11]=4)[CH:31]=3)=[CH:33][C:34]=2[O:38][CH2:37]1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccc3c(c2)OCO3)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(-c2ccc3c(c2)OCO3)cc1NC(=O)c1ccc(F)cc1
Reaction time: 5 h

Procedure:
0.054 mL of triethylamine and 0.034 mL of 4-fluorobenzoyl chloride were added to 3.5 mL of methylene chloride solution containing 60 mg of tert-butyl 2-amino-4-(benzo[1,3]dioxol-5-yl)benzoate at room temperature sequentially and stirred at the same temperature for 5 hours. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1]to obtain tert-butyl 4-(benzo[1,3]dioxol-5-yl)-2-(4-fluorobenzamido)benzoate.
Reaction SMILES: C(N1CCC(CO)CC1)(OC(C)(C)C)=O.OC1C=C(C(OC)=O)ON=1.[N].[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C([N:43](C(OCC1C=CC=CC=1)=O)[C:44](=[NH:47])SC)(OCC1C=CC=CC=1)=O>>[C:44]([N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)(=[NH:43])[NH2:47]
Reactant: C1CCNCC1
Reactant: CSC(=N)N(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: COC(=O)c1cc(O)no1
Agent: [N]
Product: N=C(N)N1CCCCC1

Procedure:
Scheme XIXb outlines the synthesis of the analogous compounds where R1 is 4-(1-amidinopiperidinyl) instead of 4-amidinophenyl. After initial condensation of N-BOC-4-piperidinylcarbinol with methyl 3-hydroxyisoxazole-5-carboxylate under Mitsunobu conditions, the intermediate ester is saponified and condensed with a 1,3-diaminpropionate using conditions described above. The piperidine nitrogen is deprotected and treated with N,N,-diCBz-S-methylisothiourea to give a protected amidinopiperdine. Hydrogenation gives the amidinopiperidine compounds as the methyl esters. ##STR76##
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH:26]([CH2:28][O:29][C:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[OH:27])=[O:23])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:55](Cl)(=[O:57])[CH3:56].O>C(O)C>[I:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH:26]([CH2:28][O:29][C:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[O:27][C:55](=[O:57])[CH3:56])=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCCCCCCCCCCCCCc1cccc(I)c1)OCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)Cl
Solvent: CCO
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OC(COC(=O)CCCCCCCCCCCCCCc1cccc(I)c1)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 7 h
Yield: 86 %

Procedure:
1-[15-(m-Iodophenyl)pentadecanoyl]-3-O-trityl-rac-glycerol (0.34 g, 0.45 mmol) was dissolved in ethanol free CHCl3 (2.2 ml) in a two-necked flask. Pyridine (0.06 ml, 0.79 mmol) was added, followed by acetyl chloride (0.09 ml, 1.26 mmol). The reaction mixture was stirred for 7 hours, then H2O was added to destroy the excess acetyl chloride. This mixture was diluted with CHCl3, washed twice with 1 N HCl and once with brine. The organic layer was dried over MgSO4 and the solvent was evaporated. Chromatographic purification yielded pure compound 34, 1-[15-(m-iodophenyl)pentadecanoyl]-2-acetyl-3-O-trityl-rac-glycerol. (0.31 g, 86% yield).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:10]([NH2:13])[CH:11]=[CH2:12].C(N(C(C)C)CC)(C)C>C(O)C>[CH2:10]([NH:13][C:3]1[C:2]([Br:1])=[CH:7][N:6]=[C:5]([Cl:8])[N:4]=1)[CH:11]=[CH2:12]
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: C=CCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: C=CCNc1nc(Cl)ncc1Br
Yield: 89 %

Procedure:
A solution of 5-bromo-2,4-dichloropyrimidine (5.0 g, 22 mmol), allylamine (1.98 mL, 26.4 mmol), and diisopropylethylamine (5.6 mL, 33.0 mmol) are stirred in ethanol (100 mL) at 50° C. overnight. The solvent is removed in vacuo and the residue is partitioned between ethyl acetate and saturated aqueous ammonium chloride solution. The organic layer is washed with brine, dried over anhydrous sodium sulfate and evaporated to provide Allyl-(5-bromo-2-chloro-pyrimidin-4-yl)-amine as a white crystalline solid (89%), which is used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([F:15])=[CH:13][C:12](B(O)O)=[CH:11][C:10]=2[F:19])=[CH:5][CH:4]=1)[CH3:2].Br[C:21]1[S:22][C:23]([CH2:26][CH3:27])=[CH:24][CH:25]=1>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([F:15])=[CH:13][C:12]([C:21]3[S:22][C:23]([CH2:26][CH3:27])=[CH:24][CH:25]=3)=[CH:11][C:10]=2[F:19])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(-c2c(F)cc(B(O)O)cc2F)cc1
Reactant: CCc1ccc(Br)s1
Product: CCc1ccc(-c2c(F)cc(-c3ccc(CC)s3)cc2F)cc1

Procedure:
The compound 2-(4′-ethyl-2,6-difluorobiphenyl-4-yl)-5-ethylthiophene (SUP-2-2) is prepared analogously to Example 1 from 4′-ethyl-2,6-difluoro-4-biphenylboronic acid and 2-bromo-5-ethylthiophene.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19](OS(C(F)(F)F)(=O)=O)[CH:20]=4)[C:15]3=[O:32])=[CH:10][C:9]=2[F:33])[CH2:4]1.[CH3:35][O:36][CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[CH3:1][N:2]([CH3:34])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([N:40]5[CH2:41][CH2:42][CH:37]([O:36][CH3:35])[CH2:38][CH2:39]5)[CH:20]=4)[C:15]3=[O:32])=[CH:10][C:9]=2[F:33])[CH2:4]1
Reactant: CN(C)[C@@H]1CCN(c2ccc(N3CCc4cc(OS(=O)(=O)C(F)(F)F)ccc4C3=O)cc2F)C1
Reactant: COC1CCNCC1
Product: COC1CCN(c2ccc3c(c2)CCN(c2ccc(N4CC[C@@H](N(C)C)C4)c(F)c2)C3=O)CC1

Procedure:
Trifluoromethanesulfonic acid 2-[4-((R)-3-dimethylaminopyrrolidin-1-yl)-3-fluorophenyl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl ester was reacted with 4-methoxypiperidine by method N. The product with the molecular weight of 466.60 (C27H35FN4O2) was obtained in this way; MS (ESI): 467 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH2:12]([NH:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH3:15].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>O1CCOCC1>[CH2:12]([N:16]([CH2:17][CH2:18][CH2:19][CH3:20])[C:8]1[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=1[O:9][CH3:10])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCNCCCC
Reactant: COc1cc(Br)cc(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1COCCO1
Product: CCCCN(CCCC)c1c(OC)cccc1OC
Temperature: 0 °C
Yield: 88.2 %

Procedure:
In a stream of argon, to 300 ml of dioxane were added 21.7 g (100 mmol) of 3,5-dimethoxybromobenzene and 13.0 g (100 mmol) of dibutylamine, and 22.0 g (110 mmol) of potassium bistrimethylsilylamide was added thereto with stirring. After well-stirred, the mixture was heated under reflux with stirring overnight. The reactant was poured into 2 L of ice water and subjected to 3 times of extraction with 200 ml of chloroform. Washing with a saturated saline solution, drying over anhydrous magnesium sulfate, and concentration were performed. The residue was purified by silica gel chromatography to give 23.4 g (yield: 88%) of 4-dibutylamino-3,5-dimethoxybenzene as a colorless transparent oily matter.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([CH:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]([C:24](=[O:35])[C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=4)[CH:16]([CH2:36][CH2:37][CH2:38][CH2:39][C:40]([OH:42])=O)[CH2:15]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:43]([NH:49][CH3:50])[CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]>>[CH:1]1[C:13]2[N:12]([CH:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]([C:24](=[O:35])[C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=4)[CH:16]([CH2:36][CH2:37][CH2:38][CH2:39][C:40]([N:49]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH3:50])=[O:42])[CH2:15]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(C(=O)N2c3ccccc3C(n3c4ccccc4c4ccccc43)CC2CCCCC(=O)O)cc1OC
Reactant: CCCCCCNC
Product: CCCCCCN(C)C(=O)CCCCC1CC(n2c3ccccc3c3ccccc32)c2ccccc2N1C(=O)c1ccc(OC)c(OC)c1
Yield: 71 %

Procedure:
Starting with 5-[4-(9H-9-carbazolyl)-1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydro-2-quinolinyl]pentanoic acid (0.12 g, 0.21 mmol) prepared in Example 128 and N-hexyl-N-methylamine (0.3 ml), the same procedure as shown in Example 129 was repeated to give the titled compound (0.10 g, yield: 71%) as a white powder (cis:trans=3:1).
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.C([O-])(=O)C.[Na+].[H][H]>[Pd].CO>[NH2:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([F:11])([F:9])[F:10])=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: Nc1ccc(C(F)(F)F)nc1Cl
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1ccc(C(F)(F)F)nc1
Yield: 92.1 %

Procedure:
3-Amino-2-chloro-6-trifluoromethylpyridine (15.0 g, 76 mmol), sodium acetate (12.53 g, 153 mmol) and 10% palladium on carbon (1.5 g) in methanol (300 ml) were hydrogenated at 50 psi hydrogen for 18 h, then the suspension was filtered. The filtrate was concentrated to give the product as a tan solid (11.38 g, 70 mmol, 92% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([NH2:21])[CH:13]=1.Cl>CC(N(C)C)=O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([NH2:21])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Oc1ccc(S)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Nc1cc(Sc2ccc(O)cc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.7 %

Procedure:
A solution of 4-hydroxybenzenethiol (46 g; 328 mmol) in DMA (500 ml) under argon was cooled to 0° C. and treated portionwise with NaH (28.9 g; 722 mmol; 60 % dispersion in oil). The mixture was stirred at room temperature for 2 hours and then solid 4-chloro-2-amino-nitrobenzene (56.6 g; 328 mmol) was added rapidly portionwise. The mixture was stirred and heated at 80° C. for 30 minutes and allowed to cool overnight. The mixture was poured into aqueous HCl (2 N) and the precipitate was filtered, washed with water, then pentane and dried in vacuo to give 4-(4-hydroxyphenylsulphanyl)-2-amino-nitrobenzene as a beige solid (86.6 g).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]([C:15]2[C:16]([CH3:27])=[N:17][O:18][C:19]=2[C:20]2[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=2)[OH:14])[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:37]=2)[CH2:35][CH2:34]1)=[O:32])[CH3:29]>>[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39]([C:23]3[CH:24]=[CH:25][C:20]([C:19]4[O:18][N:17]=[C:16]([CH3:27])[C:15]=4[CH:13]([C:11]4[N:10]=[N:9][N:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH:12]=4)[OH:14])=[CH:21][CH:22]=3)=[CH:38][CH:37]=2)[CH2:34][CH2:35]1)=[O:32])[CH3:29]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1cn(Cc2ccccc2)nn1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4cn(Cc5ccccc5)nn4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using (1-benzyl-1H-[1,2,3]triazol-4-yl)-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-methanol (Enantiomer B) and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [C:1]([C:3]1[CH:33]=[CH:32][C:6]([O:7][C:8]2[CH:9]=[C:10]([NH:23][C:24]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[O:25])[CH:11]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=3)[CH:13]=2)=[CH:5][CH:4]=1)#[N:2].Br[CH2:35][CH:36]1[CH2:38][CH2:37]1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:9]=[C:10]([NH:23][C:24]([CH:26]3[CH2:27][CH2:28][N:29]([CH2:35][CH:36]4[CH2:38][CH2:37]4)[CH2:30][CH2:31]3)=[O:25])[CH:11]=[C:12]([O:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]#[N:22])=[CH:19][CH:20]=3)[CH:13]=2)=[CH:32][CH:33]=1)#[N:2]
Reactant: BrCC1CC1
Reactant: N#Cc1ccc(Oc2cc(NC(=O)C3CCNCC3)cc(Oc3ccc(C#N)cc3)c2)cc1
Product: N#Cc1ccc(Oc2cc(NC(=O)C3CCN(CC4CC4)CC3)cc(Oc3ccc(C#N)cc3)c2)cc1
Yield: 59.4 %

Procedure:
Following the procedure of Example 11(e) 4-[3,5-bis-(4-cyano-phenoxy)-phenyl-carbamoyl]-piperidine 1.5 g (3.42 mmol) and bromomethylcyclopropane (0.647 g, 4.79 mmol) were used to afford 1.0 g of the required product. Percentage purity (LCMS): 73.1%, (M+1)=492.1+1.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:17]([NH2:19])[CH3:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][N:25]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[CH:1]1([N:7]2[C:11]3[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:17]([NH:19][C:21]2[N:29]=[CH:28][N:27]=[C:26]3[C:22]=2[N:23]=[CH:24][NH:25]3)[CH3:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1C1CCCCC1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1C1CCCCC1
Temperature: 100 °C

Procedure:
(S)-1-(1-Cyclohexyl-6-fluoro-1H-benzoimidazol-2-yl)ethylamine (0.41 g, 1.56 mmol) was dissolved in n-butanol (5 mL) and 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (0.374 g, 1.56 mmol) and DIPEA (1.38 mL, 7.82 mmol) added. The reaction mixture was heated to 100° C. overnight. The resultant mixture was allowed to cool to RT and was concentrated in vacuo. The residue was passed down an Isolute® SCX-2 cartridge, eluting with DCM, MeOH and 2M NH3 in MeOH to afford crude product. This was purified by column chromatography (silica gel, gradient 0-10% MeOH in DCM) to afford 201 as a pale yellow gum, which solidified on standing (204 mg, 35%). LCMS (Method K): RT 3.31 min [M+H]+ 380.1 1H NMR (DMSO-d6, 400 MHz): δ 8.30 (1H, s), 8.15 (1H, s), 8.04 (1H, s), 7.66-7.54 (2H, m), 7.02 (1H, td, J=9.29, 2.34 Hz), 6.00 (1H, s), 4.51-4.37 (1H, m), 2.27-2.13 (1H, m), 2.07-1.95 (1H, m), 1.88-1.75 (2H, m), 1.70 (3H, d, J=6.70 Hz), 1.64-1.44 (3H, m), 1.39-1.26 (2H, m), 0.75-0.57 (1H, m)
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]2[O:22][CH:21]=[C:20]([C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)[C:15]=2[CH:16]=[N:17][C:18]=1[NH2:19])[CH3:11].[C:29]([N:33]=[C:34]=[O:35])([CH3:32])([CH3:31])[CH3:30].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:19][C:18]1[N:17]=[CH:16][C:15]2[C:20]([C:23]3[CH2:24][CH2:25][N:26]([C:34]([NH:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])[CH2:27][CH:28]=3)=[CH:21][O:22][C:14]=2[C:13]=1[O:12][C@@H:10]([C:3]1[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[Cl:1])[CH3:11]
Reactant: C[C@@H](Oc1c(N)ncc2c(C3=CCNCC3)coc12)c1c(Cl)ccc(F)c1Cl
Reactant: CC(C)(C)N=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](Oc1c(N)ncc2c(C3=CCN(C(=O)NC(C)(C)C)CC3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 7-[(R)-1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-3-(1,2,3,6-tetrahydropyridin-4-yl)-furo[3,2-c]pyridin-6-ylamine (10.0 mg, 0.0237 mmol), tert-butyl isocyanate (0.0042 g, 0.043 mmol), DIPEA (33 μL, 0.19 mmol) in DMF (1 mL) was stirred at rt for 15 min. Purification by HPLC afforded the title compound as a colorless solid. 1H NMR (400 MHz, CD3OD): δ=1.36 (s, 9H), 1.89 (d, J=6.8 Hz, 3H), 2.49 (br. s., 2H), 3.59 (t, J=5.7 Hz, 2H), 4.04 (d, J=2.5 Hz, 2H), 6.25 (br. s., 1H), 6.48-6.53 (m, 1H), 7.22 (t, J=8.7 Hz, 1H), 7.40 (dd, J=9.0, 4.9 Hz, 1H), 7.65 (s, 1H), 8.20 (s, 1H). MS (ES+): m/z 521.07/523.09 (100/72) [MH+]. HPLC: tR=3.37 min (ZQ3, polar—5 min).
Reaction SMILES: [OH:1][CH2:2][C:3]1O[CH:5]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:7](=[O:9])[CH:8]=1.[CH2:29]([NH2:32])[CH2:30][CH3:31]>C(O)C.O>[OH:1][CH2:2][C:3]1[N:32]([CH2:29][CH2:30][CH3:31])[CH:5]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:7](=[O:9])[CH:8]=1
Reactant: CCCCCCCCCCCCCCCCCCOc1coc(CO)cc1=O
Reactant: CCCN
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOc1cn(CCC)c(CO)cc1=O

Procedure:
A mixture of 20.0 g (51 mMole) 2-hydroxymethyl-5-octadecyloxy-4-pyranone and 30 mL of a 40% solution of propylamine in ethanol is heated in an autoclave at 100°-110° C. for 5 hours. After cooling, the crystallizate formed is taken up in water, stirred, filtered off, dried and recrystallized from ethyl acetate, colorless crystals thereby being obtained; m.p. 120°-121° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][CH:12]=1.[N+:13]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([Cl:23])[CH:17]=1)([O-:15])=[O:14]>C(O)(=O)C>[N+:13]([C:16]1[CH:22]=[CH:21][C:19]([N:20]2[C:9](=[O:10])[C:4]3=[CH:3][C:2]([Cl:1])=[CH:12][CH:11]=[C:5]3[C:6]2=[O:8])=[C:18]([Cl:23])[CH:17]=1)([O-:15])=[O:14]
Reactant: Nc1ccc([N+](=O)[O-])cc1Cl
Reactant: O=C1OC(=O)c2cc(Cl)ccc21
Solvent: CC(=O)O
Product: O=C1c2ccc(Cl)cc2C(=O)N1c1ccc([N+](=O)[O-])cc1Cl

Procedure:
The starting material is prepared as follows: The mixture of 3.0 g of 4-chlorophthalic anhydride, 2.8 g of 4-nitro-2-chloroaniline and 30 ml of acetic acid is refluxed for 24 hours. It is cooled, the precipitate formed filtered off and washed with diethyl ether, to yield the N-(4-nitro-2-chlorophenyl)-4-chlorophtalimide melting at 209°-212°.