Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][C:6]1[C:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]OS(C)(=O)=O)=[CH:10][CH:9]=[CH:8][C:7]=1[O:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28].[I-:32].[Na+].C(#N)C>CCOCC>[CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][C:6]1[C:7]([O:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:8][CH:9]=[CH:10][C:11]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][I:32]
Reactant: [I-]
Reactant: COC(=O)CCCOc1cccc(CCCCCCOS(C)(=O)=O)c1CCC(=O)OC
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Product: COC(=O)CCCOc1cccc(CCCCCCI)c1CCC(=O)OC
Temperature: 25 °C
Reaction time: 17 h
Yield: 97.2 %

Procedure:
A mixture of 10.81 g (ca. 23.37 mmol) of crude 2-(4-methoxy-4-oxobutoxy)-6-[6[(methylsulfonyl)oxy]hexyl]benzenepropanoic acid methyl ester (preceding example), 7.01 g (46.7 mmol) of anhydrous sodium iodide, and 44 mL of dry acetonitrile was stirred at room temperature for 17 hr and then refluxed for 3.5 hr. After being cooled, the mixture was diluted with 200 mL of ether and filtered with suction. The solids were washed thoroughly with ether. The filtrate and washes were combined and washed with 12% aqueous sodium bisulfite, and work-up was completed in the usual manner. There was obtained 11.14 g (97.3%) of 2-(6-iodohexyl)-6-(4-methoxy-4-oxobutoxy)benzenepropanoic acid methyl ester as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C@H:12]1[CH2:21][N:16]3[CH2:17][CH2:18][NH:19][CH2:20][C@@H:15]3[CH2:14][CH2:13]1)[CH:6]=[CH:5]2.Cl[C:23]1[N:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C@H:12]1[CH2:21][N:16]3[CH2:17][CH2:18][N:19]([C:23]4[N:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=4)[CH2:20][C@@H:15]3[CH2:14][CH2:13]1)[CH:6]=[CH:5]2
Reactant: Fc1ccc2c(ccn2C[C@@H]2CC[C@H]3CNCCN3C2)c1
Reactant: Fc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Fc1cnc(N2CCN3C[C@H](Cn4ccc5cc(F)ccc54)CC[C@H]3C2)nc1
Temperature: 95 °C
Reaction time: 72 h
Yield: 39.8 %

Procedure:
A mixture of 2.20 g (7.67 mmol) of (7R,9aS)-7-(5-fluoroindol-1-yl)methyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine, 1.02 g (7.67 mmol) of 2-chloro-5-fluoropyrimidine and 1.95 g (18.4 mmol) of sodium carbonate in 100 mL of water was stirred at 95° C. for 72 h. The mixture was cooled to room temperature, extracted with chloroform (3×), the combined organic phase was washed with brine, dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with 50:50 ethyl acetate:hexane gave 1.17 g (40%) of the title compound. mp (.HCl) 180–182° C. HRMS calc for HRMS calcd for C21H23F2N5: 383.1922, found: 383.1924.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]>C(Cl)(Cl)Cl>[NH2:9][C:10]1[C:19]([Br:1])=[CH:18][C:17]([I:20])=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc(I)ccc1N
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(I)cc(Br)c1N
Reaction time: 8 h
Yield: 81.9 %

Procedure:
N-Bromosuccinimide (13.5 g, 76.0 mmol) was added in portions over 1.5 h to a stirred solution of methyl 2-amino-5-iodobenzoate (20 g, 72 mmol) in CHCl3 (320 mL) at RT. This was stirred overnight and then silica gel chromatography (step gradient elution with hexane containing 10 to 30% DCM) afforded impure methyl 2-amino-3-bromo-5-iodobenzoate (21 g) as a white solid that was used as such. A flask containing a mixture of 3- (trifluoromethyl)phenylboronic acid (3.73 g, 19 6 mmol), methyl 2-amino-3-bromo-5-iodobenzoate (7.0 g, 16 mmol), K2CO3 (6.85 g, 49 6 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (1.4 g, 1 7 mmol), dioxane (140 mL), and water (28 mL) was degassed and flushed with N2 twice and then heated at 70° C. for 3 h. It was cooled to RT, diluted with EtOAc, washed with water (2×), brine, and then dried over Na2SO4. Removal of the solvents followed by silica gel chromatography (step gradient elution with DCM containing 0 to 7% MeOH) afforded impure methyl 4-amino-5-bromo-3′-(trifluoromethyl)biphenyl-3-carboxylate (6.2 g, 10.44 mmol, 63.2% yield) as a white solid that was used as such. A mixture of 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (303 mg, 1.00 mmol), methyl 4-amino-5-bromo-3′-(trifluoromethyl)biphenyl-3-carboxylate (250 mg, 0.668 mmol), tetrakistriphenylphosphine palladium(0) (77 mg, 0.067 mmol), K2CO3 (369 mg, 2.67 mmol) in a microwave vial was flushed with nitrogen and DMF (2.7 mL) was added. The vial was sealed and heated at 100° C. overnight. The reaction was partitioned between EtOAc and water. The organic phase was washed with brine, dried over sodium sulfate, and the solvent removed. Silica gel chromatography (step gradient elution with hexane containing 0, to 20% EtOAc) afforded methyl 4′-amino-4″-(4-methylpiperidin-1-yl)-3-trifluoromethyl-[1,1′:3′,1″-terphenyl]-5′-carboxylate (150 mg, 0.532 mmol, 80% yield). MS (ESI) m/z 470.20 (M+H). 1H NMR (500 MHz, chloroform-d) δ ppm 8.16 (1H, d, J=2.14 Hz), 7.81 (1H, s), 7.73-7.78 (1H, m), 7.49-7.56 (3H, m), 7.37 (2H, d, J=8.55 Hz), 7.05 (2H, d, J=8.55 Hz), 6.15 (2H, br, s.), 3.95 (3H, s), 3.26-3.38 (4H, m), 2.60-2.69 (4H, m), 2.39 (3H, s).
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:46][C:47]([S:50][C:51]([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)([CH3:49])[CH3:48])[CH2:12][CH2:13][N:14]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:15][C:16]([CH3:38])([S:18][C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:17])C(=O)C2=CC=CC=C12.C(O)C.O.O.NN>C1COCC1>[C:42]([O:41][C:39]([N:14]([CH2:15][C:16]([CH3:38])([S:18][C:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:17])[CH2:13][CH2:12][N:11]([CH2:46][C:47]([S:50][C:51]([C:64]1[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=1)([C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1)[C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)([CH3:49])[CH3:48])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][NH2:5])=[O:40])([CH3:43])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)N(CCN(CCCCCN1C(=O)c2ccccc2C1=O)CC(C)(C)SC(c1ccccc1)(c1ccccc1)c1ccccc1)CC(C)(C)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: NN
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N(CCN(CCCCCN)CC(C)(C)SC(c1ccccc1)(c1ccccc1)c1ccccc1)CC(C)(C)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 67.8 %

Procedure:
A 250 mL single-necked round-bottomed flask, equipped with stir bar and reflux condenser, was charged with 9-phthalimido-N1 -(t-butoxycarbonyl)-N1,N4 -bis[2-methyl-2-(triphenylmethylthio)propyl]-1,4-diazanonane (5.50 g, 5.319 mmol) in 25 mL of THF. To this was added 100 mL ethanol and 5 mL water. The addition of water caused the starting material to precipitate out of solution. Hydrazine hydrate (1.2 mL, 24.7 mmol, 466 mole %) was added, and the reaction heated at reflux for two days. The reaction mixture was concentrated and partitioned between 100 mL each of water and 0.25M K2CO3. The organic layer was separated and washed once with brine (75 mL), dried over Na2SO4 and concentrated to a solid foam. Purification of the crude product by low-pressure liquid chromatography (100 g SiO2, CHCl3 -->5% methanol in CHCl3, the column pre-treated with 200 mL 2% triethylamine in CHCl3) afforded 3.27 g of pure N1 -(t-butoxycarbonyl)-N1,N4 -bis(2-methyl-2-(triphenylmethylthio)propyl]-1,4,10-triazadecane as a yellow foam (68% yield). Chemical analysis of the purified product confirmed its identity as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:13](=[O:30])[NH:14][CH:15]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:16]([F:19])([F:18])[F:17])[N:8]2[CH2:11][CH3:12])=[CH:4][C:3]=1[CH2:31][NH:32]C(=O)OC(C)(C)C.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>ClCCl>[F:40][C:41]([F:46])([F:45])[C:42]([O-:44])=[O:43].[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:13](=[O:30])[NH:14][CH:15]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=3)[C:16]([F:17])([F:19])[F:18])[N:8]2[CH2:11][CH3:12])=[CH:4][C:3]=1[CH2:31][NH3+:32]
Reactant: CCn1c(C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc2cc(CNC(=O)OC(C)(C)C)c(Cl)cc21
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1c(C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc2cc(C[NH3+])c(Cl)cc21
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
tert-Butyl {[6-chloro-1-ethyl-2-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-indol-5-yl]methyl}carbamate (0.42 g, 0.72 mmol) was dissolved in dichloromethane (5 ml), and trifluoroacetic acid (0.82 g, 7.18 mmol) was added. The reaction mixture was stirred at room temperature for 2 h and then the solvent was removed under reduced pressure. 0.42 g (97% of theory) of [6-chloro-1-ethyl-2-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-indol-5-yl]methanaminium trifluoroacetate was obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].CO.O.O[Li].O>C1COCC1>[CH3:31][C:29]([CH3:30])([CH3:32])[C:28]#[C:27][C:7]1[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([N:10]([C@H:20]2[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]2)[C:11]([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]2)=[O:12])[CH:8]=1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C#Cc1cc(N(C(=O)[C@H]2CC[C@H](C)CC2)[C@H]2CC[C@H](O)CC2)c(C(=O)O)s1
Reaction time: 2 h

Procedure:
5-(3,3-Dimethyl-but-1-ynyl)-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (0.10 g, 0.22 mmol) is dissolved in a 3:2:1 mixture of THF:methanol:H2O (5.0 mL) and treated with a 1N solution of LiOH.H2O (0.65 mL, 0.65 mmol). After 2 h of stifling at 60° C., the reaction mixture is concentrated under reduced pressure on a rotary evaporator. The mixture is partitioned between ethyl acetate and water. The water layer is acidified using 0.1 N HCl. The EtOAc layer is separated and dried over Na2SO4. Filtration and removal of the solvent under reduced pressure on a rotary evaporator followed by purification by column chromatography using methanol and dichloromethane (1:9) as eluent to obtain 5-(3,3-dimethyl-but-1-ynyl)-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid as a solid, 30 mg (30%). ESI− (M−H): 444.3.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:63])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH2:52][O:53][CH2:54][C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[CH:46]([O:61][CH3:62])[CH2:45]2)[CH:7]([CH3:64])[CH:6]([O:65][Si](C(C)(C)C)(C)C)[CH2:5][C:4]1=[O:73])[CH3:2]>C(#N)C.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:63])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH2:52][O:53][CH2:54][C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)[CH:46]([O:61][CH3:62])[CH2:45]2)[CH:7]([CH3:64])[CH:6]([OH:65])[CH2:5][C:4]1=[O:73])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCCOCc4ccccc4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCCOCc4ccccc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 44.9 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(2'"-benzyloxyethoxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone-(10 mg) in acetonitrile (500 μl) was added a solution of 2% HF in aqueous acetonitrile (200 μl), and the mixture stirred at room temperature. After 2.5 hours, the solution was diluted with ethyl acetate, extracted with saturated sodium bicarbonate solution and the organic phase dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (4 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([OH:11])=O)[C:5]([Cl:8])=[N:6][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:24]([O:26][C:27](=[O:32])[CH2:28]C(O)=O)[CH3:25].C[Mg]Br.Cl>O1CCCC1.C(OCC)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH2:28][C:27]([O:26][CH2:24][CH3:25])=[O:32])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: O=C(O)c1cc(Br)cnc1Cl
Reactant: CCOC(=O)CC(=O)O
Agent: C[Mg]Br
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cc(Br)cnc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 54.9 %

Procedure:
To a suspension of 5-bromo-2-chloropyridine-3-carboxylic acid (Intermediate 11, 7.0 g, 29.7 mmol) in anhydrous tetrahydrofuran (70 mL), 1,1′-carbonylbis(1H-imidazole) (CDI) (5.8 g, 35.7 mmol) was added. The reaction mixture was heated to reflux for 2 h then cooled to room temperature and the crude solution was used in the next step with out further purification. A solution of 3-ethoxy-3-oxopropanoic acid (3.93 g, 29.7 mmol) in anhydrous tetrahydrofuran (80 mL) was cooled to 0° C. and methyl magnesium bromide in diethyl ether (16 mL, 3M solution) was added in drop wise manner. After stirring for 20 min at 0° C., the crude solution which was prepared from Intermediate 11 and CDI was added and the reaction was heated to 60° C. After heating for 16 h, the reaction mixture was cooled to room temperature and then poured into water. The pH was adjusted to 5 with concentrated hydrochloric acid solution, and the solution was extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulphate and concentrated under reduce pressure to afford ethyl 3-(5-bromo-2-chloropyridin-3-yl)-3-oxopropanoate (5.0 g, 55%) as a reddish oil.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Br:7][C:8]1[N:9]([CH2:18][C:19]#[C:20][CH3:21])[C:10]2[C:15](=[O:16])[NH:14][N:13]=[CH:12][C:11]=2[N:17]=1.Cl[CH2:23][C:24]1[N:33]=[C:32]([CH3:34])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=1>CN(C)C=O.O>[Br:7][C:8]1[N:9]([CH2:18][C:19]#[C:20][CH3:21])[C:10]2[C:15](=[O:16])[N:14]([CH2:23][C:24]3[N:33]=[C:32]([CH3:34])[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)[N:13]=[CH:12][C:11]=2[N:17]=1
Reactant: CC#CCn1c(Br)nc2cn[nH]c(=O)c21
Reactant: Cc1nc(CCl)nc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCn1c(Br)nc2cnn(Cc3nc(C)c4ccccc4n3)c(=O)c21
Temperature: 80 °C
Reaction time: 1 h

Procedure:
489 mg (1.5 mol) cesium carbonate were added to a solution of 300 mg (1.12 mmol) 2-bromo-3-(but-2-ynyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one and 344 mg (1.35 mmol) 2-chloromethyl-4-methyl-quinazoline in 4 ml of dimethylformamide and this mixture was stirred for 1 h under an argon atmosphere at 80° C. Then the mixture was diluted with 10 ml of water, the solution was cooled to approx. 10° C., the precipitate formed was suction filtered and dried and purified by column chromatography (silica gel; eluant: dichloromethane/ethanol 1:0->19:1).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].N1C=CC=CC=1.[CH3:11][CH:12]1[N:16]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:15](=[O:23])[NH:14][CH2:13]1.[CH3:24][N:25]1[CH:29]=[C:28]([C:30]2[CH:35]=[C:34]([O:36][C:37]3[CH:38]=[CH:39][C:40]([NH2:43])=[N:41][CH:42]=3)[CH:33]=[CH:32][N:31]=2)[CH:27]=[N:26]1>C(Cl)Cl>[CH3:11][CH:12]1[CH2:13][N:14]([C:1]([NH:43][C:40]2[CH:39]=[CH:38][C:37]([O:36][C:34]3[CH:33]=[CH:32][N:31]=[C:30]([C:28]4[CH:27]=[N:26][N:25]([CH3:24])[CH:29]=4)[CH:35]=3)=[CH:42][N:41]=2)=[O:2])[C:15](=[O:23])[N:16]1[CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: Cn1cc(-c2cc(Oc3ccc(N)nc3)ccn2)cn1
Reactant: O=C(Cl)Cl
Reactant: CC1CNC(=O)N1C1CCOCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1CN(C(=O)Nc2ccc(Oc3ccnc(-c4cnn(C)c4)c3)cn2)C(=O)N1C1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 9 %

Procedure:
A 0° C. solution of phosgene (15% in toluene, 2 mL, 2.84 mmol) in DCM (5 mL) was treated drop-wise with a solution of pyridine (0.1 mL, 1.236 mmol) and 5-methyl-1-(tetrahydro-2H-pyran-4-yl)imidazolidin-2-one (0.103 g, 0.561 mmol) in DCM (5 mL), stirred at RT for 1 h, then concentrated to dryness. The residue was dissolved in DCM (5 mL), cooled to 0° C., treated with a solution of Example A2 (0.10 g, 0.374 mmol) and pyridine (0.1 mL) in DCM (5 mL), warmed to RT and stirred overnight. The solids were removed via filtration, washed with DCM and the filtrate concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 4-methyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (16 mg, 9%). 1H NMR (400 MHz, DMSO-d6): δ 10.96 (s, 1 H), 8.36 (d, J=5.7 Hz, 1 H), 8.25 (s, 1 H), 8.23 (d, J=2.9 Hz, 1 H), 8.06 (d, J=9.0 Hz, 1 H), 7.95 (s, 1 H), 7.71 (dd, J=9.0, 2.9 Hz, 1 H), 7.22 (d, J=2.4 Hz, 1 H), 6.68 (dd, J=5.7, 2.4 Hz, 1 H), 3.90 (m, 4H), 3.87 (m, 1 H), 3.84 (s, 3 H), 3.66 (m, 1 H), 3.39 (m, 1 H), 3.34 (m, 1 H), 2.05 (m, 1 H), 1.90 (m, 1 H), 1.70 (m, 1 H), 1.68 (m, 1 H), 1.28 (d, J=5.4 Hz, 3H); MS (ESI) m/z: 478.2 (M+H+).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:32].O1CCOCC1>ClCCl.C(OC(C)C)(C)C>[ClH:32].[NH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][CH:19]([C:22]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[O:30])[CH2:20][CH2:21]2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(C(=O)c3ccc(F)cc3)CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Product: N[C@H]1CC[C@H](CCN2CCC(C(=O)c3ccc(F)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
Trans-(4-{2-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-ethyl}-cyclohexyl)-carbamic acid tert-butyl ester (1.4 g, 3.24 mmol) was dissolved in 2 ml dichloromethane and 4N HCl in dioxane (9.7 ml, 38.8 mmol) was added. The white suspension was stirred for 4 hours at room temperature, diluted with diisopropylether and filtered. The crystals were washed with diisopropylether and dried for 2 hours at 50° C. and <20 mbar, to get the desired salt as a white solid (1.2 g, 100%) [MS: m/e=333.3 (M+H+)].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.ON1C2C=CC=CC=2N=N1.Cl.N1(S(N)(=O)=O)CCNCC1.Cl.[F:36][C:37]1[C:42]([F:43])=[CH:41][CH:40]=[CH:39][C:38]=1[CH2:44][S:45][C:46]1[N:51]=[C:50]([NH:52][S:53]([N:56]2[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)(=[O:55])=[O:54])[CH:49]=[C:48]([O:62][CH3:63])[N:47]=1.CN1CCOCC1>CN(C=O)C>[F:36][C:37]1[C:42]([F:43])=[CH:41][CH:40]=[CH:39][C:38]=1[CH2:44][S:45][C:46]1[N:51]=[C:50]([NH:52][S:53]([N:56]2[CH2:57][CH2:58][N:59]([C:10](=[O:12])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:60][CH2:61]2)(=[O:54])=[O:55])[CH:49]=[C:48]([O:62][CH3:63])[N:47]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: COc1cc(NS(=O)(=O)N2CCNCC2)nc(SCc2cccc(F)c2F)n1
Agent: Cl
Agent: NS(=O)(=O)N1CCNCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1cc(NS(=O)(=O)N2CCN(C(=O)CNC(=O)OC(C)(C)C)CC2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(tert-butoxycarbonyl)glycine (0.11 g) in DMF (10 mL) was added 1,3-Dicyclohexycarbodiimide (0.14 g) and 1-hydroxybenzotriazole hydrate (94 mg). After stirring at room temperature for 1 h, a solution of N42-[[(2,3-Difluorophenyl)methyl]thio]-6-methoxypyrimidin-4-yl]piperazine-1-sulfonamide, hydrochloride salt (the product of step i, 0.27 g) and N-methylmorpholine (78 μL) in DMF (5 mL) was added dropwise and stirring continued at room temperature for 24 h. The mixture was filtered, rinsed with DCM and the filtrate evaporated. The crude material was purified by column chromatography on silica gel using EtOAc/isohexane (3:2) as eluent to give the subtitle compound as a foam. Yield: 0.24 g
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]2[N:13]=[C:14]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[NH:15][C:16]=2[CH3:17])=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[NH:25]1[CH2:28][CH:27]([C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)[CH2:26]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]2[NH:13][C:14]([CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[N:15][C:16]=2[CH3:17])=[CH:7][C:3]=1[C:4]([N:25]1[CH2:28][CH:27]([C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)[CH2:26]1)=[O:5]
Reactant: Cc1cc(C)c(-c2nc(C3CCOCC3)[nH]c2C)cc1C(=O)O
Reactant: N#Cc1ccc(C2CNC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c(-c2[nH]c(C3CCOCC3)nc2C)cc1C(=O)N1CC(c2ccc(C#N)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.8 %

Procedure:
The mixture of 2,4-dimethyl-5-(5-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-4-yl)benzoic acid (compound 164.2, 157 mg, 0.5 mmol), 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2, 126 mg, 0.65 mmol), EDCI (143 mg, 0.75 mmol), HOBt (93 mg, 0.55 mmol) and DIEA (345 μL, 2.00 mmol) in DMF (4 mL) was stirred at room temperature for 16 hours. The reaction was diluted with water and extracted with EtOAc (30 mL). The organic phase was washed with saturated NaHCO3 (10 mL), brine (3×20 mL), dried over MgSO4 and concentrated under reduced pressure. The residue was purified by preparative TLC with 5% methanol in dichloromethane and lyophilized to give 95 mg (42%) of the title compound as a white solid. m/z (ES+) 455 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([N:6]([CH2:9][CH3:10])[CH2:7][CH3:8])[CH2:3][CH2:4][Br:5].S(C1C=CC(C)=CC=1)(O[CH2:15][CH:16](C)[CH2:17]CCCOC1C=CC=CC=1)(=O)=O>>[BrH:5].[CH2:1]([CH:2]([N:6]([CH2:9][CH3:10])[CH2:7][CH3:8])[CH2:3][CH2:4][Br:5])[CH:16]([CH3:17])[CH3:15]
Reactant: CCN(CC)C(C)CCBr
Reactant: Cc1ccc(S(=O)(=O)OCC(C)CCCCOc2ccccc2)cc1
Product: Br
Product: CCN(CC)C(CCBr)CC(C)C
Yield: 75 %

Procedure:
The procedures of preparing 1-methyl-3-bromopropyldiethylamine as described above were repeated except that 11.31 g of 2-methyl-6-phenoxyhexyl tosylate was employed instead of the 10 g of 4-phenoxy-2-butyl tosylate, and 5.33 g of 1-isobutyl-3-bromopropyldiethylamine hydrobromide was obtained in a yield of 75%.