Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][OH:12])=[CH:2]1.[C:13]([NH2:16])(=[O:15])[CH3:14]>C1C=CC=CC=1>[C:13]([NH:16][CH2:3][CH2:2][CH2:1][C:9]1([CH3:8])[C:2]2[CH2:1][C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[C:3]=2[CH2:10][CH2:11][O:12]1)(=[O:15])[CH3:14]
Reactant: CC(N)=O
Reactant: OCCC1=CCc2ccccc21
Solvent: c1ccccc1
Product: CC(=O)NCCCC1(C)OCCC2=C1Cc1ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of indene-3-ethanol (4.2 g) and N-(4-oxopentyl(acetamide (3.7 g), described by L. P. Kuhn et al., J. Am. Chem. Soc., 89, 3858 (1967), in 300 ml of dry benzene is stirred and heated at reflux. Water is collected in a Dean-Stark trap. After removal of the water five drops of boron trifluoride-etherate is added and the mixture refluxed 30 min. using the water-separator again. After stirring at room temperature overnight the reaction mixture is evaporated to dryness. The solid residue is dissolved in chloroform and washed successively with 10% aqueous sodium bicarbonate, water, and brine. The chloroform solution is dried over magnesium sulfate, filtered, and evaporated to yield 1-[3-(acetamido)propyl]-1-methyl-1,3,4,9-tetrahydroindeno[2,1-c]pyran, νmaxCHCl3 1650 cm-1.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:6]([N:13]=1)=[N+:7]([O-])[CH:8]=[CH:9][C:10]=2[CH3:11])[CH3:2].O=P(Cl)(Cl)[Cl:16].[NH4+].[OH-]>C(Cl)(Cl)Cl>[Cl:16][C:8]1[N:7]=[C:6]2[N:13]=[C:3]([CH2:1][CH3:2])[NH:4][C:5]2=[C:10]([CH3:11])[CH:9]=1
Reactant: CCc1nc2c([nH]1)c(C)cc[n+]2[O-]
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCc1nc2nc(Cl)cc(C)c2[nH]1
Temperature: 80 °C

Procedure:
A mixture of 29.75 g (0.168 mol) of the product of Step A, CHCl3 (25 mL) and POCl3 (160 mL) was heated to 80° C. for 1 hour. After pouring over ice, the mixture was neutralized by careful addition of NH4OH and extracted with EtOAc. Concentration gave 23.8 g of the title compound as a solid.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([N:17]3[CH2:22][CH:21]=[C:20](B4OC(C)(C)C(C)(C)O4)[CH2:19][CH2:18]3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1.Br[C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[C:37]#[N:38]>>[CH3:1][N:2]([CH3:32])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([N:17]3[CH2:22][CH:21]=[C:20]([C:34]4[CH:41]=[CH:40][CH:39]=[C:36]([C:37]#[N:38])[CH:35]=4)[CH2:19][CH2:18]3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1
Reactant: CN(C)C1CCN(c2ccc(NC(=O)N3CC=C(B4OC(C)(C)C(C)(C)O4)CC3)cc2)C1
Reactant: N#Cc1cccc(Br)c1
Product: CN(C)C1CCN(c2ccc(NC(=O)N3CC=C(c4cccc(C#N)c4)CC3)cc2)C1

Procedure:
4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide was reacted with 3-bromobenzonitrile by method O-a. This resulted in the product with the molecular weight of 415.54 (C25H29N5O); MS (ESI): 416 (M+H+)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)=[CH:9][CH2:10][OH:11])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:38]([O:40][C:41](=[O:54])[CH:42]([O:51][CH2:52][CH3:53])[CH2:43][C:44]1[CH:49]=[CH:48][C:47](O)=[CH:46][CH:45]=1)[CH3:39].CCOC(/N=N/C(OCC)=O)=O>>[CH2:38]([O:40][C:41](=[O:54])[CH:42]([O:51][CH2:52][CH3:53])[CH2:43][C:44]1[CH:49]=[CH:48][C:47]([O:11][CH2:10][CH:9]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([Br:18])=[CH:16][CH:17]=2)[C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:46][CH:45]=1)[CH3:39]
Reactant: OCC=C(c1ccc(Br)cc1)c1ccc(Br)cc1
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C(Cc1ccc(OCC=C(c2ccc(Br)cc2)c2ccc(Br)cc2)cc1)OCC
Yield: 56.2 %

Procedure:
Reaction of 3,3-bis-(4-bromophenyl)-prop-2-en-1-ol (0.50 g, 1.36 mmol), triphenylphosphine (0.39 g, 1.50 mmol), 2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (0.39 g, 1.63 mmol) and diethy lazodicarboxylate (0.26 g, 1.51 mmol) in an identical manner to example 1 gave the title compound (450 mg, 56%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[NH:15][C:14](=[O:16])[C:13]2[C:8](=[CH:9][C:10]([Cl:18])=[C:11]([CH3:17])[CH:12]=2)[N:7]=1)(=[O:3])[CH3:2].[Br:19]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([O:4][CH2:5][C:6]1[NH:15][C:14](=[O:16])[C:13]2[C:8](=[CH:9][C:10]([Cl:18])=[C:11]([CH2:17][Br:19])[CH:12]=2)[N:7]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)OCc1nc2cc(Cl)c(C)cc2c(=O)[nH]1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)OCc1nc2cc(Cl)c(CBr)cc2c(=O)[nH]1
Reaction time: 3.5 h

Procedure:
To a suspension of 2-acetoxymethyl-7-chloro-6-methyl-3,4-dihydroquinazolin-4-one (2.00 g, 7.5 mmol) in anhydrous carbon tetrachloride (120 ml) was added N-bromosuccinimide (1.47 g, 8.3 mmol) followed by dibenzoyl peroxide (7.0 mg) under argon. The reaction mixture was placed in a preheated oil bath at 120° C. and stirred at this temperature for 3.5 hours while illuminating. The solvent was removed in vacuo and the residue was twice purified by column chromatography using 40% ethyl acetate in chloroform as eluant (1.02 g, 40%), mp 190-195° C., 1H-NMR (DMSO-d6) 2.14 (s, 3H, CH3CO), 4.91, 4.97 (2×s, 4H, 2-CH2 and 6-CH2), 7.78 (s, 1H, 8-H), 8.36 (s, 1H, 5-H), 12.61 (s, 1H, N3—H). This product was used in the next experiment without any further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH2:14][NH:13][CH2:12][C:9]21[CH2:11][CH2:10]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:17][C:18]#[N:19]>>[CH2:1]([N:8]1[CH2:15][CH2:14][N:13]([CH2:17][C:18]#[N:19])[CH2:12][C:9]21[CH2:10][CH2:11]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCBr
Reactant: c1ccc(CN2CCNCC23CC3)cc1
Product: N#CCN1CCN(Cc2ccccc2)C2(CC2)C1

Procedure:
The title compound is synthesized by coupling of 4-Benzyl-4,7-diaza-spiro[2.5]octane (which prepared in analogy to a published literature procedure (WO030828859)) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+H=242.2: CtRef=3.84.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].Cl[O-].[Na+].O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[F:1][C:2]([F:11])([F:12])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: OC(c1ccccc1)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccccc1)C(F)(F)F

Procedure:
10.0 g (0.057 mol) of 2,2,2-trifluoro-1-phenylethanol and 0.96 g (0.0028 mol) of tetrabutylammonium hydrogen sulfate are dissolved in 250 ml of methylene chloride at room temperature. 35 ml (0.068 mol) of an approximately 12% strength sodium hypochlorite solution are metered in within 20 minutes with vigorous stirring and the mixture is stirred for a further 6 hours at room temperature. The reaction mixture is added to 200 ml of water, the phases are separated, the aqueous phase is extracted several times with methylene chloride and the combined organic phases are washed with saturated aqueous sodium chloride solution. After drying the organic phase with sodium sulfate, the volatiles are distilled off. Following distillation of the crude product in a kugelrohr (24 torr, 90°-115° C. bath temperature), 7.45 g (75% of theory) of trifluoroacetylbenzene are obtained. nD20 : 1.4658.
Reaction SMILES: [OH:1][C@H:2]([CH:7]([CH3:9])[CH3:8])[C:3]([O:5][CH3:6])=[O:4].[Cl:10][C:11]1[CH:16]=[CH:15][C:14](O)=[CH:13][C:12]=1[CH3:18]>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([O:1][C@@H:2]([CH:7]([CH3:9])[CH3:8])[C:3]([O:5][CH3:6])=[O:4])=[CH:13][C:12]=1[CH3:18]
Reactant: Cc1cc(O)ccc1Cl
Reactant: COC(=O)[C@H](O)C(C)C
Product: COC(=O)[C@@H](Oc1ccc(Cl)c(C)c1)C(C)C

Procedure:
The title compound was prepared following the same protocol as described in Step 1, Example 42, using the (R)-methyl 2-hydroxy-3-methylbutanoate instead of the (S)-methyl 2-hydroxypropanoate and the 4-chloro-3-methylphenol instead of the m-cresol.
Reaction SMILES: [CH:1]1([C:6]2[N:14]3[C:9]([C:10](=[O:28])[NH:11][C:12]([C:15]4[CH:16]=[C:17]([S:24](Cl)(=[O:26])=[O:25])[CH:18]=[CH:19][C:20]=4[O:21][CH2:22][CH3:23])=[N:13]3)=[C:8]([CH2:29][CH3:30])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>ClCCl.CN(C)C1C=CN=CC=1>[CH2:22]([O:21][C:20]1[CH:19]=[CH:18][C:17]([S:24]([N:35]2[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]2)(=[O:26])=[O:25])=[CH:16][C:15]=1[C:12]1[NH:11][C:10](=[O:28])[C:9]2=[C:8]([CH2:29][CH3:30])[N:7]=[C:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:14]2[N:13]=1)[CH3:23]
Reactant: CN1CCNCC1
Reactant: CCOc1ccc(S(=O)(=O)Cl)cc1-c1nn2c(C3CCCC3)nc(CC)c2c(=O)[nH]1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1-c1nn2c(C3CCCC3)nc(CC)c2c(=O)[nH]1
Temperature: 0 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
0.42 g (0.92 mmol) of 3-(7-cyclopentyl-5-ethyl-4-oxo-3,4-dihydroimidazo-[5,1-f][1,2,4]triazin-2-yl)-4-ethoxybenzenesulphonyl chloride are dissolved in 15 ml of dichloromethane and cooled to 0° C. After addition of a spatula tip of 4-dimethylaminopyridine, 0.28 g (2.76 mmol) of N-methylpiperazine are added, and the reaction mixture is stirred at room temperature overnight. The mixture is diluted with dichloromethane, the organic phase is washed with ammonium chloride solution and dried over sodium sulphate and the solvent is removed under reduced pressure. Crystallization from ether gives 0.395 g (80%) of a colourless solid.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH3:9][C:10]1[CH:11]=[C:12]([NH:21][C:22]2[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=2)[CH:13]=[C:14]([C:16]2[S:20][CH:19]=[N:18][CH:17]=2)[CH:15]=1.[CH:32]([CH:34]1[CH2:39][CH2:38][CH:37]([C:40]([O:42][CH3:43])=[O:41])[CH2:36][CH2:35]1)=[O:33]>C1COCC1.O.C(OCC)(=O)C>[OH:33][CH:32]([C:19]1[S:20][C:16]([C:14]2[CH:13]=[C:12]([NH:21][C:22]3[N:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:25]=[CH:24][N:23]=3)[CH:11]=[C:10]([CH3:9])[CH:15]=2)=[CH:17][N:18]=1)[CH:34]1[CH2:35][CH2:36][CH:37]([C:40]([O:42][CH3:43])=[O:41])[CH2:38][CH2:39]1
Reactant: COC(=O)C1CCC(C=O)CC1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncs2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C1CCC(C(O)c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1
Temperature: -78 °C

Procedure:
A flask containing THF (5 mL) was cooled to −78° C. LDA (1.8 M in THF/heptane/ethylbenzene, 3.3 mL, 5.95 mmol) was added followed by a solution of N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (0.50 g, 1.49 mmol) in THF (5 mL) in one portion and the resulting solution was allowed to stir at −78° C. for thirty minutes. A solution of methyl 4-formylcyclohexanecarboxylate (336 mg, 1.93 mmol) in THF (5 mL) was then added in one portion and the resulting solution was stirred for 1 hour at −78° C. The reaction was then diluted with water and allowed to warm to room temperature. The mixture was then further diluted with water and ethyl acetate. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel to afford methyl 4-{hydroxyl[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]methyl}cyclohexanecarboxylate as a mixture of 4 isomers. MS ESI calc'd. for C24H25F3N4O3S [M+H]+ 507. found 507. 1H NMR (500 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.82 (d, J=5.1, 1H), 7.96 (s, 1H), 7.95 (s, 1H), 7.44 (s, 1H), 7.27 (d, J=4.9, 1H), 7.15 (s, 1H), 6.20 (d, J=5.0, 1H), 3.55 (s, 3H), 2.30 (s, 3H), 1.99 (m, 1H), 1.88 (m, 2H), 1.66 (s, 3H), 1.45 (m, 1H), 1.37-1.15 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[O:22]([CH2:29][C:30](O)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.C(OCC)C.C(OCC)(=O)C.CCCCCC>[O:21]=[C:20]1[C:4]2[C:5]3[C:6](=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]=3[CH:10]=[C:2]([NH:1][C:30](=[O:31])[CH2:29][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:3]=2)[CH:17]=[N:18][NH:19]1
Reactant: O=C(O)COc1ccccc1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(COc1ccccc1)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 20.4 %

Procedure:
Preparation of example 18 from the title compound of Example 7 (15 mg, 0.054 mmol), phenoxy-acetic acid (9 mg, 0.062 mmol), triethylamine (0.030 mL, 0.22 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (25 mg, 0.065 mmol) in N,N-dimethylformamide (1.0 mL) was carried out analogously to Example 11. Silica gel chromatography (1:1 ethyl acetate:hexane increasing to 100% ethyl acetate), also in an analogous manner, followed by diethyl ether trituration afforded the title compound (4.5 mg, 0.011 mmol) as a yellow powder in 20% yield.
Reaction SMILES: C[O:2][C@:3]1([C@@H:23]2[CH2:27][S:26][C:25](=[O:28])[N:24]2CC2C=CC(OC)=CC=2)[CH2:18][C@H:17]2[CH2:19][C@@H:5]([CH2:6][CH2:7][C@H:8]([CH3:22])[CH:9]=[CH:10][CH2:11][CH2:12][C:13]([CH3:21])=[CH:14][C:15](=[O:20])[O:16]2)[O:4]1.CO[C@]1([C@@H]2CSC(=O)N2CC2C=CC(OC)=CC=2)C[C@H]2C[C@@H](CCCC=CCCC(C)=CC(=O)O2)O1>>[OH:2][C@:3]1([C@@H:23]2[CH2:27][S:26][C:25](=[O:28])[NH:24]2)[CH2:18][C@H:17]2[CH2:19][C@@H:5]([CH2:6][CH2:7][C@H:8]([CH3:22])[CH:9]=[CH:10][CH2:11][CH2:12][C:13]([CH3:21])=[CH:14][C:15](=[O:20])[O:16]2)[O:4]1
Reactant: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CC[C@H](C)C=CCCC(C)=CC(=O)O3)O2)cc1
Agent: C/C1=C/C(=O)O[C@@H]2C[C@@H](CC[C@H](C)/C=C/CC1)O[C@@](O)([C@@H]1CSC(=O)N1)C2
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCC/C=C\CC/C(C)=C\C(=O)O3)O2)cc1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCCC=CCCC(C)=CC(=O)O3)O2)cc1
Product: CC1=CC(=O)O[C@@H]2C[C@@H](CC[C@H](C)C=CCC1)O[C@@](O)([C@@H]1CSC(=O)N1)C2

Procedure:
Application of the method shown in Example 46, with the modification that (R)-4-((1R,4Z,8E,10S,13R,15R)-15-methoxy-5,10-dimethyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one was substituted for (R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one, afforded the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)=[CH:20][CH:19]=4)[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>ClCCl>[N:27]1([CH2:26][CH2:25][O:24][C:21]2[CH:22]=[CH:23][C:18]([NH:17][C:15]3[N:16]=[C:12]4[CH:11]=[CH:10][CH:9]=[C:8]([C:5]5[CH:6]=[CH:7][C:2]([NH:1][C:39](=[O:46])[C:40]6[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=6)=[CH:3][CH:4]=5)[N:13]4[N:14]=3)=[CH:19][CH:20]=2)[CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: Nc1ccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred suspension of [5-(4-amino-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (0.05 g, 0.121 mmol) and triethylamine (19 μl, 0.133 mmol) in dichloromethane (1 ml) was added benzoyl chloride (17 μl, 0.133 mmol). The mixture was stirred for 18 hours at room temperature, then filtered through a plug of silica, washed with methanol and the filtrates combined and concentrated in vacuo. The product was purified by preparatory LCMS to provide the desired product. RT: 2.77 min, MI: 519, Method: 2; 1H NMR (DMSO, 300 MHz): 8.62 (s, 1H), 8.07 (2H, d), 7.97 (2H, d), 7.92 (d, 2H) 7.54-7.41 (m, 5H), 7.01 (1H, d), 6.85 (d, 2H), 4.31 (t, 2H), 3.37 (t, 2H), 3.26 (s, 4H), 3.12 (s, 1H), 2.99 (s, 1H), 2.02 (s, 4H).
Reaction SMILES: [C:1]([O:16][CH2:17][C@@H:18]([O:48][C:49](=[O:63])[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])[CH2:19][S:20][CH2:21][C@H:22]([NH:30][C:31]([O:33][CH2:34][CH:35]1[C:47]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:41]2[C:36]1=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:32])[C:23]([O:25]C(C)(C)C)=[O:24])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(O[C@H](COC(=O)CCCCCCCCCCC)CSC[C@@H](C(O)=O)NC(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)(=O)CCCCCCCCCCC>>[CH:37]1[C:36]2[CH:35]([CH2:34][O:33][C:31](=[O:32])[NH:30][C@H:22]([C:23]([OH:25])=[O:24])[CH2:21][S:20][CH2:19][C@H:18]([O:48][C:49](=[O:63])[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])[CH2:17][O:16][C:1](=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:41]=2[CH:40]=[CH:39][CH:38]=1
Reactant: CCCCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C)OC(=O)CCCCCCCCCCCCC
Agent: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OC(=O)CCCCCCCCCCC
Product: CCCCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OC(=O)CCCCCCCCCCCCC

Procedure:
The product was prepared from (R)-3-((R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-tert-butoxy-3-oxopropylthio)propane-1,2-diyl ditetradecanoate by following the procedure described for compound 6.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10](=[O:15])[CH2:11][CH2:12][CH2:13][NH2:14])[CH3:8].[C:16]([C@H:19](OS(C)(=O)=O)[CH2:20][CH3:21])(=[O:18])[NH2:17]>C(#N)C>[CH2:7]([O:9][C:10](=[O:15])[CH2:11][CH2:12][CH2:13][NH:14][C@H:19]([C:16](=[O:18])[NH2:17])[CH2:20][CH3:21])[CH3:8]
Reactant: CC[C@@H](OS(C)(=O)=O)C(N)=O
Reactant: CCOC(=O)CCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCCN[C@@H](CC)C(N)=O
Temperature: 80 °C

Procedure:
A mixture of powdered potassium carbonate (14.0 g, 96.2 mmol, 5 equiv.), ethyl-4-aminobutyrate (IVb) (6.5 g, 38.6 mmol, 2 equiv.) and methanesulfonic acid (R)-1-carbamoyl-propyl ester (IIi) (3.5 g, 19.3 mmol, 1 equiv.) in acetonitrile (40 ml, 11 vol.) is heated to 80° C. for 17 hours. The mixture is then filtered and the cake rinsed with acetonitrile (30 ml). Combined filtrates are concentrated to dryness under reduced pressure. The crude methyl-(S)-4-(1-carbamoylpropylamino)butyrate (VIg) obtained as a yellow oil is used directly in the next step.
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2-].[Na+].[CH2:17]1[O:20][CH:18]1[CH3:19].O>C1(C)C(C)=CC=CC=1>[OH:20][CH:18]([CH3:19])[CH2:17][N:13]1[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[S:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Reactant: CC1CO1
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: CC(O)CN1c2ccccc2Sc2ccccc21

Procedure:
A solution of phenothiazine (5 g, 25.1 mmol) and sodium amide (95%, 1.2 g, 29 mmol) in xylene (30 ml) was heated under reflux for 3 hours. Then propylene oxide (2.5 ml, 37 mmol) was added thereto under ice-cooling, and the reaction mixture was heated under reflux for 3 hours. To the reaction mixture was added water, and the mixture was extracted with chloroform, washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated. The thus-obtained black-brown solution containing xylene was purified by column chromatography on silica gel to give a dark black oil. Yield 4.19 g (65%).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][C:7]2[CH:8]=[C:9]([C:14]([C@@H:16]3[O:25][C@H:19]4[O:20][C:21]([CH3:24])([CH3:23])[O:22][C@H:18]4[C@@H:17]3[OH:26])=[O:15])[CH:10]=[CH:11][C:12]=2[CH3:13])=[CH:4][CH:3]=1.O.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:8]=[C:9]([C@H:14]([OH:15])[C@@H:16]3[O:25][C@H:19]4[O:20][C:21]([CH3:24])([CH3:23])[O:22][C@H:18]4[C@@H:17]3[OH:26])[CH:10]=[CH:11][C:12]=2[CH3:13])=[CH:27][CH:28]=1
Reactant: Cc1ccc(C(=O)[C@@H]2O[C@H]3OC(C)(C)O[C@H]3[C@@H]2O)cc1Cc1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccc([C@H](O)[C@@H]2O[C@H]3OC(C)(C)O[C@H]3[C@@H]2O)cc1Cc1ccc(Cl)cc1
Reaction time: 0.08 h
Yield: 99 %

Procedure:
(3-(4-chlorobenzyl)-4-methyl phenyl)((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)methanone (4, 26.1 g, 64.9 mmol) and CeCl3.7 H2O (29.0 g, 77.9 mmol) were suspended in 520 mL of MeOH. Sodium borohydride (982 mg, 26.0 mmol, dissolved in 10 mL of 1N aqueous NaOH) was added and the reactants slowly went into solution over about 5 minutes. Another 100 mg (2.6 mmol) of sodium borohydride was added to push the reaction to completion. The reaction was stirred for 10 minutes and quenched with 500 mL of saturated aqueous NH4Cl. Most of the MeOH was removed in vacuo and the residual solvents were diluted with a 1:1 (v:v) solution of saturated aqueous NH4Cl:brine. The aqueous layer was extracted three times with 500 mL of EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The crude product was used without further purification in the next step (26.2 g, 99% yield, >10:1 d.r.). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.14-7.31 (m, 5 H), 7.04 (d, J=8.3 Hz, 2 H), 6.04 (d, J=3.8 Hz, 1 H), 5.24 (t, J=3.4 Hz, 1H), 4.51 (d, J=3.8 Hz, 1 H), 4.14-4.21 (m, 2 H), 4.04 (d, J=1.5 Hz, 1 H), 3.97 (s, 2 H), 2.77 (d, J=3.0 Hz, 1 H), 2.20-2.27 (m, 3 H), 1.46 (s, 3 H), 1.33 (s, 3 H). MS (ES+) [M+NH4]+=422.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.[C:25](C1NC=CN=1)(C1NC=CN=1)=[O:26]>O1CCCC1>[F:8][C:7]1[C:2]2[NH:1][C:25](=[O:26])[N:11]([CH:12]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]3)[C:3]=2[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=1
Reactant: COc1cc(F)c(N)c(NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: COc1cc(F)c2[nH]c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 50 °C

Procedure:
A mixture of 1,1-dimethylethyl 4-[(2-amino-3-fluoro-5-methoxyphenyl)amino]-1-piperidinecarboxylate (D13a) (230 mg, 0.7 mmol), carbonyl diimidazole (150 mg, 1.0 mmol), and tetrahydrofuran (6 ml) was heated 1 h at 50° C. then partitioned between dichloromethane and water. The organic layer was purified by chromatography on silicagel eluting with 0 to 10% methanol in dichloromethane containing 0.2M ammonia to give the title compound as white crystals, 47%, 120 mg, M−-H=364.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([C:12]([NH2:14])=[O:13])[CH2:7][CH2:6][C:5]2([F:16])[F:15].CC1(C)C(C)(C)OB([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)O1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>O1CCOCC1.O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[F:15][C:5]1([F:16])[C:4]2[C:9](=[N:10][CH:11]=[C:2]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[CH:3]=2)[N:8]([C:12]([NH2:14])=[O:13])[CH2:7][CH2:6]1
Reactant: NC(=O)N1CCC(F)(F)c2cc(Br)cnc21
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: NC(=O)N1CCC(F)(F)c2cc(-c3cccnc3)cnc21
Temperature: 100 °C
Yield: 44.3 %

Procedure:
A mixture of 6-bromo-4,4-difluoro-3,4-dihydro-2H [1,8]naphthyridine-1-carboxylic acid amide (89.6 mg, 0.31 mmol), 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (92.3 mg, 0.46 mmol), K2CO3 (105 mg, 0.77 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II) (21.8 mg, 0.03 mmol) in 1 mL dioxane/water (9:1) is heated at 100° C. for 2 hrs. 30 mL of EtOAc is added. The mixture is washed with 2×10 mL of NaHCO3 and 1×10 mL brine. The organic phase is dried with MgSO4, filtered and concentrated. The residue is applied to a silica preparative TLC plate and purified (10% MeOH/CH2Cl2) to give 39.9 mg of the titled product.