Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:25])[CH2:4][CH2:5][CH2:6][CH2:7][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][CH2:22][CH2:23][CH3:24].[Br:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]Br.Cl>CCCCCC.C1(C)C=CC=CC=1>[CH2:3]([O:25][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][Br:26])[CH2:4][CH2:5][CH2:6][CH2:7][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][CH2:22][CH2:23][CH3:24]
Reactant: BrCCCCCCCCCCCCBr
Reactant: CCCCCCCCCCCCCCCCCCCCCCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCCCCCOCCCCCCCCCCCCBr
Temperature: 85 °C
Reaction time: 48 h
Yield: 78 %

Procedure:
Sodium hydride (60%, 0.98 g, 24.5 mmol) washed with hexane was suspended in toluene (16 ml), 1-docosanol (4.00 g, 12.2 mmol) was added, 1,12-dibromododecane (8.04 g, 24.5 mmol) was added, and the mixture was stirred at 85° C. for 2 days. The reaction mixture was cooled to room temperature, 1N hydrochloric acid (30 ml) was added dropwise thereto in a water bath to quench the reaction. The mixture was extracted with chloroform (100 ml), and washed 3 times with 1N hydrochloric acid (30 ml), 3 times with 5% aqueous sodium hydrogen carbonate solution (30 ml), and once with 20% aqueous sodium chloride solution (30 ml). The organic layer was dried over sodium sulfate, and the solvent of the filtrate was evaporated. The residue was isolated and purified by silica gel column chromatography and precipitated with methanol (70 ml) to give 12-docosyloxy-dodecyl bromide (yield 78%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1B(O)O.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:13]1[CH:12]=[CH:11][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: CN(N)C(=O)OC(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CN(Nc1ccc2ccccc2c1)C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 45.1 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 1.50 g, 10.26 mmol), 2-naphthaleneboronic acid (Lancaster; 1.90 g, 11.05 mmol), copper(II) acetate (1.90 g, 10.46 mmol) and triethylamine (3.6 mL, 25.8 mmol) in 1,2-dichloroethane (40 mL) was heated in an oil bath at 50° C. for 45 min. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 120 g column, eluting with 15-20% ethyl acetate/hexanes, to give N-methyl-N′-naphthalen-2-yl-hydrazinecarboxylic acid tert-butyl ester (1.26 g, 45%) as an orange oil that partially solidified. The Boc region of the 1H NMR spectrum integrated high, but the material was used directly in subsequent steps without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][C:6]([C:12]([OH:14])=O)=[CH:5]2.[F:15][B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.F[CH:38]1[CH2:43][CH:42]([F:44])[CH2:41][CH2:40][NH:39]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][C:6]([C:12]([N:39]1[CH2:40][CH2:41][C:42]([F:44])([F:15])[CH2:43][CH2:38]1)=[O:14])=[CH:5]2
Reactant: F[B-](F)(F)F
Reactant: O=C(O)c1cc2cc(Br)cc(Cl)c2[nH]1
Reactant: FC1CCNC(F)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc2cc(Br)cc(Cl)c2[nH]1)N1CCC(F)(F)CC1
Yield: 89 %

Procedure:
The title compound was synthesized in analogy to example 1 from 5-bromo-7-chloro-1H-indole-2-carboxylic acid (commercially available), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 2,4-difluoro piperidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product as a colorless foam (89%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][C:3]=1[N+:24]([O-])=O.[CH:27]1([C:31](O)=[O:32])[CH2:30][CH2:29][CH2:28]1.C(N(CC)C(C)C)(C)C.P(Cl)(Cl)(Cl)=O>ClCCl>[CH:27]1([C:31]([NH:24][C:3]2[CH:4]=[C:5]([CH:8]3[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=4)[NH:9]3)[CH:6]=[CH:7][C:2]=2[F:1])=[O:32])[CH2:30][CH2:29][CH2:28]1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c([N+](=O)[O-])c1)N2
Reactant: O=C(O)C1CCC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(F)c(NC(=O)C3CCC3)c1)N2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 89 %

Procedure:
To an ice-cold mixture of methyl 2-(4-fluoro-3-nitrophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (0.3 mmol, 1.0 eq.), cyclobutanecarboxylic acid (0.46 mmol, 1.5 eq.), N,N-diisopropylethylamine (0.6 mmol, 2.0 eq.) in dichloromethane (5 mL) was added a solution of phosphorus oxychloride (0.36 mmol, 1.2 eq.). Then the reaction mixture was stirred at room temperature for 2.5 hours. LC-MS indicated that the starting material was consumed completely. The reaction was quenched by 20 mL water extracted with ethyl acetate (20 mL×2). The combined organic layer was concentrated and the residue was purified by column chromatography (petroleum ether/ethyl acetate=3:1) to afford methyl 2-(3-(cyclobutanecarboxamido)-4-fluorophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a pale yellow solid; Yield: 89%; MS (ESI+APCI) M+1=411.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([CH3:8])[CH2:6][CH2:5][CH:4]([CH3:9])[CH:3]1[OH:10].[N:11]1[CH:16]=[CH:15]C=[CH:13][CH:12]=1.Cl[C:18](Cl)([O:20]C(=O)OC(Cl)(Cl)Cl)Cl.C(NCC)C>ClCCl>[CH3:1][CH:2]1[CH:7]([CH3:8])[CH2:6][CH2:5][CH:4]([CH3:9])[CH:3]1[O:10][C:18](=[O:20])[N:11]([CH2:12][CH3:13])[CH2:16][CH3:15]
Reactant: CC1CCC(C)C(O)C1C
Reactant: c1ccncc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCNCC
Product: CCN(CC)C(=O)OC1C(C)CCC(C)C1C
Temperature: 0 °C
Yield: 51.8 %

Procedure:
4.27 g (30 mmol) of 2,3,6-trimethylcyclohexanol were placed with 110 ml dichlormethane in a 250 ml vessel at room temperature and 3.08 g (39 mmol) of pyridine were added. The reaction mixture was cooled to 0° C. and 3.56 g (12 mmol) of triphosgene in 15 ml dichlormethane were added dropwise. After five minutes 2.37 g (30 mmol) pyridine were added. Subsequently, 2.19 g (30 mmol) of diethylamine in 15 ml dichlormethane were added dropwise, the resulting mixture was allowed to come to ambient temperature and then quenched with water. After separation of the phases, the water phase was extracted once with dichlormethane and the combined organic phases were concentrated. The raw product was purified by distillation and column chromatography to yield 1.5 g of the desired product as a mixture of isomers with a purity of 99.4%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.NCCN[S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24].C1CCN2[C:35](=[N:36]CCC2)[CH2:34]C1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:36][CH2:35][CH2:34][S:23]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)(=[O:24])=[O:25])[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: NCCNS(=O)(=O)c1ccccc1
Agent: Cl
Solvent: COCCOC
Product: N#Cc1c(NCCS(=O)(=O)c2ccccc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, N-(2-amino-ethyl)-benzenesulfonamide hydrochloride and DBU in DME. ES-MS m/e (%): 370 (M+H+, 100).
Reaction SMILES: [Na].C([C:4]1([CH2:12][CH3:13])[O:8][C@@H:7]([CH2:9]CI)[CH2:6][O:5]1)C.C(OCC)(=O)CC(OCC)=[O:17].CCOCC>C(O)C.O>[OH:5][CH2:6][C@H:7]1[O:8][C:4](=[O:17])[CH2:12][CH2:13][CH2:9]1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCC1(CC)OC[C@H](CCI)O1
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: O=C1CCC[C@@H](CO)O1
Yield: 25.5 %

Procedure:
To a solution of 0.55 g of sodium in 20 ml of absolute ethanol were added 6 g of (S)-2,2-diethyl-4-(2-iodoethyl)-1,3-dioxolane synthesized in Example 1 and 3.7 g of diethyl malonate, and the mixture was refluxed for 2 hr. Then, 50 ml of an ether and 50 ml of water were successively added to the resultant solution, and the ether phase was collected. The resultant ether solution was washed with a saturated saline solution, dried over magnesium sulfate, the solvent was removed from the dried ether solution by distillation, and the resultant residue was purified by a silica gel column chromatography through the use of hexane-ethyl acetate as a developing solvent. The purified product was dissolved in an ether, and 2N sodium hydroxide was added thereto. The mixture was refluxed for hydrolysis and decarboxylation, the pH was adjusted to 5 with 1N hydrochloric acid, and the reaction product was extracted with ethyl acetate. The solvent was removed from the extract, the resultant residue was dissolved in THF, a few drops of sulfuric acid was added thereto, the solution was concentrated, and the solute was purified from the concentrate by a silica gel column chromatography through the use of a mixed solution comprising hexane and ethyl acetate as a developing solution to obtain 0.7 g of (S)-5-hydroxymethyl-valerolactone.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C@H:10]([CH2:13][O:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[O:9][C:8]=2[C:25]=1[CH:26]=[C:27]([N+]([O-])=O)[CH2:28][CH3:29])([O-])=O.[H][H]>C(OCC)(=O)C.[Pt]=O>[CH3:24][C:21]1[CH:20]=[CH:19][C:18]([S:15]([O:14][CH2:13][CH:10]2[O:9][C:8]3=[C:25]4[C:4](=[CH:5][CH:6]=[C:7]3[O:12][CH2:11]2)[NH:1][C:27]([CH2:28][CH3:29])=[CH:26]4)(=[O:17])=[O:16])=[CH:23][CH:22]=1
Reactant: [H][H]
Reactant: CCC(=Cc1c([N+](=O)[O-])ccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2)[N+](=O)[O-]
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CCc1cc2c3c(ccc2[nH]1)OCC(COS(=O)(=O)c1ccc(C)cc1)O3

Procedure:
0.70 g (1.5 mmole) of toluene-4-sulfonic acid (2R)-7-nitro-8-(2-nitro-but-1-enyl)-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester was dissolved in 100 mL of ethyl acetate and 0.10 g of platinum oxide added. The mixure was treated with 45 psi of hydrogen on a Parr hydrogenation apparatus for 5 hours. The mixture was then filtered through celite and concentrated in vacuum. The residue was column chromatographed on silica gel with 1:1 ethyl acetate/hexane to give 0.52 g of the (R)-enantiomer of the title compound as a yellow oil. 1H-NMR (CDCl3): doublet 7.8 δ (2 H); doublet 7.3 δ (2 H); doublet 6.76 δ (1 H); doublet 6.64 δ (1 H); singlet 6.16 δ (1 H); multiplet 4.5 δ (1 H); multiplet 4.3 δ (3 H); quartet 4.1 δ (1 H); quartet 2 H); singlet 2.5 δ (3 H); triplet 1.3 δ (3 H).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]#[C:19][CH2:20][CH2:21][CH2:22]OS(C)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.C([CH2:33][NH2:34])C=C.[CH3:35][CH2:36][O:37]CC>CN(C=O)C.O>[CH3:33][N:34]([CH2:22][CH2:21][CH2:20][C:19]#[C:18][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:28])[F:29])=[CH:8][CH:7]=3)=[N:10][S:11][C:12]=2[CH:17]=1)[CH2:35][CH2:36][OH:37]
Reactant: CCOCC
Reactant: CS(=O)(=O)OCCCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Reactant: C=CCCN
Solvent: CN(C)C=O
Solvent: O
Product: CN(CCO)CCCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Yield: 56 %

Procedure:
150 mg (0.34 mmol) Methanesulfonic acid 5-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl ester in 1.5 ml DMF w ere treated with 140 μl (1.7 mmol) N-allylmethylamine at 50° C. for 4 h. The solution was diluted with ether and water, the organic phase was washed with 0.5 M NaOH, and dried over Na2SO4. Column chromatography on silica gel gave 80 mg (56%) 2-(Methyl-{5-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-amino)-ethanol as light yellow, MS: 419(MH+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2(O)[C:14]3[CH:15]=[C:16]([I:19])[CH:17]=[CH:18][C:13]=3[CH:12]=[CH:11][C:10]3[CH:20]=[CH:21][CH:22]=[CH:23][C:9]2=3)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>>[CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[C:16]([I:19])[CH:17]=[CH:18][C:13]=3[CH:12]=[CH:11][C:10]3[CH:20]=[CH:21][CH:22]=[CH:23][C:9]2=3)[CH2:4][CH2:3]1
Reactant: CN1CCC(C2(O)c3ccccc3C=Cc3ccc(I)cc32)CC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(=C2c3ccccc3C=Cc3ccc(I)cc32)CC1

Procedure:
A solution of 3.23 g. of 1-methyl-4-(3-iodo-5-hydroxy-5H-dibenzo[a,d]cyclohepten-5-yl)piperidine, 30 ml. of trifluoroacetic acid and 10 ml. of trifluoroacetic anhydride is refluxed for 6 hours. The solution is concentrated on a rotary evaporator and the residue is made basic with 5% sodium hydroxide solution. The oil that precipitates is extracted into ether, and this ether phase is washed with water, dried over magnesium sulfate, filtered, and the ether removed on a rotary evaporator. The residue is triturated with acetonitrile, collected and dried to give 2.36 g. of material. This material is recrystallized from ether acetate to give pure (±)-1-methyl-4-(3-iodo-5H-dibenzo[a,d]cyclohepten-5-ylidene)-piperidine, m.p. 166°-170°.
Reaction SMILES: [F:1][CH:2]([F:18])[CH2:3][N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:17])[C:13]([O:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=2[C:29]([NH:31][CH3:32])=[O:30])[C:23]([Cl:37])=[CH:22][N:21]=1>>[Cl:37][C:23]1[C:24]([NH:26][C:27]2[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=2[C:29]([NH:31][CH3:32])=[O:30])=[N:25][C:20]([NH:17][C:12]2[C:13]([O:15][CH3:16])=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:3][CH:2]([F:1])[F:18])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:21][CH:22]=1
Reactant: COc1cc2c(cc1N)CCN(CC(F)F)CC2
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1ccccc1Nc1nc(Nc2cc3c(cc2OC)CCN(CC(F)F)CC3)ncc1Cl

Procedure:
The title compound was prepared from 3-(2,2-Difluoro-ethyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide in an analogous manner to Example 61e. Product isolated as an off-white solid (0.005 g, 5%). MP: 169-172° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 11.23 (br s, 1H), 8.58 (d, 1H, J=8.6 HZ), 8.06 (s, 1H), 7.97 (br s, 1H), 7.50 (d, 1H, J=7.8 Hz), 7.38 (t, 1H, J=7.8 Hz), 7.10 (t, 1H, J=7.6 Hz), 6.66 (s, 1H), 6.26 (br s, 1H), 6.20-5.87 (m, 1H), 3.86 (s, 3H), 3.15-2.75 (m, 14H). MS: 517 (MH)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:6](=[O:7])[N:5]([C@@H:8]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:9]([O:11]C(C)(C)C)=O)[C:4](=[O:20])[NH:3]1.Cl[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]=[CH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:26][CH:25]=1.[NH2:38][C@H:39]([CH3:48])[CH2:40][C:41]([O:43]C(C)(C)C)=[O:42]>>[CH3:21][C:2]1([CH3:1])[C:6](=[O:7])[N:5]([C@@H:8]([CH2:16][CH:17]([CH3:18])[CH3:19])[C:9]([NH:38][C@H:39]([CH3:48])[CH2:40][C:41]([OH:43])=[O:42])=[O:11])[C:4](=[O:20])[N:3]1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]=[CH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:26][CH:25]=1
Reactant: CC(C)C[C@@H](C(=O)OC(C)(C)C)N1C(=O)NC(C)(C)C1=O
Reactant: C[C@@H](N)CC(=O)OC(C)(C)C
Reactant: ClCc1ccc(C=Cc2ccccc2)cc1
Product: CC(C)C[C@@H](C(=O)N[C@H](C)CC(=O)O)N1C(=O)N(Cc2ccc(C=Cc3ccccc3)cc2)C(C)(C)C1=O

Procedure:
The compound was prepared according to the general preparation processes, steps A, B, D, E and J. In step D, tert-butyl (S)-2-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(2-methylpropyl)acetate was alkylated with 4-chloromethylstilbene. In step J, tert-butyl (R)-3-amino-3-methylpropionate was employed as an amino compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:4][CH:3]=1.Br[CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].C(N(CC)C(C)C)(C)C.O>C1(C)C=CC=CC=1>[C:16]([NH:15][C:12]1[S:13][CH:14]=[C:10]([CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:3][CH:4]=2)[N:11]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Nc1nc(CCc2ccc(N)cc2)cs1
Reactant: CC(C)(C)OC(=O)NCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)Nc1nc(CCc2ccc(NCCNC(=O)OC(C)(C)C)cc2)cs1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a suspension of N-(4-[2-(4-aminophenyl)ethyl]-1,3-thiazol-2-yl}acetamide (100 mg) in toluene were added tert-butyl (2-bromoethyl)carbamate (87.5 mg) and N,N-diisopropylethylamine (52 μl), and the mixture was stirred at 80° C. for 24 h. The reaction mixture was allowed to cool to room temperature, water (10 ml) was added, and the organic layer was separated, washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated in vacuo to give tert-butyl {2-[(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}phenyl)amino]ethyl}carbamate as a pale brown amorphous.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.C([Li])CCC.[CH3:17][S:18]SC.[Cl-].[NH4+]>C1COCC1>[Cl:11][C:9]1[C:10]2[C:2]([S:18][CH3:17])=[CH:3][NH:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: CSSC
Reactant: Clc1ncnc2[nH]cc(Br)c12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CSc1c[nH]c2ncnc(Cl)c12
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
A solution of 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (Example 35) (2.53 g, 10 mmol) in THF (30 mL) was cooled to -78° C. and a solution of n-butyl lithium (12 mL of 2.3M solution, 25 mmol) was added keeping the reaction temperature below -72° C. The reaction mixture was stirred at -78° C. for 45 min, a solution of methyl disulfide (0.95 mL, 10 mmol) in tetrahydrofuran (10 mL) was added over a period of 30 minutes maintaining the temperature below -72° C. The reaction mixture was stirred at -78° C. for 2.5 hours then allowed to warm to room temperature. A saturated solution of ammonium chloride (40 mL) was added to the reaction with stirring. The organic layer was separated, the aqueous layer extracted with ethyl acetate (2×40 mL) and the combined organic extracts were dried, filtered and evaporated to obtain a pale yellow solid which was crystallized from EtOH: yield 1.65 g; (70%) m.p. 166°-167° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[N:18]([CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=43)[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+].[C:42]([NH:46][C:47](=[O:50])[CH2:48]Cl)([CH3:45])([CH3:44])[CH3:43]>C1COCC1.C(Cl)Cl>[C:42]([NH:46][C:47](=[O:50])[CH2:48][N:33]1[CH2:34][CH2:35][CH:30]([C:28]2[CH:27]=[CH:26][C:23]3[C:24]4[N:18]([CH:17]=[C:16]([C:15]5[N:11]([CH:8]([CH3:10])[CH3:9])[N:12]=[CH:13][N:14]=5)[N:25]=4)[CH2:19][CH2:20][O:21][C:22]=3[CH:29]=2)[CH2:31][CH2:32]1)([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C)(C)NC(=O)CCl
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCNCC3)cc1OCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCN(CC(=O)NC(C)(C)C)CC3)cc1OCC2
Reaction time: 120 h
Yield: 55.7 %

Procedure:
To a suspension of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene trifluoroacetic acid salt (300 mg, 0.61 mmol) in THF (5 mL) was added potassium carbonate (295 mg, 2.13 mmol) and N-tert-butyl-2-chloro-acetamide (100 mg, 0.67 mmol). The mixture was stirred for 5 days before being diluted with DCM and washed with water (2×30 mL). The organic phase was dried (MgSO4) and concentrated in vacuo. The resultant residue was triturated in diethyl ether, affording 274 as a cream solid (169 mg, 0.34 mmol, 56%). LCMS: RT=3.12 min, [M+H]+=492. 1H NMR δ (ppm) (DMSO-d): 8.29 (1H, d, J=8.29 Hz), 7.86 (1H, d, J=0.63 Hz), 7.85 (1H, s), 7.15 (1H, s), 7.03 (1H, dd, J=8.36, 1.77 Hz), 6.89 (1H, d, J=1.71 Hz), 5.90-5.80 (1H, m), 4.48-4.41 (4H, m), 2.85 (2H, d, J=11.24 Hz), 2.81 (2H, s), 2.20-2.09 (2H, m), 1.78-1.67 (2H, m), 1.70-1.58 (2H, m), 1.44 (6H, d, J=6.60 Hz), 1.25 (9H, s). 1H obscured by solvent.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH:13]([OH:16])[CH2:14][OH:15])=[N:9][C:8]([O:17][CH3:18])=[CH:7][CH:6]=2.N1C=CN=C1.[CH3:24][C:25]([Si:28](Cl)([CH3:30])[CH3:29])([CH3:27])[CH3:26]>C1COCC1.CN(C=O)C.CC(=O)OCC>[C:25]([Si:28]([CH3:30])([CH3:29])[O:15][CH2:14][CH:13]([OH:16])[CH2:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:17][CH3:18])[N:9]=2)[N:4]=[CH:3][C:2]=1[F:1])([CH3:27])([CH3:26])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc2ncc(F)c(CC(O)CO)c2n1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc2ncc(F)c(CC(O)CO[Si](C)(C)C(C)(C)C)c2n1
Yield: 86.5 %

Procedure:
A solution of rac-3-(3-fluoro-6-methoxy-[1,5]naphthyridin-4-yl)-propane-1,2-diol (3.6 g, 14.2 mmol, prepared as described in WO 2008/003690) in THF (150 mL) and DMF (10 mL) was treated with imidazole (1.07 g, 1.1 eq.) and a solution of TBDMSCl (2.15 g, 1 eq.) in THF (10 mL) at 0° C., the mixture was stirred at rt for 24 h, diluted with EA and washed with water (2×100 mL) and brine, dried over MgSO4 and concentrated. The residue was purified by CC (Hept/EA 1:1) to give the desired intermediate as a colourless solid (4.5 g, 87% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:52])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[C:23]([CH3:36])=[N:24][N:25]([CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=5)[C:26]=4[CH3:27])=[CH:20][N:19](S(C4C=CC(C)=CC=4)(=O)=O)[C:16]3=[N:17][CH:18]=2)=[CH:9][C:8]=1[NH:47][S:48]([CH3:51])(=[O:50])=[O:49].[OH-].[Li+]>C1COCC1.CO.O>[CH3:52][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[C:23]([CH3:36])=[N:24][N:25]([CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=5)[C:26]=4[CH3:27])=[CH:20][NH:19][C:16]3=[N:17][CH:18]=2)=[CH:9][C:8]=1[NH:47][S:48]([CH3:51])(=[O:50])=[O:49]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(OCCCN(C)C)c(NS(C)(=O)=O)c4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1c[nH]c2ncc(-c3ccc(OCCCN(C)C)c(NS(C)(=O)=O)c3)cc12
Yield: 16.9 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(2-(3-(dimethylamino)propoxy)-5-(3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)methanesulfonamide (40 mg, 0.05 mmol) was hydrolyzed by lithium hydroxide (4 mg, 0.16 mmol), THF/methanol/water (1/1/0.5 ml) to afford 5 mg (16% yield) of the titled compound after purification by preparative TLC (SiO2)-eluted by 5% methanol in DCM. 1H NMR (CDCl3, 400 MHz): δ 8.88 (s, 1H), 8.54-8.53 (d, 1H), 7.84 (s, 1H), 7.808-7.803 (d, 1H), 7.33-7.23 (m, 3H), 7.05-7.03 (d, 1H), 6.99-6.90 (m, 2H), 6.87-6.852 (d, 1H), 5.31 (s, 2H), 4.16-4.13 (t, 2H), 2.96 (s, 3H), 2.52-2.49 (t, 2H), 2.31 (s, 6H), 2.25 (s, 3H), 2.17 (s, 3H), 2.00-1.97 (m, 2H). MS: m/z=591.4 (M+1), HPLC: 91.28% in method B.