Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([NH2:4])[CH3:3].CCN(C(C)C)C(C)C.CO[CH:16]=[N:17][C:18]1[C:19]([CH3:32])=[N:20][C:21]([O:25][CH2:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[C:22]([Br:24])[CH:23]=1>ClCCl>[Br:24][C:22]1[CH:23]=[C:18]([NH:17][CH:16]=[N:4][CH2:2][CH3:3])[C:19]([CH3:32])=[N:20][C:21]=1[O:25][CH2:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30]
Reactant: COC=Nc1cc(Br)c(OCCCC(C)C)nc1C
Reactant: CCN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN=CNc1cc(Br)c(OCCCC(C)C)nc1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 94.4 %

Procedure:
In a 50 ml single-necked round-bottomed flask, 540 mg of N-[5-Bromo-2-methyl-6-(4-methyl-pentyloxy)-pyridin-3-yl]-formimidic acid methyl ester is dissolved in 6.60 ml of dry dichloromethane. Under stirring at an ambient temperature, 214 mg of ethylamine hydrochloride along with 0.45 ml of Hünig's base are added. Stirring is continued at room temperature for 20 hours. Then, the volatiles are removed in vacuo at 50° C. After purification on silica gel (eluent: heptane/ethyl acetate 8:1 (v:v) with 5% triethylamine) to give 530 mg of the title compound in the form of a brown oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[C:6]([N+:12]([O-])=O)[CH:5]=1)[CH3:2].[NH2:15][C:16]1[CH:33]=[CH:32][C:19]([O:20][CH2:21][C@@H:22]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH3:23])=[CH:18][CH:17]=1>>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]2[C:6]([CH:5]=1)=[N:12][N:15]([C:16]1[CH:17]=[CH:18][C:19]([O:20][CH2:21][C@@H:22]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])[CH3:23])=[CH:32][CH:33]=1)[CH:8]=2)[CH3:2]
Reactant: C[C@@H](COc1ccc(N)cc1)NC(=O)OC(C)(C)C
Reactant: CCOc1ccc(C=O)c([N+](=O)[O-])c1
Product: CCOc1ccc2cn(-c3ccc(OC[C@H](C)NC(=O)OC(C)(C)C)cc3)nc2c1

Procedure:
Using 4-ethoxy-2-nitrobenzaldehyde (293 mg) and tert-butyl [(1S)-2-(4-aminophenoxy)-1-methylethyl]carbamate (399 mg), and in the same manner as in Example 25, step F, the title compound was obtained as a pale-brown solid (459 mg).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][N:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][NH:26][CH:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CN1CCC(N)CC1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: CN1CCC(NCc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carboxaldehyde 10 was reacted with 1-methyl-piperidin-4-ylamine using standard reductive amination conditions. The resulting crude solid was purified on silica using a gradient of 0-20% methanol in ethyl acetate as the eluent to give (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-(1-methyl-piperidin-4-yl)-amine as an off white solid (34% yield), which was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine according to General Procedure A. The resulting solid was triturated with methanol to give 333 as an off white solid (35% yield). NMR (CDCl3, 400 MHz), 1.42-1.50 (3H, m), 1.94-2.02 (4H, m), 2.28 (3H, s), 2.54-2.60 (1H, m), 2.84 (2H, d, J=11.9), 3.88-3.91 (4H, m), 4.04-4.06 (4H, m), 4.18 (2H, s), 5.23 (2H, br s), 7.27 (1H, s), 9.30 (2H, s). MS: (ESI+): MH+=441
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>C(Cl)Cl.O.S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][O:11][C:1]1[CH:2]=[CH:3][CH:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2
Reactant: Oc1cccc2c1CCCC2
Reactant: BrCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: BrCCCCOc1cccc2c1CCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.1 %

Procedure:
A solution of 5,6,7,8 tetrahydronaphthalene-1-ol (4.2 g, 0.028 mol) in methylene chloride (50 ml) was mixed with a solution of sodium hydroxide (2.3 g, 0.0575 mol) in water (50 ml). After adding tetra-n butylammonium bisulfate (9.6 g, 0.028 mol) and 1,4-dibromobutane (31 g, 0.14 mol), the reaction mixture was refluxed with vigorous stirring for 2 hrs. The reaction was cooled to room temperature, the layers separated and the organic phase washed with saturated sodium chloride solution. After drying over sodium sulfate, the organic phase was concentrated on the rotary evaporator and the residual oil heated under vacuum (0.1 mm Hg) to remove remaining 1,4-dibromobutane. The residue was chromatographed on silica gel using 100% hexane as eluent to give 8.1 g (71%) of the title compound as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@@H:11]3[CH2:24][C@@H:14]4[CH2:15][N:16]([C:18](=[O:23])[C:19]([OH:22])([CH3:21])[CH3:20])[CH2:17][C@@H:13]4[C@H:12]3[CH3:25])=[C:8]([C:26]([NH2:28])=[O:27])[CH:7]=[N:6][N:5]2[CH:29]=1.[CH3:30][NH:31][C:32](=[O:48])[C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][N:34]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O>[OH:22][C:19]([CH3:20])([CH3:21])[C:18]([N:16]1[CH2:17][C@@H:13]2[C@@H:12]([CH3:25])[C@H:11]([NH:10][C:9]3[C:4]4[N:5]([CH:29]=[C:2]([C:36]5[CH:35]=[N:34][C:33]([C:32](=[O:48])[NH:31][CH3:30])=[CH:38][CH:37]=5)[CH:3]=4)[N:6]=[CH:7][C:8]=3[C:26]([NH2:28])=[O:27])[CH2:24][C@@H:14]2[CH2:15]1)=[O:23]
Reactant: C[C@@H]1[C@H]2CN(C(=O)C(C)(C)O)C[C@H]2C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Reactant: CNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(-c2cc3c(N[C@@H]4C[C@@H]5CN(C(=O)C(C)(C)O)C[C@@H]5[C@H]4C)c(C(N)=O)cnn3c2)cn1
Temperature: 90 °C
Reaction time: 0.42 h
Yield: 52.1 %

Procedure:
A mixture of 6-bromo-4-(((3aS,4R,5R,6aS)-2-(2-hydroxy-2-methylpropanoyl)-4-methyloctahydrocyclopenta[c]pyrrol-5-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (32 mg, 0.055 mmol), N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide (29.0 mg, 0.111 mmol) and 2.0 M aqueous K3PO4 (0.111 mL, 0.221 mmol) in dimethylformamide (1 mL) was heated to 90° C. under nitrogen for 1 h. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 0-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (14.9 mg, 52% yield). 1H NMR (500 MHz, 1:1 mixture of methanol-d4/chloroform-d) d 8.93 (d, J=2.0 Hz, 1H), 8.28-8.08 (m, 3H), 8.04 (d, J=1.5 Hz, 1H), 7.28 (d, J=1.5 Hz, 1H), 4.45-4.19 (m, 2H), 4.03-3.91 (m, 1H), 3.77-3.56 (m, 2H), 3.10-2.99 (m, 3H), 2.96-2.79 (m, 2H), 2.53-2.32 (m, 1H), 1.87-1.75 (m, 1H), 1.66-1.54 (m, 1H), 1.51-1.35 (m, 6H), 1.22 (d, J=6.4 Hz, 3H); MS (ES+) m/z: 520.2 (M+H); LC retention time: 1.135 min (analytical HPLC Method I).
Reaction SMILES: [OH:1][CH:2]([CH2:17][OH:18])[CH2:3][NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH-].[K+].[OH:21][CH:22]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:23](OC)=[O:24]>>[OH:1][CH:2]([CH2:17][OH:18])[CH2:3][N:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:23](=[O:24])[CH:22]([OH:21])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCCCNCC(O)CO
Reactant: CCCCCCC(O)C(=O)OC
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCCCCCCN(CC(O)CO)C(=O)C(O)CCCCCC

Procedure:
N-(2,3-dihydroxypropyl)-N-dodecylamine (1.0 g, 0.0039 mole) and potassium hydroxide (0.01 g, 0.18 mmole) were heated to 85° C. under vacuum and methyl 2-hydroxyoctanoate (0.6718 g, 0.0039 mole) was added dropwise to the reaction. The reaction was heated under vacuum for 5 hours. A waxy off-white solid was obtained (crude yield=1.38 g). The waxy solid was recrystalized from hot hexane (yield=0.44 g).
Reaction SMILES: N(CC(O)=O)C.[NH2:7][CH2:8][CH2:9][S:10]([NH2:13])(=[O:12])=[O:11].[F:14][C:15]1[CH:45]=[CH:44][C:18]([CH2:19][N:20]2[C@@H:28]3[C@@H:24]([CH2:25][CH2:26][CH2:27]3)[C:23]([OH:29])=[C:22]([C:30]3[NH:35][C:34]4[CH:36]=[CH:37][C:38](I)=[CH:39][C:33]=4[S:32](=[O:42])(=[O:41])[N:31]=3)[C:21]2=[O:43])=[CH:17][CH:16]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I>[F:14][C:15]1[CH:45]=[CH:44][C:18]([CH2:19][N:20]2[C@@H:28]3[C@@H:24]([CH2:25][CH2:26][CH2:27]3)[C:23]([OH:29])=[C:22]([C:30]3[NH:35][C:34]4[CH:36]=[CH:37][C:38]([NH:13][S:10]([CH2:9][CH2:8][NH2:7])(=[O:12])=[O:11])=[CH:39][C:33]=4[S:32](=[O:42])(=[O:41])[N:31]=3)[C:21]2=[O:43])=[CH:17][CH:16]=1
Reactant: NCCS(N)(=O)=O
Reactant: O=C1C(C2=NS(=O)(=O)c3cc(I)ccc3N2)=C(O)[C@@H]2CCC[C@@H]2N1Cc1ccc(F)cc1
Agent: [Cu]I
Agent: CNCC(=O)O
Agent: O=P([O-])([O-])[O-]
Product: NCCS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3CCC[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Temperature: 100 °C
Reaction time: 2 h
Yield: 10.1 %

Procedure:
A reaction flask was charged with copper(I) iodide (268 mg, 1.41 mmol), sarcosine (N-methyl glycine) (188 mg, 2.11 mmol), 2-amino-ethanesulfonic acid amide (1.80 g, 11.2 mmol), cis-1-(4-fluoro-benzyl)-4-hydroxy-3-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-1,4a,5,6,7,7a-hexahydro-[1]pyrindin-2-one (1.0 g, 1.76 mmol) and potassium phosphate (2.61 g, 12.32 mmol). The flask was degassed and backfilled with nitrogen, and then anhydrous N,N-dimethylformamide (16 mL) was added. The resulting suspension was vigorously stirred at 100° C. for 2 h and then at 120° C. for 1.5 h, cooled to 25° C., passed through a plug of Celite and rinsed with 10% methanol-dichloromethane. The filtrate was concentrated in vacuo, and the residue was purified by prep-HPLC [Column ODS-A 5μ 100 Å, 150×21.2 mm, 5 micron, 30%-100% in 13.5 min @ 22 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, cis-2-amino-ethanesulfonic acid {3-[1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,4a,5,6,7,7a-hexahydro-1H-[1]pyrindin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-amide (100 mg, 0.178 mmol, 10%), as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.52 (3H, m), 1.99 (2H, m), 2.06 (1H, m), 3.17 (2H, m), 3.30 (1H, m), 3.46 (2H, t, J=6.8 Hz), 3.86 (1H, bs), 4.48 (1H, bs), 4.90 (1H, d, J=14.8 Hz), 7.16 (2H, m), 7.39 (2H, m), 7.51 (1H, m), 7.61 (2H, m), 7.82 (3H, s), 10.55 (1H, s). LC-MS (ESI) calcd for C24H26FN5O6S2 563.13, found 564.2 [M+H+].
Reaction SMILES: [C:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH:10]([OH:28])[CH2:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24]C)=[O:23])=[C:17]([Cl:26])[C:16]=2[Cl:27])(=[O:14])=[O:13])=[C:6]([CH2:31][CH2:32][CH3:33])[C:5]=1[OH:34])(=[O:3])[CH3:2].C(C1C=CC(OCCCSC2C=CC(CC(OC)=O)=C(Cl)C=2Cl)=C(CCC)C=1O)(=O)C>>[C:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH:10]([OH:28])[CH2:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[C:17]([Cl:26])[C:16]=2[Cl:27])(=[O:14])=[O:13])=[C:6]([CH2:31][CH2:32][CH3:33])[C:5]=1[OH:34])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCC(O)CS(=O)(=O)c2ccc(CC(=O)OC)c(Cl)c2Cl)ccc(C(C)=O)c1O
Agent: CCCc1c(OCCCSc2ccc(CC(=O)OC)c(Cl)c2Cl)ccc(C(C)=O)c1O
Product: CCCc1c(OCC(O)CS(=O)(=O)c2ccc(CC(=O)O)c(Cl)c2Cl)ccc(C(C)=O)c1O

Procedure:
By following Step H of Example 1, but substituting the product from Step A of this example for the ester of Step G of Example 1, the title compound, mp 181°-183° C., was obtained.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:13][C:14]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=1[C:22]1(O)[CH2:31][CH2:30][C:25]2([O:29][CH2:28][CH2:27][O:26]2)[CH2:24][CH2:23]1.[OH-].[Na+]>C1(C)C=CC=CC=1>[F:13][C:14]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=1[C:22]1[CH2:31][CH2:30][C:25]2([O:26][CH2:27][CH2:28][O:29]2)[CH2:24][CH:23]=1
Reactant: OC1(c2cc(F)c(F)cc2F)CCC2(CC1)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1cc(F)c(C2=CCC3(CC2)OCCO3)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round-bottomed flask (3 L) under nitrogen atmosphere equipped with a Dean-Stark trap, toluene (350 mL), para-toluenesulphonic acid monohydrate (p-TSA) (1 g) and 8-(2,4,5-trifluorophenyl)-1,4-dioxaspiro[4.5]decan-8-ol (94.2 g) were added and the mixture was refluxed overnight. Additional p-TSA (1 g) was added. Refluxing was continued overnight and then the reaction was stirred at room temperature for two more days. The reaction mixture was treated with 0.1N aqueous sodium hydroxide solution (500 mL) and extracted with heptanes (500 mL). The organic layer was washed with water (3×500 mL), dried over anhydrous sodium sulfate, filtered and evaporated to yield crude product which was purified by column chromatography (silica gel, gradient 2% to 40% ethyl acetate in heptanes) to yield the title compound.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10](=[O:21])[CH2:11][C:12]([CH3:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])([CH3:3])[CH3:2].[Na].I[CH3:24]>O1CCCC1.O.C(OCC)(=O)C>[CH3:24][C@@H:11]([C:12]([CH3:20])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH3:13])[C:10]([N:5]1[C@@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][O:7][C:6]1=[O:9])=[O:21]
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)CC(C)(C)c1ccccc1
Reactant: CI
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@H]1COC(=O)N1C(=O)[C@@H](C)C(C)(C)c1ccccc1
Temperature: 25 °C
Yield: 70.9 %

Procedure:
A solution of (4S)-4-isopropyl-3-(3-methyl-3-phenylbutanoyl)-1,3-oxazolidin-2-one (0.23 g, 0.79 mmol, from Reference Example 23) in anhydrous tetrahydrofuran (3 mL) is cooled to −78° C. in a dry-ice/acetone bath while stirring under a nitrogen atmosphere. Sodium hexamethylsilazide (1.0 M solution in tetrahydrofuran, 0.95 mL, 0.95 mmol) is added dropwise to the solution via syringe. After stirring for 30 minutes at −78° C., iodomethane (0.25 mL, 4.0 mmol) in tetrahydrofuran (1 mL) is added dropwise. The reaction mixture is stirred overnight (18 hours) while warming to room temperature. The reaction mixture is diluted with water (10 mL) and ethyl acetate (10 mL). The aqueous phase is extracted thrice with ethyl acetate. The combined extracts are washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, dried over sodium sulfate, decanted, and concentrated under reduced pressure to afford a clear yellow oil, which slowly solidified to an amorphous solid under high vacuum. The crude material is purified by flash chromatography (ethyl acetate/hexanes) to afford a crystalline solid (0.17 g, 71%). MS (ES+): (M+H)=303.9
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:28][C:27]2[CH:26]=[CH:25][C:24]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=3)=[CH:31][CH:30]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccc(-c2ccccn2)cc1
Reactant: CC(C)(C)OC(=O)COc1cccc(CN)c1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3ccccn3)cc2)c1

Procedure:
The title compound of Step A was prepared from (3-aminomethyl-phenoxy)-acetic acid tert-butyl ester, of Preparation 20, and 4-pyridin-2-yl-benzaldehyde, of Preparation 22, using the method described in Example 3, Step A, except no triethylamine was used. 1H NMR (400 MHz, CDCl3) δ 8.67 (d, 1H), 7.94 (d, 2H), 7.72 (m, 2H), 7.44 (d, 2H), 7.22 (m, 2H), 6.95 (m, 2H), 6.78 (dd, 1H), 4.51 (s, 2H), 3.84 (s, 2H), 3.78 (s, 2H), 1.47 (s, 9H); MS 405 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([Cl:18])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][CH:38]=[N:39][CH:40]=2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([Cl:18])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[N:39][CH:38]=[N:37][CH:36]=2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(C(F)(F)F)c(Cl)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cncnc2)c1
Product: CC(C)(C)OC(=O)Nc1cc(C(F)(F)F)c(Cl)cc1NC(=O)CC(=O)c1cccc(-c2cncnc2)c1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J24) (311 mg, 1.0 mmol) and 3-oxo-3-(3-pyrimidin-5-yl-phenyl)-propionic acid tert-butyl ester (Example K13) (298 mg, 1.0 mmol) according to the general procedure M. Obtained as a yellow oil (320 mg, 60%).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][C@H:29]2[CH2:34][CH2:33][CH2:32][C@@H:31]([NH:35][C:36]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[O:37])[CH2:30]2)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=2)=[N:6][CH:7]=1.C[O-].[Na+]>CO>[F:1][C:2]1[C:3]([NH:28][C@H:29]2[CH2:34][CH2:33][CH2:32][C@@H:31]([NH:35][C:36]([N:38]3[CH2:39][CH2:40][O:41][CH2:42][CH2:43]3)=[O:37])[CH2:30]2)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@H](NC(=O)N5CCOCC5)C4)n3)c3cc(F)cnc32)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(N[C@@H]1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(F)cc34)ncc2F)C1)N1CCOCC1
Reaction time: 1 h

Procedure:
N-[(1R,3S)-3-[[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]cyclohexyl]morpholine-4-carboxamide, 44f, (2.0 g, 3.2 mmol) was suspended in methanol (50 mL) and treated with 25% sodium methoxide in methanol (19.9 mL, 92.3 mmol). After stirring for 1 hour, the solvent was evaporated under reduced pressure, and the residue was partitioned between water (100 mL) and ethyl acetate (100 mL). The organic layer was collected, dried on Na2SO4 and concentrated to provide the crude product as a yellow solid. This material was purified by silica gel chromatography on a 40 g column, using DCM/MeOH 1-6%. The purified fractions were treated with 2N HCl in ether and concentrated to provide 1.5 g of N-[(1R,3S)-3-[[5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]cyclohexyl]-morpholine-4-carboxamide as a white solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH:22]=O)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:24]1[CH2:29][CH2:28][CH:27]([CH2:30][OH:31])[CH2:26][CH2:25]1>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(O)C>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3([CH2:22][N:24]4[CH2:29][CH2:28][CH:27]([CH2:30][OH:31])[CH2:26][CH2:25]4)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:14][CH:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCC1CCNCC1
Reactant: O=CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCO
Product: OCC1CCN(CC2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)CC1
Yield: 89.3 %

Procedure:
4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbaldehyde (700 mg, 2.205 mmol, 1 wt), 4-piperidinemethanol (485 mg, 4.21 mmol), absolute ethanol (28 ml, 40 vol), activated 3 Å molecular sieves (700 mg), titanium (IV) isopropoxide (3.25 ml, 11.03 mmol) and STAB (3.97 g, 18.7 mmol) was reacted in accordance with the general procedure D. The isolated waxy solid was purified by column chromatography on silica eluting with DCM:MeOH:NH3 95:4:1 to give the title compound as a colorless oil (820 mg, 72%). 1H NMR (400 MHz, CDCl3) δ7.20 (d, 2H), 6.85 (d, 2H), 4.02 (t, 2H), 3.75 (dt, 2H), 3.59-3.46 (m, 2H), 3.42 (d, 2H), 2.63 (t, 2H), 2.53 (br s, 4H), 2.39-2.26 (m, 4H), 2.15-1.03 (m, 18H).
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C@H:7]([CH2:9][C:10]([OH:12])=O)[OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:23][C@H:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH3:25].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.O>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C@H:7]([CH2:9][C:10]([NH:23][C@H:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH3:25])=[O:12])[OH:8])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)[C@@H](O)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)[C@@H](O)CC(=O)N[C@@H](C)C(=O)OC(C)(C)C
Reaction time: 14 h

Procedure:
371 mg of Z-Sta-OH (cf. stage 1.12), 240 mg of H-Ala-OC(CH3)3 and 184 mg of HOBt×H2O are dissolved in 10 ml of DMF. After cooling the solution to 0°, 133 mg of N-methylmorpholine and 321 mg of DCCI are added. The whole is stirred for 1 hour at 0° and for 14 hours at 25°, then the DCH formed is filtered off and the filtrate is concentrated to dryness by evaporation. The residue is taken up in ethyl acetate and the solution is extracted with saturated sodium bicarbonate solution. The organic phases are dried, concentrated by evaporation and the residue is flash-chromatographed over 80 g of silica gel (grain size 0.04-0.063 mm) [eluant: methylene chloride/ether (4:1), fractions of approximately 25 ml]. Fractions 24-40 are combined, concentrated by evaporation, the residue is dissolved in a small amount of methylene chloride, and the solution is filtered and concentrated by evaporation once more. After drying the residue in a high vacuum, Z-Sta-Ala-OC(CH3)3 is obtained as a slightly yellowish oil; Rf (methylene chloride/diethyl ether [4:1])=0.10.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[C:5](=[O:8])[NH:6][N:7]=1.[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH2:16][CH2:17]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[C:5](=[O:8])[N:6]([CH2:17][CH2:16][C:12]2[S:11][CH:15]=[CH:14][CH:13]=2)[N:7]=1
Reactant: Cn1c(=O)[nH]nc(Br)c1=O
Reactant: OCCc1cccs1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cn1c(=O)c(Br)nn(CCc2cccs2)c1=O
Temperature: 70 °C
Yield: 78.3 %

Procedure:
0.4 g (1.94 mmol) of intermediate 2a are placed in the presence of 0.24 mL (2.14 mmol) of 2-thiophen-2-yl-ethanol, 0.61 g (2.33 mmol) of triphenylphosphine in 4 mL of THF. At 0° C., 0.54 mL (2.33 mmol) of DEAD in solution in toluene are added dropwise. The reaction medium is heated for 7 h at 70° C. After concentration, the obtained residue is taken up with ethyl acetate and washed with water. After drying on MgSO4, the organic phase is dry concentrated. The obtained residue is purified by flash chromatography on silica (CH2Cl2/MeOH, gradient 100/0 to 97/3 over 30 min). 0.48 g of crystals corresponding to the compound 4k are obtained (yield: 79%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[C:19]1[S:23][C:22]([S:24]([N:27]2[CH:31]=[CH:30][CH:29]=[CH:28]2)(=[O:26])=[O:25])=[CH:21][CH:20]=1>>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:19]2[S:23][C:22]([S:24]([N:27]3[CH:31]=[CH:30][CH:29]=[CH:28]3)(=[O:25])=[O:26])=[CH:21][CH:20]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=S(=O)(c1ccc(Br)s1)n1cccc1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=S(=O)(c1ccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)s1)n1cccc1
Yield: 93 %

Procedure:
N-{5-[3,5-bis(trifluoromethyl)phenyl]thiophene-2-sulfonyl}pyrrole was prepared in the same manner as described in Example 32C from 3,5-bis(trifluoromethyl)benzeneboronic acid (619 mg, 2.26 mmol) and N-[5-bromothiophene-2-sulfonyl]pyrrole (60 mg, 2.05 mmol). Purification by column chromatography using 2% ethyl acetate/hexanes gave the pure sulfonamide as a white solid in 93% yield.