Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:21][CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O.[Cl:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH3:43])[C:38]=1[S:44]([N:47]([CH2:51][CH2:52][O:53][CH2:54]C(O)=O)[CH:48]1[CH2:50][CH2:49]1)(=[O:46])=[O:45].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>ClCCl>[Cl:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH3:43])[C:38]=1[S:44]([N:47]([CH2:51][CH2:52][O:53][CH2:54][C:14]([N:11]1[CH2:10][CH2:9][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)([CH2:21][CH2:22][CH2:23][N:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)[CH2:13][CH2:12]1)=[O:15])[CH:48]1[CH2:50][CH2:49]1)(=[O:46])=[O:45]
Reactant: Cc1cccc(Cl)c1S(=O)(=O)N(CCOCC(=O)O)C1CC1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCN2CCCC2)(c2cccc(Cl)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(Cl)c1S(=O)(=O)N(CCOCC(=O)N1CCC(CCCN2CCCC2)(c2cccc(Cl)c2)CC1)C1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 25 %

Procedure:
A solution of tert-butyl 4-(3-chlorophenyl)-4-(3-(pyrrolidin-1-yl)propyl)piperidine-1-carboxylate (0.15 g, 0.37 mmol) in dichloromethane (3 ml) was Boc-deprotected using standard reaction conditions (see step (vi)/example 25; TFA (3-13 eq.)) and added dropwise to a solution containing 2-(2-(2-chloro-N-cyclopropyl-6-methylphenylsulfonamido)ethoxy)acetic acid [carboxylic acid 2] (1 eq.), EDCI (1.5 eq.), HOBt (1 eq.) and DIPEA (6 eq.) in dichloromethane (5 ml) at 0° C. The resulting mixture was then stirred at room temperature for 16 h. The reaction mixture was diluted with dichloromethane and washed with aq. ammonium chloride, aq. sodium hydrogen carbonate and water respectively. The organic layer was dried over sodium sulfate, concentrated in vacuo and the crude product purified by chromatography (silica). Yield: 25%
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrCC[CH2:16][CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28].C([O-])([O-])=O.[K+].[K+]>CCN(CC)CC.CN(C=O)C>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:16][CH2:17][N:18]3[C:22](=[O:23])[C:21]4=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]4[C:19]3=[O:28])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCN1CCN(c2ccccc2)CC1

Procedure:
1-Phenylpiperazine 2 (2.21 g, 7.81 mmol) was reacted with N-(4-bromobutyl)phthalimide (1.26 g, 7.81 mmol) in the presence of K2CO3 (8.0 g) in Et3N (1.0 mL) and DMF (20 mL) to give a yellow solid 3a, 2.70 (95%) (Procedure A). 1H NMR (CDCl3) 1.55-1.82 (m, 4H, CH2CH2), 2.40-2.45 (t, J=7.5 Hz, 2H, NCH2), 2.57-2.61 (t, J=4.8 Hz, 4H, N(CH2)2), 3.17-3.20 (t, J=4.8 Hz, 4H, N(CH2)2), 3.71-3.75 (t, J=6.7 Hz, 2H, NCH2), 6.82-6.94 (3H, Ar—H), 7.23-7.28 (m, 2H, Ar—H), 7.70-7.74 (m, 2H, Ar—H), 7.83-7.86 (m, 2H, Ar—H).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:17][C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:21][CH:20]=3)=[N:15][CH:14]=2)=[CH:9][CH:8]=1>C(Cl)Cl>[N:28]1([CH2:27][CH2:26][O:25][C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:16]3[S:17][C:13]([C:10]4[CH:9]=[CH:8][C:7]([OH:6])=[CH:12][CH:11]=4)=[CH:14][N:15]=3)=[CH:24][CH:23]=2)[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: COc1ccc(-c2cnc(Nc3ccc(OCCN4CCCC4)cc3)s2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(-c2cnc(Nc3ccc(OCCN4CCCC4)cc3)s2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A 1 N solution of BBr3 in CH2Cl2 (0.4 mL, 0.404 mmol, 8.0 equiv) is added dropwise to a cold (−10° C.) solution of [5-(4-methoxy-phenyl)thiazol-2-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine (Example 3) (20 mg, 0.0506 mmol) in CH2Cl2 (0.4 mL), under an argon atmosphere. The reaction mixture is allowed to warm to RT and to stir for 1.5 h. The mixture is then cooled to 0° C. and quenched with MeOH. The resulting red solution is concentrated in vacuo. Purification of the crude material by silica gel (9 g) column chromatography (CH2Cl2/MeOH, 90/10) affords the title compound as a beige solid: ES-MS: 382.0 [M+H]+; single peak at tR=5.47 min (System 1); Rf=0.28 (CH2Cl2/MeOH, 80/20).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1.Cl[CH2:27][C:28]1[O:29][C:30](=[O:34])[O:31][C:32]=1[CH3:33]>>[CH3:27][C:28]1[O:29][C:30](=[O:34])[O:31][C:32]=1[CH2:33][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1
Reactant: COc1cc(C(=O)/C=C/c2c[nH]c3ccccc23)cc(OC)c1OC
Reactant: Cc1oc(=O)oc1CCl
Product: COc1cc(C(=O)/C=C/c2cn(Cc3oc(=O)oc3C)c3ccccc23)cc(OC)c1OC
Yield: 6 %

Procedure:
Substantially the same procedure as in Example 3 was repeated using Compound 1 (2.37 g) obtained in Example 1 and 4-chloromethyl-5-methyl-1,3-dioxol-2-one (1.63 g) except that the obtained crude crystals were further purified by preparative high-pressure liquid chromatography (HPLC), to give Compound 11 (188 mg).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[NH2:4][C:5]1[S:6][C:7]2[C:13]([C:14]([OH:16])=O)=[CH:12][C:11]([O:17][CH3:18])=[CH:10][C:8]=2[N:9]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CO.CN(C=O)C.CCOC(C)=O>[NH2:4][C:5]1[S:6][C:7]2[C:13]([C:14]([NH:3][CH2:1][CH3:2])=[O:16])=[CH:12][C:11]([O:17][CH3:18])=[CH:10][C:8]=2[N:9]=1
Reactant: COc1cc(C(=O)O)c2sc(N)nc2c1
Reactant: CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CN(C)C=O
Product: CCNC(=O)c1cc(OC)cc2nc(N)sc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
Ethylamine (2 mL, 4.02 mmol, 2M soln in methanol) was added to a solution of 2-amino-5-methoxy-1,3-benzothiazole-7-carboxylic acid (300 mg, 1.34 mmol), diisopropyl ethylamine (0.93 mL, 5.36 mmol) and HATU (560 mg, 1.47 mmol) in DMF (6 mL). The reaction was stirred at ambient temperature for 2 hours after which time LCMS indicated clean conversion to the product. The reaction was diluted with EtOAc, washed with water and brine then dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by trituration with DCM to give the product as an off white solid, 178 mg, 53% yield.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:11]=[C:12]([NH2:14])[N:13]=2)[CH:5]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[CH:7]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>O1CCOCC1.O>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[C:3]3[N:4]([N:11]=[C:12]([NH2:14])[N:13]=3)[CH:5]=[C:6]([CH:8]3[CH2:10][CH2:9]3)[CH:7]=2)=[CH:18][CH:17]=1
Reactant: Nc1nc2c(Br)cc(C3CC3)cn2n1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: Nc1nc2c(-c3ccc(Cl)cc3)cc(C3CC3)cn2n1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
To a solution of 8-bromo-6-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (300 mg, 1.29 mmol) and 4-chlorophenyl boronic acid (463 mg, 2.96 mmol) in dioxane (15 mL) was added an aqueous solution of Na2CO3 (2 M, 2 mL) and degassed with argon for 5 minutes. PdCl2 (dppf)2.CH2Cl2 (30.34 mg, 0.04 mmol) was added and stirred at 80° C. for 90 minutes. The reaction mixture was cooled to room temperature and water (20 mL) was added. The aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue purified by silica gel chromatography using ethyl acetate/hexane as eluent. The title compound was obtained as an off white solid (252 mg, 75%).
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[CH:5]=[C:6]([O:17][CH:18]2[CH2:22][CH2:21][NH:20][CH2:19]2)[C:7]([NH:10][C:11]2[S:12][CH:13]=[C:14]([CH3:16])[N:15]=2)=[N:8][CH:9]=1.C(N(CC)CC)C.[C:30]([Cl:33])(=[O:32])[CH3:31].Cl>O.C1COCC1>[ClH:33].[Br:3][C:4]1[CH:5]=[C:6]([O:17][CH:18]2[CH2:22][CH2:21][N:20]([C:30](=[O:32])[CH3:31])[CH2:19]2)[C:7]([NH:10][C:11]2[S:12][CH:13]=[C:14]([CH3:16])[N:15]=2)=[N:8][CH:9]=1
Reactant: Cc1csc(Nc2ncc(Br)cc2OC2CCNC2)n1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N1CCC(Oc2cc(Br)cnc2Nc2nc(C)cs2)C1
Temperature: 25 °C
Yield: 23.1 %

Procedure:
A mixture of N-(5-bromo-3-(pyrrolidin-3-yloxy)pyridin-2-yl)-4-methylthiazol-2-amine dihydrochloride (prepared according to Example 62; 70 mg, 0.16 mmol), triethylamine (0.11 mL, 0.82 mmol), and THF (2 mL) was stirred at room temperature. Acetyl chloride (0.009 mL, 0.16 mmol) was added and stirred at room temperature for 30 minutes. Water (15 mL) was added and extracted with EtOAc. The organic layer was dried with sodium sulfate, filtered and concentrated. The residue was purified on silica gel (10% methanol in EtOAc) to afford 1-(3-(5-bromo-2-(4-methylthiazol-2-ylamino)pyridin-3-yloxy)pyrrolidin-1-yl)ethanone hydrochloride (16 mg, 22.56% yield) as a white solid after HCl salt formation. 1H NMR (d6-DMSO) δ 11.60 (bs, 1H), 8.11 (m, 1H), 7.82 (m, 1H), 6.90 (m, 1H), 5.28 (m, 1H), 3.81 (m, 1H), 3.59 (m, 3H), 2.33 (s, 3H), 2.25 (m, 2H), 1.97 (m, 3H); Mass spectrum (apci) m/z=399.1 (M+H—HCl).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:24][S:25]([CH2:28][CH2:29][CH3:30])(=[O:27])=[O:26])=[N:4][CH:5]=[C:6]([F:23])[C:7]=1[NH:8][C:9]1[C:14]([C:15]2[CH:20]=[C:19](SC)[N:18]=[CH:17][N:16]=2)=[N:13][CH:12]=[CH:11][N:10]=1.[CH2:31]([NH2:33])[CH3:32]>CC(O)C>[CH2:31]([NH:33][C:19]1[N:18]=[CH:17][N:16]=[C:15]([C:14]2[C:9]([NH:8][C:7]3[C:6]([F:23])=[CH:5][N:4]=[C:3]([NH:24][S:25]([CH2:28][CH2:29][CH3:30])(=[O:27])=[O:26])[C:2]=3[F:1])=[N:10][CH:11]=[CH:12][N:13]=2)[CH:20]=1)[CH3:32]
Reactant: CCN
Reactant: CCCS(=O)(=O)Nc1ncc(F)c(Nc2nccnc2-c2cc(SC)ncn2)c1F
Solvent: CC(C)O
Product: CCCS(=O)(=O)Nc1ncc(F)c(Nc2nccnc2-c2cc(NCC)ncn2)c1F
Temperature: 120 °C
Reaction time: 16 h

Procedure:
A stirred mixture of N-(3,5-difluoro-4-(3-(6-(methylthio)pyrimidin-4-yl)pyrazin-2-ylamino)pyridin-2-yl)propane-1-sulfonamide (70 mg, 0.15 mmol), ethylamine (70% solution in water, 3 mL) and 2-propanol (3 mL) was heated with stirring at 120° C. for 16 h. The reaction mixture was cooled to rt and concentrated. The residue was chromatographed on silica gel (10-50% ethyl acetate in hexanes eluant) to provide the title compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH:17]=[CH:16][C:15]=1[S:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:39])[CH3:38])=[CH:32][CH:31]=1>C(O)C>[CH3:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH2:21][O:20][C:18]1[CH:17]=[CH:16][C:15]([S:29][C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:39])[CH3:38])=[CH:32][CH:31]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:19]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: CC(=O)Nc1ccc(Sc2ccc(OCc3ccccc3C)cc2N)cc1
Solvent: CCO
Product: CC(=O)Nc1ccc(Sc2ccc(OCc3ccccc3C)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 1d (18 mg, 0.085 mmol) was reacted in ethanol (1 mL) with the product from Example 119a (32 mg, 0.085 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (23 mg, 42%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J=7.35 Hz, 3H) 1.69-1.94 (m, 2 H) 2.02 (s, 3 H) 2.32 (s, 3 H) 2.99 (t, J=7.35 Hz, 2 H) 5.14 (s, 2H) 6.32 (d, J=6.99 Hz, 1 H) 6.98-7.30 (m, 7 H) 7.41 (dd, J=11.40, 8.82 Hz, 4 H) 7.80 (d, J=8.82 Hz, 1 H) 8.38 (d, J=6.99 Hz, 1 H) 8.97 (d, J=8.46 Hz, 1 H) 9.98 (s, 1 H) 11.02 (s, 1 H) 14.37 (s, 1 H); MS (ESI+) m/z 549(M+H)+.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([CH2:21]OS(C)(=O)=O)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C-:27]#[N:28].[Na+].O>CS(C)=O>[Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[C@H:11]([CH2:21][C:27]#[N:28])[CH2:10]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1COS(C)(=O)=O
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CC#N
Temperature: 80 °C
Reaction time: 20 h
Yield: 70.4 %

Procedure:
The mixture of tert-butyl (2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-{[(methylsulfonyl)oxy]methyl}pyrrolidine-1-carboxylate (13.95 g, 32.6 mmol, J. Med. Chem. 1988, 31, 1598-611) and sodium cyanide (3.20 g, 65.2 mmol) in dimethylsulfoxide (100 mL) was stirred at 80° C. for 20 h. After cooling to room temperature, water (200 mL) was added to the mixture. The resulting mixture was extracted with ethyl acetate (400 mL×2). The combined organic layer was washed with water (200 mL), brine (200 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (5:1) to give 7.81 g (70%) of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.C1C(=O)N([I:18])C(=O)C1>C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([I:18])=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2cn[nH]c2c1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: Clc1ccc2c(I)n[nH]c2c1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
An acetonitrile solution (250 mL) containing the intermediate from Step A (6.14 g, 40.2 mmol) and NIS (9.33 g, 41.4 mmol) was heated at 60° C. for 3 hours. The reaction solution was cooled to room temperature and concentrated to approximately 70 mL volume. The reaction was then diluted with water (ca 400 mL). The suspension was stirred for 10 minutes and then filtered. The solid was air dried on the filter to give the indicated product. The material was used in Step C without further purification. 1H NMR (400 MHz, CH 3 CN-d3): δ 1.52 (broad s, 1H); 7.62 (d, J=1.7 Hz, 1H); 7.44 (d, J=8.6 Hz, 1H); 7.21 (dd, J=8.6, 1.7 Hz, 1H). m/z=279.0 (M+H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:21])[CH2:10][CH2:11][CH2:12][NH:13][C:14]1[C:15]([NH2:20])=[CH:16][CH:17]=[CH:18][CH:19]=1.[C:22](Cl)(=O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>C(Cl)(Cl)Cl>[CH3:21][N:9]([CH3:8])[CH2:10][CH2:11][CH2:12][N:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]=[C:35]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22]
Reactant: CCCCCCCCCCCCCC(=O)Cl
Reactant: CN(C)CCCNc1ccccc1N
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCc1nc2ccccc2n1CCCN(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Triethylamine (0.80 ml) was added to a solution containing N-[3-(dimethylamino)propyl]-1,2-benzenediamine (1.00 g) in chloroform (10 ml), and then tetradecanoyl chloride (1.42 ml) was added thereto while being cooled with ice. After being stirred for 3 hours at room temperature, the reaction mixture was diluted with chloroform, washed with saturated sodium hydrogencarbonate aqueous solution and water successively, dried over sodium sulfate anhydride, and concentrated. Concentrated hydrochloric acid (4.3 ml) was added to a solution containing the residue (2.29 g) in ethanol (23 ml). After being stirred for 1.5 hours at 90° C., the reaction mixture was concentrated. The residue, with ethyl acetate added thereto, was washed with 1N sodium hydroxide aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue (2.18 g) was purified by silica gel column chromatography (silica gel 50 g, chloroform:methanol=50:1), thereby yielding the entitled compound (1.38 g) as pale brown wax.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[CH:15][C:16](O)=[O:17])[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.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.Cl.[CH3:49][O:50][C:51](=[O:58])[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][NH2:57]>[Cl-].[Na+].O.CN(C=O)C>[CH3:49][O:50][C:51](=[O:58])[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][NH:57][C:16](=[O:17])[CH:15]=[C: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: O=C(O)C=C1c2ccccc2Sc2ccccc21
Reactant: COC(=O)CCCCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCNC(=O)C=C1c2ccccc2Sc2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.8 %

Procedure:
2-(9H-thioxanthen-9-ylidene)acetic acid (254 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxybenzo-triazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and 6-aminocaproic acid methyl ester hydrochloride (219 mg, 1.2 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (312 mg, 82% yield) as a white solid. LC-MS (m/z) 382 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)=[O:9])[CH:3]=1.Cl.[NH:21]1[C:26]2[N:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:24]2([CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[O:23][C:22]1=[O:36].CCN(C(C)C)C(C)C>CN(C=O)C>[F:19][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[N:10]([C:8]([C:4]1[N:5]=[CH:6][N:7]=[C:2]([N:33]3[CH2:32][CH2:31][C:24]4([O:23][C:22](=[O:36])[NH:21][C:26]5[N:27]=[CH:28][CH:29]=[CH:30][C:25]4=5)[CH2:35][CH2:34]3)[CH:3]=1)=[O:9])[CH2:11][CH2:12]2
Reactant: O=C(c1cc(Cl)ncn1)N1CCc2cc(F)ccc21
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Nc2ncccc2C2(CCN(c3cc(C(=O)N4CCc5cc(F)ccc54)ncn3)CC2)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.10 g (0.36 mmol) (6-chloro-pyrimidin-4-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone were added to 92 mg (0.36 mmol) spiro[piperidine-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one-hydrochloride and 146 μL (0.84 mmol) DIPEA in 1.8 mL DMF. The reaction mixture was stirred overnight at RT. Then the reaction mixture was purified by preparative HPLC-MS. The product fractions were combined and lyophilised.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]([OH:16])=O.C(Cl)(=O)C([Cl:20])=O.CN(C=O)C>C(Cl)Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]([Cl:20])=[O:16]
Reactant: O=C(O)CCN1C(=O)c2ccccc2C1=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.5 %

Procedure:
To a solution of 137g (20.0 g, 91 mmol) in DCM (250 mL) were added oxalyl chloride (13.8 g, 109 mmol) and DMF (0.1 mL). See FIG. 2. The mixture was stirred at RT for 4 h. Upon reaction completion, the mixture was concentrated to give 3-(1,3-dioxoisoindolin-2-yl)propanoyl chloride 137h (20.0 g, 92%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:20][CH3:21])[C:9]([C:11]([N:13]([CH:17]3[CH2:19][CH2:18]3)[CH:14]3[CH2:16][CH2:15]3)=[O:12])=[CH:10][C:5]2=[C:4]2[N:22]([CH3:25])[CH:23]=[N:24][C:3]=12.Cl[C:27]1[S:28][C:29]([C:32]#[N:33])=[CH:30][N:31]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].COCCOC>[C:32]([C:29]1[S:28][C:27]([NH:1][C:2]2[N:7]=[C:6]3[N:8]([CH2:20][CH3:21])[C:9]([C:11]([N:13]([CH:17]4[CH2:19][CH2:18]4)[CH:14]4[CH2:16][CH2:15]4)=[O:12])=[CH:10][C:5]3=[C:4]3[N:22]([CH3:25])[CH:23]=[N:24][C:3]=23)=[N:31][CH:30]=1)#[N:33]
Reactant: N#Cc1cnc(Cl)s1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N)nc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3ncc(C#N)s3)nc21
Temperature: 85 °C

Procedure:
To a mixture of 4-amino-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 1J, 60 mg, 0.177 mmol), 2-chlorothiazole-5-carbonitrile (38.5 mg, 0.266 mmol), Pd2(dba)3 (24.4 mg, 0.027 mmol), BINAP (49.7 mg, 0.080 mmol) and sodium tert-butoxide (27.3 mg, 0.284 mmol) was added DME (1 ml). The mixture was purged with argon gas for 5 min and heated to 85° C. for 3 h. The reaction mixture showed ˜60% conversion by HPLC and was filtered through a plug of Celite and concentrated. The crude product was purified by preparative HPLC to afford 4-(5-cyanothiazol-2-ylamino)-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide as a off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][C:10](C)([O-])[CH3:11].[K+].C(Br)C=C>CS(C)=O.[Cl-].[Na+].O>[CH2:11]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH:10]=[CH2:9]
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: C=CCBr
Solvent: O
Solvent: CS(C)=O
Product: C=CCOc1ccc(Br)cc1
Reaction time: 0.33 h
Yield: 79.3 %

Procedure:
To a solution of 4-bromophenol (43.25 g, 250 mmol) in DMSO (500 mls) was added potassium t-butoxide (32.26 g, 287.5 mmol) and the mixture was stirred for 20 mins. Allyl bromide (36.29 g, 300 mmol) was then added dropwise and the reaction was stirred for 1 hr. It was then diluted with brine (2 liters) and extracted with ethylacetate (3×2 liters) The organics were combined, dried with MgSO4 and concentrated. The crude residue was distilled (b.p.=157° C. at 30 mm Hg) to afford 42.25 g (79%) of 4-allyloxybromobenzene as a colorless oil.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[N:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[Cl:15][C:16]1[CH:17]=[C:18]([CH:27]([NH2:29])[CH3:28])[CH:19]=[CH:20][C:21]=1[O:22][CH2:23][CH:24]([F:26])[F:25]>>[Cl:13][C:12]1[C:3]2[CH2:2][N:29]([CH:27]([C:18]3[CH:19]=[CH:20][C:21]([O:22][CH2:23][CH:24]([F:25])[F:26])=[C:16]([Cl:15])[CH:17]=3)[CH3:28])[C:5](=[O:7])[C:4]=2[CH:9]=[CH:10][N:11]=1
Reactant: COC(=O)c1ccnc(Cl)c1CBr
Reactant: CC(N)c1ccc(OCC(F)F)c(Cl)c1
Agent: Cl
Product: CC(c1ccc(OCC(F)F)c(Cl)c1)N1Cc2c(ccnc2Cl)C1=O
Yield: 99 %

Procedure:
The title compound is prepared in >99% yield (340 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (214 mg, 0.81 mmol) and 1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethanamine hydrochloride (200 mg, 0.74 mmol, Amine-24, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:5][N:4]=1.[CH:24]1([CH2:30][OH:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([CH2:30][O:31][C:3]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=3[Cl:16])[C:6]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[CH:5][N:4]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CSc1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: OCC1CCCCC1
Product: Clc1ccc(-c2cnc(OCC3CCCCC3)nc2-c2ccc(Cl)cc2Cl)cc1

Procedure:
2-Methylthio-5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)pyrimidine from Reference Example 3 was reacted with cyclohexylmethanol according to the procedure described in Example 59 to afford 2-(cyclohexylmethoxy)-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine (HRf): HPLC/MS: m/e=447 (M++1); Rt=5.17 min; 1H-NMR 400 MHz (CDCl3): δ 1.02-1.20 (m, 2H), 1.20-1.40 (m, 4H), 1.64-1.80 (m, 3H), 1.81-1.98 (m, 2H), 4.23 (d, J=9 Hz, 2H), 7.01 (d, J=9 Hz, 2H), 7.22-7.30 (m, 4H), 7.38 (d, J=2 Hz,1H), 8.58 (s, 1H).