Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([C:6]([N:8]2[CH2:13]COC[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[Br:16]C1C=C(C=CC=1)C(Cl)=O.CNC>>[Br:16][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:2]=1)[C:6]([N:8]([CH3:13])[CH3:9])=[O:7]
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: O=C(c1ccc(Br)cc1)N1CCOCC1
Agent: CNC
Product: CN(C)C(=O)c1cccc(Br)c1
Yield: 85 %

Procedure:
Following the general method as outlined in Intermediate 174, starting from 3-bromobenzoyl chloride and dimethylamine, the title compound was obtained as a orange sticky solid in 85% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[C:11]1[C:16]([F:17])=[CH:15][C:14]([F:18])=[CH:13][N:12]=1.Br[C:20]1[N:24]2[N:25]=[CH:26][C:27]([C:29]([OH:32])([CH3:31])[CH3:30])=[N:28][C:23]2=[N:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCCC1>[F:17][C:16]1[C:11]([C:3]2[CH:4]=[C:5]([C:20]3[N:24]4[N:25]=[CH:26][C:27]([C:29]([OH:32])([CH3:30])[CH3:31])=[N:28][C:23]4=[N:22][CH:21]=3)[CH:6]=[CH:7][C:2]=2[F:1])=[N:12][CH:13]=[C:14]([F:18])[CH:15]=1
Reactant: OB(O)c1ccc(F)c(-c2ncc(F)cc2F)c1
Reactant: CC(C)(O)c1cnn2c(Br)cnc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(O)c1cnn2c(-c3ccc(F)c(-c4ncc(F)cc4F)c3)cnc2n1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
To 4-fluoro-3-(3,5-difluoropyridin-2-yl)phenylboronic acid (0.40 g) and 2-(7-bromoimidazo[1,2-b][1,2,4]triazin-3-yl)propan-2-ol (0.391 g) was added tetrahydrofuran (5 ml) and 2 N aqueous sodium carbonate (1.5 ml). Tetrakis(triphenylphosphine)palladium(0) (0.07 g) was added, the mixture was thoroughly degassed with nitrogen, and then stirred at 60° C. for 24 h. On cooling to room temperature, the reaction was partitioned between water and ethyl acetate. The organic extracts were evaporated, and the residue was subjected to chromatography (silica gel, 35% EtOAc/CH2Cl2). The product was crystallised from dichloromethane/isohexane, and the resulting pale yellow solid was collected by filtration and dried in vacuo at 60° C. to afford the title compound: 1H NMR (400 MHz, DMSO-d6) δ 1.56 (6H, s), 5.76 (1H, s), 7.58 (1H, dd, J 8.8, 10 Hz), 8.17 (1H, m), 8.29-8.36 (2H, m), 8.48 (1H, s), 8.74 (1H, d, J 2.3 Hz), 9.02 (1H, s); MS (ES+) m/z 386 [M+H]+.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][CH2:5][CH2:6][CH2:7][NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:32])[CH:15]([NH:17][C:18](=[O:31])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]([NH2:30])=[NH:29])[OH:16].Cl.[CH3:34]O>CO>[NH2:4][CH2:5][CH2:6][CH2:7][NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:32])[CH:15]([NH:17][C:18](=[O:31])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]([NH2:30])=[NH:29])[O:16][CH3:34]
Reactant: N=C(N)NCCCCCCCCC(=O)NC(O)C(=O)NCCCCNCCCN
Reactant: CO
Agent: Cl
Product: COC(NC(=O)CCCCCCCCNC(=N)N)C(=O)NCCCCNCCCN
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
To a solution of 160 mg (0.31 mmole) of N-[4-(3-aminopropyl)aminobutyl]-2-(9-guanidinononanamido)-2-hydroxyethanamide trihydrochloride in 3.2 ml of anhydrous methanol was added 0.32 ml of 2N hydrogen chloride-methanol. The mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and the resulting white powder was purified in a manner as that in Example 7, using CM-Sephadex® C-25 (Na-type) and Sephadex® LH-20 to yield 107 mg (65% yield) of a white powder of N-[4-(3-aminopropyl)aminobutyl]-2-(9-guanidinonoanamido)-2-methoxyethanamide trihydrochloride.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[NH:17][N:18]=[CH:19][CH:20]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1.Br[CH2:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[C:27]#[N:28]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:23][C:24]4[CH:31]=[CH:30][CH:29]=[C:26]([C:27]#[N:28])[CH:25]=4)[N:17]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1cccnc1
Reactant: N#Cc1cccc(CBr)c1
Product: Cc1nc(-c2ccn(Cc3cccc(C#N)c3)n2)sc1C(=O)NCc1cccnc1

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide and 3-bromomethyl-benzonitrile as described in Example 49 and isolated as white solid (0.054 g, 40% yield). 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.54-8.56 (m, 1H), 7.71 (d, J=8 Hz, 1H), 7.60-7.63 (m, 1H), 7.46-7.51 (m, 3H), 7.28-7.31 (m, 2H), 6.89 (s, 1H), 6.17-6.21 (m, 1H), 5.38 (s, 2H), 4.63 (d, J=8 Hz, 2H), 2.75 (s, 3H); MS (M+H)+=415.2; Rt=1.16 min; HRMS (M+H)+=415.13.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[CH3:14][NH:15][C:16]([C:18]1[CH:22]=[C:21]([CH2:23][OH:24])[O:20][N:19]=1)=[O:17].N1C=CC=CC=1>ClCCl>[C:2](=[O:3])([O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[O:24][CH2:23][C:21]1[O:20][N:19]=[C:18]([C:16](=[O:17])[NH:15][CH3:14])[CH:22]=1
Reactant: CNC(=O)c1cc(CO)on1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CNC(=O)c1cc(COC(=O)Oc2ccc([N+](=O)[O-])cc2)on1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
2.58 g (12.81 mmoles) of 4-nitrophenyl chloroformate are added in small portions to a solution of 2.00 g (12.81 mmoles) of 3-methylcarbamoyl-isoxazol-5-ylmethanol (commercial), 1.52 g (19.21 mmoles) of pyridine and 0.157 g (1.28 moles) of N,N-dimethylaminopyridine in 15 ml of dichloromethane, cooled to about 0° C. The medium is maintained with stirring for 1 hr at 0° C. then for 1 hr at ambient temperature. The precipitate formed is filtered off, then copiously rinsed with diisopropyl ether. After drying under vacuum at about 60° C., 2.6 g of pure product are obtained in the form of a white powder.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[C:3]=1[C:4]([NH:6][C:7]1[S:18][C:10]2[C:11]([CH3:17])([CH3:16])[O:12][C:13]([CH3:15])([CH3:14])[C:9]=2[C:8]=1[C:19]([OH:21])=O)=[O:5].[NH2:30][CH2:31][C@@H:32]1[CH2:36][CH2:35][CH2:34][O:33]1>>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[C:3]=1[C:4]([NH:6][C:7]1[S:18][C:10]2[C:11]([CH3:17])([CH3:16])[O:12][C:13]([CH3:15])([CH3:14])[C:9]=2[C:8]=1[C:19]([NH:30][CH2:31][C@@H:32]1[CH2:36][CH2:35][CH2:34][O:33]1)=[O:21])=[O:5]
Reactant: CC1(C)OC(C)(C)c2c1sc(NC(=O)c1c(F)cccc1C(F)(F)F)c2C(=O)O
Reactant: NC[C@@H]1CCCO1
Product: CC1(C)OC(C)(C)c2c1sc(NC(=O)c1c(F)cccc1C(F)(F)F)c2C(=O)NC[C@@H]1CCCO1

Procedure:
The title compound was prepared from the product of Example 45A and commercially available (S)-2-aminomethyltetrahydrofuran using the procedure described for Example 2B. 1H NMR (DMSO-d6, 300 MHz) δ 1.45 (s, 6H), 1.48 (s, 6H), 1.50-1.58 (m, 2H), 1.66-0.191 (m, 3H), 3.13-3.29 (m, 2H), 3.39-3.46 (m, 1H), 3.60-3.67 (m, 1H), 3.85-3.94 (m, 1H), 7.69-7.82 (m, 3H), 8.03 (t, J=5.8 Hz, 1H), 11.42 (br s, 1H). MS (ESI+) m/z 515 (M+H)+. Anal. calcd. for C24H26F4N2O4S: C, 56.02; H, 5.09; N, 5.44. Found: C, 55.98; H, 5.05; N, 5.48.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].Cl[C:8]1[C:13]2[CH:14]=[C:15]([N:17]3[CH2:21][CH2:20][N:19]([C:22]4[CH:23]=[N:24][CH:25]=[CH:26][C:27]=4[CH3:28])[C:18]3=[O:29])[S:16][C:12]=2[CH:11]=[CH:10][N:9]=1.CB(O)O.CO>C(Cl)(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:28][C:27]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1[N:19]1[CH2:20][CH2:21][N:17]([C:15]2[S:16][C:8]3[N:9]=[CH:10][CH:11]=[C:12]([CH3:1])[C:13]=3[CH:14]=2)[C:18]1=[O:29]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccncc1N1CCN(c2cc3c(Cl)nccc3s2)C1=O
Agent: [Pd]
Agent: CB(O)O
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ccncc1N1CCN(c2cc3c(C)ccnc3s2)C1=O
Yield: 10.7 %

Procedure:
Tetrakis (triphenylphosphine) palladium (33 mg, 0.0288 mmol) was added to potassium carbonate (120 mg, 0.8649 mmol) previously purged with argon (30 minutes). The reaction mixture was purged with argon for 15 minutes, followed by the addition of 1-(4-chloro-thieno[3,2-c]pyridin-2-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (98A: 100 mg, 0.2883 mmol) and methyl boronic acid (21 mg, 0.3459 mmol). The reaction mixture was heated to reflux for 6 hours. The reaction was monitored by TLC (10% MeOH in CHCl3). The reaction mixture was concentrated to afford the crude product. Purification by column chromatography on silica gel (3-4% MeOH in CHCl3), followed by preparative HPLC afforded 10 mg of the product (16.39% yield).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C@H:7]2[CH2:13][C@H:12]3[N:14]([CH2:15][CH2:16][C@H:17]([NH:24][C:25]([CH:27]4[CH2:32][CH2:31][C:30]([F:34])([F:33])[CH2:29][CH2:28]4)=[O:26])[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C@H:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]([CH:35]([CH3:37])[CH3:36])=[N:4][N:3]=1.P([O-])([O-])([O-])=O.N.C1CCCCC1>C(OC)(C)(C)C.O>[CH:35]([C:5]1[N:6]([CH:7]2[CH2:13][CH:12]3[N:14]([CH2:15][CH2:16][C@H:17]([NH:24][C:25]([CH:27]4[CH2:28][CH2:29][C:30]([F:34])([F:33])[CH2:31][CH2:32]4)=[O:26])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:2]([CH3:1])=[N:3][N:4]=1)([CH3:36])[CH3:37]
Reactant: Cc1nnc(C(C)C)n1[C@@H]1C[C@H]2CC[C@@H](C1)N2CC[C@H](NC(=O)C1CCC(F)(F)CC1)c1ccccc1
Agent: N
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCCCC1
Solvent: O
Solvent: COC(C)(C)C
Product: Cc1nnc(C(C)C)n1C1CC2CCC(C1)N2CC[C@H](NC(=O)C1CCC(F)(F)CC1)c1ccccc1
Reaction time: 0.25 h
Yield: 80.6 %

Procedure:
Crystalline form 1 of maraviroc phosphate (5 gm) was dissolved in methyl tert-butyl ether (60 ml) and water (40 ml). The pH of the reaction mass was adjusted to 8.0 to 8.5 with ammonia solution (3 ml) and stirred for 15 minutes. The separated organic layer was dried with sodium sulfate and treated with carbon. The methyl tert-butyl ether was distilled off under vacuum at below 45° C. to obtain residual mass. To the residual mass was added cyclohexane (50 ml) and stirred for 20 minutes at room temperature, filtered. The solid obtained was dried to obtain 3.4 gm of maraviroc amorphous form.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([CH:10]1[S:14][C:13](=[O:15])[NH:12][C:11]1=[O:16])(=[O:9])=[O:8].[F:17][C:18]([F:34])([F:33])[C:19]1[CH:20]=[C:21]([C:29]#[C:30][CH2:31]Br)[CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1.FC1C=C(C#CCBr)C=C(F)C=1>>[F:17][C:18]([F:33])([F:34])[C:19]1[CH:20]=[C:21]([C:29]#[C:30][CH2:31][C:10]2([S:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)(=[O:9])=[O:8])[S:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])[CH:22]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:24]=1
Reactant: O=C1NC(=O)C(S(=O)(=O)c2ccccn2)S1
Reactant: FC(F)(F)c1cc(C#CCBr)cc(C(F)(F)F)c1
Agent: Fc1cc(F)cc(C#CCBr)c1
Product: O=C1NC(=O)C(CC#Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(S(=O)(=O)c2ccccn2)S1

Procedure:
By the procedure described in Example 43, this compound was prepared from 5-(Pyridine-2-sulfonyl)-thiazolidine-2,4-dione of formula (V).Example 19 and [3-(3,5-bis(trifluoromethyl)phenyl)-prop-2-ynyl]-bromide of formula (IX), Example 31: mp 150°-152° C.: NMR (DMSO, d 6): δ8.79 (d, J=4.4 Hz, 1H, pyH), 8.16 (dr, J=1.6, 7.9 Hz, 1H, pyH), 8.11 (s, 1H, ArH), 8.05 (d, J=7.9 Hz, 1H, pyH), 7.94 (s, 2H, ArH), 7.9 (dd, J=4.9, 7.3 Hz, 1H, ArH), 3.87 (d, J=17.2 Hz, 1H, CH2), 3.71 (d, J=17.2 Hz, 1H, CH2); MS(CI): 509 (MI+1, 100%), 367 (32%), 366 (352%), 287 (35%), 194 (25%), 194 (20%); Anal. Calc. for C19H10F6N2O4S2 : C, 44.89; H, 1.98; N, 5.51; Found: C, 42.80; H, 2.09; N, 5.77.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:15][C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[C:9]=2[CH:8]=[N:7]1)C.[BH4-].[Na+].Cl>CO>[CH2:19]([O:18][C:16](=[O:17])[NH:15][C@@H:10]1[CH2:11][CH2:12][CH2:13][C:14]2[N:6]([CH2:5][CH2:4][OH:3])[N:7]=[CH:8][C:9]1=2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)Cn1ncc2c1CCC[C@H]2NC(=O)OCc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C(N[C@@H]1CCCc2c1cnn2CCO)OCc1ccccc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
To a solution of ((R)-4-benzyloxycarbonylamino-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid ethyl ester (2.00 g, 5.60 mmol) in methanol (150 mL) was added sodium borohydride (1.61 g, 39.5 mmol). The mixture was stirred at 70° C. for 2 hours. After being cooled to room temperature, the reaction mixture was acidified to pH 7 with 5N hydrochloric acid, and then concentrated to remove methanol. The resulting mixture was extracted with dichloromethane (20 mL). After filtering out any insoluble materials from the organic layer, the filtrate was concentrated in vacuo to give (R)-[1-(2-hydroxy-ethyl)-4,5,6,7-tetrahydro-1H-indazol-4-yl]-carbamic acid benzyl ester (1.68 g, 95%) as a white solid. MS calcd. for C17H21N3O3 315, obsd. (ESI+) [(M+H)+] 316.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH:22]3[CH2:23][CH:24]([C:26]4([OH:29])[CH2:28][CH2:27]4)[CH2:25][CH:14]2[CH2:15][C:16]2([CH2:21]3)[O:20][CH2:19][CH2:18][O:17]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.I[CH3:31]>C1COCC1.CCOC(C)=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH:14]3[CH2:25][CH:24]([C:26]4([O:29][CH3:31])[CH2:28][CH2:27]4)[CH2:23][CH:22]2[CH2:21][C:16]2([CH2:15]3)[O:20][CH2:19][CH2:18][O:17]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)N1C2CC(C3(O)CC3)CC1CC1(C2)OCCO1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC1(C2CC3CC4(CC(C2)N3S(=O)(=O)c2ccc(Cl)cc2)OCCO4)CC1
Reaction time: 0.17 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 46 mg, 1.16 mol) was added to a solution of 1-{9-[(4-chlorophenyl)sulfonyl]spiro[9-azabicyclo[3.3.1]nonane-3,2′-[1,3]dioxolan]-7-yl}cyclopropanol (55) (321 mg, 0.775 mmol) in THF (2 mL). The resulting solution was stirred for 10 minutes, after which iodomethane (72 μL, 1.16 mmol) was added. The reaction mixture was stirred at room temperature for 18 h and was subsequently diluted with EtOAc and washed with brine. The organic phase was dried (Na2SO4), filtered, and concentrated to give 9-[(4-chlorophenyl)sulfonyl]-7-(1-methoxycyclopropyl)spiro[9-azabicyclo[3.3.1]nonane-3,2′-[1,3]dioxolane] (56). MS (ESI) 428.1 (M+H).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:27]=[C:28]([C:31]3[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=3)[CH:29]=[CH:30][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C(O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:27]=[C:28]([C:31]3[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=3)[CH:29]=[CH:30][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(C3=NNC(=O)CC3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1nc2ccc(C3=NNC(=O)CC3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 64 from methyl 4'-[[2-n-butyl-6-(4,5-dihydro-2H-pyridazin-3-on-6-yl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylate and sodium hydroxide solution in ethanol.
Reaction SMILES: N(C[C@@H](C1C=CC(OCC2C=CC=CC=2)=C2C=1C=CC(=O)N2)O)=[N+]=[N-].[Si]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][N:43]([C:46]([C:48]2[CH:49]=[C:50]([S:54]([C:57]3[CH:58]=[C:59]4[C:64](=[C:65]([CH3:67])[CH:66]=3)[N:63]=[CH:62][C:61]([C:68]([NH2:70])=[O:69])=[C:60]4[NH:71][C:72]3[CH:77]=[CH:76][CH:75]=[C:74]([O:78][CH3:79])[CH:73]=3)(=[O:56])=[O:55])[CH:51]=[CH:52][CH:53]=2)=[O:47])[CH2:42][CH2:41]1)(C(C)(C)C)(C)C>>[OH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][N:40]1[CH2:41][CH2:42][N:43]([C:46]([C:48]2[CH:49]=[C:50]([S:54]([C:57]3[CH:58]=[C:59]4[C:64](=[C:65]([CH3:67])[CH:66]=3)[N:63]=[CH:62][C:61]([C:68]([NH2:70])=[O:69])=[C:60]4[NH:71][C:72]3[CH:77]=[CH:76][CH:75]=[C:74]([O:78][CH3:79])[CH:73]=3)(=[O:56])=[O:55])[CH:51]=[CH:52][CH:53]=2)=[O:47])[CH2:44][CH2:45]1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N5CCN(CCCCCCO[Si](C)(C)C(C)(C)C)CC5)c4)cc23)c1
Agent: [N-]=[N+]=NC[C@H](O)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N5CCN(CCCCCCO)CC5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 5, using Intermediate 85 as a substrate. ES/MS calcd. for C35H42N5O6S+ 660.3. Found m/z=660.3 (M+H)+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][C:28]([O:30][CH3:31])=[O:29])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH:32]1([CH:38]=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>O1CCCC1.CCCCCC>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]([CH:38]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[OH:39])[C:28]([O:30][CH3:31])=[O:29])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)Cc1ccccc1OCc1ccccc1
Reactant: O=CC1CCCCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C(c1ccccc1OCc1ccccc1)C(O)C1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.3 %

Procedure:
To a dry ice-acetone bath cooled solution of diisopropylamine (4.84 g) in tetrahydrofuran (100 ml) was added a 1.61M solution of n-butyl lithium in n-hexane (24.8 ml) and the mixture was stirred for 30 minutes at the same temperature. Methyl (2-benzyloxyphenyl)acetate (5.12 g) was added and the mixture was stirred at −70° C. for 30 minutes and allowed to warm to 0° C. Cyclohexanecarbaldehyde (2.24 g) was added and the solution was stirred for 30 minutes. The reaction mixture was quenched by 1N aqueous hydrochloric acid solution (80 ml), washed with aqueous sodium bicarbonate solution and brine, dried, and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluting with 20% diethyl ether in hexane) to afford less polar isomer of methyl (2RS,3SR)-2-(2-benzyloxyphenyl)-3-cyclohexyl-3-hydroxypropionate (isomer A) (394 mg) and more polar isomer of methyl (2RS,3RS)-2-(2-benzyloxyphenyl)-3-cyclohexyl-3-hydroxypropionate (isomer B) (2.67 g).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH2:11])[CH:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.CN1C(=O)CCC1>O1CCOCC1>[O:15]1[CH2:16][CH2:17][N:12]([C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([NH2:11])[CH:3]=2)[CH2:13][CH2:14]1
Reactant: Nc1cc(Cl)n2nccc2n1
Reactant: C1COCCN1
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Nc1cc(N2CCOCC2)n2nccc2n1
Temperature: 100 °C
Yield: 38 %

Procedure:
7-Chloropyrazolo[1,5-a]pyrimidin-5-amine (1E, 10 g, 30 mmol) and morpholine were added to NMP (20 ml) and dioxane (80 ml). The mixture was heated to 100° C. and the resulting suspension was concentrated in vacuo to remove most of the dioxane. Brine was added and the mixture was extracted with EtOAc five times. Combined organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Trituration of the residue with Et2O gave the desired product 7-morpholinopyrazolo[1,5-a]pyrimidin-5-amine (9A, 5.0 g, 38%) as an off-white solid.
Reaction SMILES: OS(O)(=O)=O.[CH2:6]([C:8]1[CH:9]=[C:10]([C:15]#[C:16][Si](C)(C)C)[CH:11]=[CH:12][C:13]=1[F:14])[CH3:7].[O:21]1CCCC1>O.[Hg]=O>[CH2:6]([C:8]1[CH:9]=[C:10]([C:15](=[O:21])[CH3:16])[CH:11]=[CH:12][C:13]=1[F:14])[CH3:7]
Reactant: CCc1cc(C#C[Si](C)(C)C)ccc1F
Reactant: C1CCOC1
Agent: O=S(=O)(O)O
Agent: O=[Hg]
Solvent: O
Product: CCc1cc(C(C)=O)ccc1F
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of H2SO4 (0.25 mL) in H2O (3 mL), HgO (154 mg, 0.712 mmol) was added. Another portion of H2SO4 (0.5 mL) was added so that all of the mercury oxide dissolved. Then the mixture was warmed to 60° C. and (3-ethyl-4-fluoro-phenylethynyl)-trimethyl-silane (1.57 g, 7.12 mmol) was added with tetrahydrofuran (2 mL) during 20 minutes. After the addition, the mixture was stirred for an additional 30 minutes and then cooled and extracted with ether. The extract was passed through a celite pad, washed with saturated brine and dried (Na2SO4). Removal of solvent on a rotary evaporator gave a brown oil, which was chromatographed (25%, dichloromethane/hexanes) to give a yellow oil. 404 mg, 34%.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][NH2:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].CS[C:14]1[S:15][C:16]2[C:21]([N:22]=1)=[CH:20][CH:19]=[CH:18][N:17]=2>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([CH2:10][NH:11][C:14]2[S:15][C:16]3[C:21]([N:22]=2)=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(CN)CC1
Reactant: CSc1nc2cccnc2s1
Product: CC(=O)N1CCC(CNc2nc3cccnc3s2)CC1
Temperature: 140 °C
Yield: 93 %

Procedure:
A mixture of 11 parts of 1-acetyl-4-piperidinemethanamine and 9 parts of 2-(methylthio)thiazolo[5,4-b]pyridine was stirred and heated for 20 hours at 140° C. The whole was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fraction were collected and the eluent was evaporated, yielding 13.5 parts (93%) of 1-acetyl-N-(thiazolo[5,4-b]pyridin-2-yl)-4-piperidinemethanamine as a residue (intermediate 51).
Reaction SMILES: [C:1]1([CH:7]([NH:9][C:10]([C:12]2[S:13][C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26](Br)[CH:25]=4)[N:18]=3)=[CH:15][CH:16]=2)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:31][N:32]([CH3:38])[CH:33]1[CH2:37][CH2:36][NH:35][CH2:34]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.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.C(Cl)(Cl)Cl.[Pd].[Pd]>[C:1]1([CH:7]([NH:9][C:10]([C:12]2[S:13][C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([N:35]5[CH2:36][CH2:37][CH:33]([N:32]([CH3:38])[CH3:31])[CH2:34]5)[CH:25]=4)[N:18]=3)=[CH:15][CH:16]=2)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(NC(=O)c1ccc(-c2ccnc(Nc3cccc(Br)c3)n2)s1)c1ccccc1
Reactant: CN(C)C1CCNC1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(NC(=O)c1ccc(-c2ccnc(Nc3cccc(N4CCC(N(C)C)C4)c3)n2)s1)c1ccccc1
Temperature: 65 °C
Reaction time: 48 h
Yield: 500 %

Procedure:
5-[2-(3-Bromo-phenylamino)-pyrimidin-4-yl]-thiophene-2-carboxylic acid (1-phenyl-ethyl)-amide (20 mg, 41 μmol), 3-dimethylamino pyrrolidine (6 mg, 0.5 μmol), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (1.5 mg, 2 μmol), and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (2 mg, 5 μmol) were suspended in 0.2 mL lithium bis(trimethylsilyl)amide solution in THF (1M). The reaction mixture was stirred at 65° C. for 48 hours. The reaction was quenched with 1 mL MeOH and concentrated and the crude product was redissolved in DMSO and purified by mass triggered reverse phase HPLC to afford 1.2 mg of pure 5-{2-[3-(3-Dimethylamino-pyrrolidin-1-yl)-phenylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic acid (1-phenyl-ethyl)-amide (2.5 μmol, 6%, 1:1 mixture of diastereomers). 1H NMR (500 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.94 (d, J=8 Hz, 1H), 8.50 (d, J=5 Hz, 1H), 7.97 (d, J=4 Hz, 1H), 7.92 (d, J=4 Hz, 1H), 7.39 (d, J=5 Hz, 2H), 7.33 (m, 4H), 7.23 (t, J=7 Hz, 1H), 7.18 (s, 1H), 6.98 (m, 1H), 6.17 (d, J=7.5 Hz, 1H), 5.14 (quintet, J=6.5 Hz, 1H), 3.45 (q, J=8 Hz, 1H), 3.39 (t, J=8 Hz, 1H), 3.32 (m, 2H), 3.02 (q, J=8 Hz, 1H), 2.77 (m, 1H), 2.15 (s, 6H), 1.79 (m, 1H), 1.49 (d, J=6.5 Hz, 3H). MS: m/z 513 (M+H+).