Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:22][C:21](=[O:23])[C:20]4[C:15](=[C:16]([C:27]#[N:28])[CH:17]=[C:18]5[CH:26]=[N:25][NH:24][C:19]5=4)[N:14]=3)=[CH:11][C:10]([C:29]([F:32])([F:31])[F:30])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.[C:34]1([NH2:40])([CH:37]2[CH2:39][CH2:38]2)[CH2:36][CH2:35]1.C(N(CC)CC)C>CN(C)C=O>[C:34]1([NH:40][C:21]([C:20]2[C:15]([NH:14][C:13]([C:12]3[N:8]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=4)[N:9]=[C:10]([C:29]([F:31])([F:30])[F:32])[CH:11]=3)=[O:22])=[C:16]([C:27]#[N:28])[CH:17]=[C:18]3[C:19]=2[NH:24][N:25]=[CH:26]3)=[O:23])([CH:37]2[CH2:39][CH2:38]2)[CH2:36][CH2:35]1
Reactant: N#Cc1cc2cn[nH]c2c2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Reactant: NC1(C2CC2)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1cc2cn[nH]c2c(C(=O)NC2(C3CC3)CC2)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 60 °C
Reaction time: 24 h

Procedure:
To a solution of 500 mg of the above 7-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-9-oxo-1,9-dihydro-8-oxa-1,2,6-triaza-cyclopenta[a]naphthalene-5-carbonitrile in 8 mL of N,N-dimethylformamide is added 218 mg (1.63 mmol) of bicyclopropyl-1-ylamine hydrochloride and 303 μL (2.18 mmol) of triethylamine. The reaction is stirred at 60° C. for 24 hours and then concentrated in vacuo. The residue is taken-up with water and ethyl acetate. The phases are separated and the aqueous layer is washed with ethyl acetate. The combined organic layers are washed several times with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography (SiO2, hexanes/ethyl acetate 3:9) affords 76 mg (12% over two steps) of the product as white solid; LC/MS: 555/557 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([NH:11][C:12]([C:14]2[N:15]=[N:16][N:17]([C:46]3[CH:51]=[CH:50][C:49]([C:52]([NH:54][CH2:55][CH3:56])=[O:53])=[CH:48][CH:47]=3)[C:18]=2[CH2:19][NH:20][CH2:21][C:22]2[N:23](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:24]=[CH:25][N:26]=2)=[O:13])[CH2:10][CH2:9]1>>[CH:8]1([NH:11][C:12]([C:14]2[N:15]=[N:16][N:17]([C:46]3[CH:47]=[CH:48][C:49]([C:52]([NH:54][CH2:55][CH3:56])=[O:53])=[CH:50][CH:51]=3)[C:18]=2[CH2:19][NH:20][CH2:21][C:22]2[NH:26][CH:25]=[CH:24][N:23]=2)=[O:13])[CH2:9][CH2:10]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CNCc2nccn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CNCc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
Trifluoroacetic acid (0.5 ml) was added to N-cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-5-({[(1-trityl-1H-imidazol-2-yl)methyl]amino}methyl)-1H-1,2,3-triazole-4-carboxamide (78 mg, 0.12 mmol) obtained in Example 1198, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, water (2 ml) was added to the residue, and precipitated crystals were filtered off. The filtrate was neutralized with 1N aqueous sodium hydroxide solution and concentrated to dryness. The residue was purified by silica gel column (hexane/ethyl acetate=1/1 to ethyl acetate/methanol=4/1) to give the title compound as a colorless powder (30 mg, 61%).
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[NH2:20][C:21]1[CH:30]=[CH:29][C:24]2[N:25]=[C:26]([SH:28])[S:27][C:23]=2[CH:22]=1>CN(C=O)C>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:20][C:21]2[CH:30]=[CH:29][C:24]3[NH:25][C:26](=[S:28])[S:27][C:23]=3[CH:22]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: Nc1ccc2nc(S)sc2c1
Solvent: CN(C)C=O
Product: CCCCN1C(=O)C(Nc2ccc3[nH]c(=S)sc3c2)=C(c2ccccc2)S1(=O)=O
Temperature: 140 °C
Yield: 4.8 %

Procedure:
2-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (110 mg, 0.330 mmol) was dissolved in dry DMF (0.5 mL) under nitrogen atmosphere. 6-Amino-1,3-benzothiazole-2-thiol (181 mg, 0.991 mmol) was added and the reaction mixture was heated in a microwave reactor for 25 mins at 140° C. The crude product was purified by preparative HPLC affording the title compound (7 mg, 4.5%). 1H NMR (500 MHz, CD3CN): δ 1.00 (t, 3H), 1.43-1.52 (m, 2H), 1.78-1.85 (m, 2H), 3.75 (t, 2H), 6.86-7.00 (m, 3H), 7.11-7.28 (m, 5H), 7.84 (bs, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[C:23]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)(=[O:25])[CH3:24].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>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].O1CCOCC1.O1CCOCC1.O>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)=[CH:3][C:2]=1[C:29]1[CH:30]=[CH:31][C:26]([C:23](=[O:25])[CH3:24])=[CH:27][CH:28]=1
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Reactant: CC(=O)c1ccc(B(O)O)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)c1ccc(-c2cc(-c3cnc4c(F)c(C(C)(C)O)ccn34)ccc2F)cc1
Temperature: 70 °C
Yield: 5 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol, 4acetylbenzeneboronic acid and potassium phosphate were placed in a dry tube with 1,4dioxane/water (3:1) and this was heated to 70° C. under nitrogen. Tris(dibenzylideneacetone)dipalladium(0), tri-tert-butylphosphine (0.2M in 1,4dioxane) and 1,4-dioxane (0.5 ml) were mixed in a vial, and this mixture was added to the hot reaction via syringe. The resulting reaction mixture was heated at 70° C. for 12 h. The reaction was allowed to cool to room temperature then partitioned between dichloromethane and 2N hydrochloric acid. The aqueous layer was filtered through glass microfibre filter paper and evaporated to dryness. The residue was dissolved in methanol and evaporated to dryness. The residue was dissolved in dimethylsulfoxide (˜25 mg/ml), filtered through glass microfibre filter paper and purified by LC-MS. Appropriate fractions were combined and evaporated to give 1-{2′-fluoro-5′-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyridin-3-yl]biphenyl-4-yl}ethanone as an off-white solid (6 mg, 5%); m/z (ES+) 407 [MH+].
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[C:20]([C:24]1[CH:25]=[C:26]([NH2:43])[N:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][N:36]3[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]3)[CH:30]=2)[N:28]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:25]=[C:26]([NH:43][C:17](=[O:19])[CH2:16][C:13]2[CH:12]=[CH:11][C:10]([N:3]3[C:4]4=[N:5][CH:6]=[CH:7][CH:8]=[C:9]4[N:1]=[CH:2]3)=[CH:15][CH:14]=2)[N:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][N:36]3[CH2:37][CH2:38][N:39]([CH3:42])[CH2:40][CH2:41]3)[CH:30]=2)[N:28]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CN1CCN(Cc2cccc(-n3nc(C(C)(C)C)cc3N)c2)CC1
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Product: CN1CCN(Cc2cccc(-n3nc(C(C)(C)C)cc3NC(=O)Cc3ccc(-n4cnc5cccnc54)cc3)c2)CC1

Procedure:
The title compound is prepared as described in Example 28 but using 2-(4-Imidazo[4,5-b]pyridine-3-yl-phenyl)-acetic acid and 5-tert-butyl-2-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl)-2H-pyrazol-3-ylamine. Title compound: ES-MS: 563.12 [M+H]+; tR=2.67 min (System 3).
Reaction SMILES: C([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:17][OH:18])[CH:14]=2)[CH2:9]1)C1C=CC=CC=1>[Pd].C(O)C>[CH2:9]1[C:10]2[C:15](=[CH:14][C:13]([CH2:17][OH:18])=[CH:12][CH:11]=2)[CH2:16][NH:8]1
Reactant: OCc1ccc2c(c1)CN(Cc1ccccc1)C2
Agent: [Pd]
Solvent: CCO
Product: OCc1ccc2c(c1)CNC2
Temperature: 50 °C
Reaction time: 30 h
Yield: 99.9 %

Procedure:
10% Palladium on activated carbon (200 mg) was added to a solution of (2-benzyl-2,3-dihydro-1H-isoindol-5-yl)-methanol (2.39 g, 10.0 mmol) in ethanol (60 ml) and the resulting mixture was placed in a Parr apparatus, heated to 50° C. and shaken under a hydrogen atmosphere at 60 psi for 30 hours. Upon cooling to room temperature the mixture was filtered under gravity, the solids were rinsed with ethanol (2×10 ml) and the solvent removed in vacuo to afford (2,3-dihydro-1H-isoindol-5-yl)-methanol (1.49 g, 100%) as an off-white solid. 1H NMR (DMSO-d6) 7.20 (1H, s), 7.18 (1H, d), 7.12 (1H, d), 5.10 (1H, br s), 4.46 (2H, s), 4.05 (4H, s). MS: [M+H]+ 150.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[N:21](COCC[Si](C)(C)C)[N:22]=[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][CH2:31][C:32]5[S:33][CH:34]=[CH:35][CH:36]=5)[CH:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[S:33]1[CH:34]=[CH:35][CH:36]=[C:32]1[CH2:31][NH:30][C:26]1[CH:25]=[C:24]([C:23]2[C:18]3[C:19](=[N:20][C:15]([NH:14][CH:11]4[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]4)=[N:16][CH:17]=3)[NH:21][N:22]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2ncc3c(-c4cccc(NCc5cccs5)c4)nn(COCC[Si](C)(C)C)c3n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCC(Nc2ncc3c(-c4cccc(NCc5cccs5)c4)n[nH]c3n2)CC1
Reaction time: 4 h

Procedure:
To a stirred solution of {4-[3-{3-[(thiophen-2-ylmethyl)-amino]-phenyl}-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (290 mg, 0.44 mmol) in dichloromethane (10 mL) was added TFA (15 mL) at room temperature. The resulting mixture was stirred for another four hours at this temperature. The solvent was evaporated under reduced pressure and the residue was treated with saturated aqueous NaHCO3 (5 mL) and extracted with EtOAc (30 mL). The organic phase was washed with brine (5 mL) and dried to give crude product. It was purified by chromatography (silica gel, 200-300 mesh, MeOH.:DMC, 1:20, v/v) to give N-(3-{3-[(thiophen-2-ylmethyl)-amino]-phenyl}-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-cyclohexane-1,4-diamine as solid. (Yield 27 mg, 14.6%).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[NH2:13][CH2:14]/[CH:15]=[CH:16]/[C:17]1[CH2:18][C@H:19]2[C:25](=[O:26])[N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:23]3[CH:35]=[C:36]([O:41][CH2:42][CH2:43][CH2:44][O:45][C:46]4[C:47]([O:83][CH3:84])=[CH:48][C:49]5[C:55](=[O:56])[N:54]6[CH:57]=[C:58]([C:60]7[CH:65]=[CH:64][C:63]([N:66]8[CH2:71][CH2:70][N:69]([CH3:72])[CH2:68][CH2:67]8)=[CH:62][CH:61]=7)[CH2:59][C@H:53]6[C:52](=[O:73])[N:51]([CH2:74][O:75][CH2:76][CH2:77][Si:78]([CH3:81])([CH3:80])[CH3:79])[C:50]=5[CH:82]=4)[C:37]([O:39][CH3:40])=[CH:38][C:22]=3[C:21](=[O:85])[N:20]2[CH:86]=1.[CH:87]1[C:99]2[CH:98]([CH2:100][O:101][C:102]([NH:104][C@@H:105]([CH:114]([CH3:116])[CH3:115])[C:106]([NH:108][C@@H:109]([CH3:113])[C:110](O)=[O:111])=[O:107])=[O:103])[C:97]3[C:92](=[CH:93][CH:94]=[CH:95][CH:96]=3)[C:91]=2[CH:90]=[CH:89][CH:88]=1>ClCCl>[CH3:40][O:39][C:37]1[C:36]([O:41][CH2:42][CH2:43][CH2:44][O:45][C:46]2[C:47]([O:83][CH3:84])=[CH:48][C:49]3[C:55](=[O:56])[N:54]4[CH:57]=[C:58]([C:60]5[CH:61]=[CH:62][C:63]([N:66]6[CH2:71][CH2:70][N:69]([CH3:72])[CH2:68][CH2:67]6)=[CH:64][CH:65]=5)[CH2:59][C@H:53]4[C:52](=[O:73])[N:51]([CH2:74][O:75][CH2:76][CH2:77][Si:78]([CH3:80])([CH3:79])[CH3:81])[C:50]=3[CH:82]=2)=[CH:35][C:23]2[N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:34])[CH3:32])[C:25](=[O:26])[C@@H:19]3[CH2:18][C:17](/[CH:16]=[CH:15]/[CH2:14][NH:13][C:110](=[O:111])[C@@H:109]([NH:108][C:106](=[O:107])[C@@H:105]([NH:104][C:102](=[O:103])[O:101][CH2:100][CH:98]4[C:99]5[CH:87]=[CH:88][CH:89]=[CH:90][C:91]=5[C:92]5[C:97]4=[CH:96][CH:95]=[CH:94][CH:93]=5)[CH:114]([CH3:116])[CH3:115])[CH3:113])=[CH:86][N:20]3[C:21](=[O:85])[C:22]=2[CH:38]=1
Reactant: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(c4ccc(N5CCN(C)CC5)cc4)C[C@H]1C(=O)N3COCC[Si](C)(C)C)N(COCC[Si](C)(C)C)C(=O)[C@@H]1CC(/C=C/CN)=CN1C2=O
Reactant: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(c4ccc(N5CCN(C)CC5)cc4)C[C@H]1C(=O)N3COCC[Si](C)(C)C)N(COCC[Si](C)(C)C)C(=O)[C@@H]1CC(/C=C/CNC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)OCC3c4ccccc4-c4ccccc43)C(C)C)=CN1C2=O
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 60.2 %

Procedure:
1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.0541 g, 0.282 mmol, 1.0 eq.) was added to a solution of allylamine 17e (assumed 100% yield, 0.296 g, 0.282 mmol, 1.0 eq.) and HO-Ala-Val-Fmoc 12 (0.116 g, 0.282 mmol, 1.0 eq.) in dry dichloromethane (18 mL). The reaction mixture was stirred for 80 minutes at room temperature when the reaction mixture was diluted with dichloromethane (30 mL) and washed sequentially with water (30 mL) and brine (30 mL). The organic layer was dried over MgSO4 filtered and excess dichloromethane removed under reduced pressure. The resulting residue was purified by flash chromatography (silica gel; 40:1 v/v DCM/MeOH to 20:1 v/v DCM/MeOH) to afford the product as a yellow solid (0.245 g, 60%). LC/MS (2.706 min (ES+)), m/z: 721.5 ½[M+2H]+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1>N1C=CC=CC=1>[N:22]1[CH:23]=[CH:24][C:19]([N:16]2[CH2:15][CH2:14][N:13]([C:10]3[CH:11]=[CH:12][C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:8][CH:9]=3)[CH2:18][CH2:17]2)=[CH:20][CH:21]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(N2CCN(c3ccncc3)CC2)cc1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(N2CCN(c3ccncc3)CC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 42.1 %

Procedure:
Methanesulphonyl chloride (0.50 g) was added dropwise to a stirred solution of 1-(4-aminophenyl)-4-(4-pyridyl)piperazine (1.00 g) in dry pyridine (10 ml) at room temperature. The mixture was stirred at room temperature for 20 hours and then evaporated. The residue was dissolved in water and the solution was basified with sodium bicarbonate solution and allowed to stand for 2 hours. The solid was filtered off, washed with water, dried and crystallised from methanol/ethyl acetate to give the title compound (0.55 g), m.p. 230°-232° C. Found: C,57.80; H,6.07; N,16.89. C16H20N4O2S requires: C,57.81; H,6.06; N,16.85%.
Reaction SMILES: [H-].[Na+].[O:3]1[C@@H:15]2[C@@:16]34[CH2:18][CH2:19][N:20]([CH3:21])[C@@H:10]([C@@H:11]3[CH:12]=[CH:13][C@@H:14]2[OH:22])[CH2:9][C:8]2=[C:17]4[C:4]1=[C:5]([O:23][CH2:24][O:25][CH3:26])[CH:6]=[CH:7]2.Cl[C:28]1[N:38]=[CH:37][CH:36]=[CH:35][C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]>CN(C=O)C>[O:3]1[C@@H:15]2[C@@:16]34[CH2:18][CH2:19][N:20]([CH3:21])[C@@H:10]([C@@H:11]3[CH:12]=[CH:13][C@@H:14]2[O:22][C:37]2[CH:36]=[CH:35][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][N:38]=2)[CH2:9][C:8]2=[C:17]4[C:4]1=[C:5]([O:23][CH2:24][O:25][CH3:26])[CH:6]=[CH:7]2
Reactant: COCOc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Reactant: CCOC(=O)c1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(O[C@H]2C=C[C@H]3[C@H]4Cc5ccc(OCOC)c6c5[C@@]3(CCN4C)[C@H]2O6)nc1

Procedure:
NaH (0.72 g, 30 mmol) is stirred with absolute DMF (12 ml) at RT and then 4,5α-epoxy-3-methoxymethoxy-17-methyl-morphinan-7-en-6α-ol (1.9764 g, 6 mmol) in DMF (12 ml) is added. After the development of gas has ceased, a solution of ethyl 2-chloro-nicotinate (5.568 g, 30 mmol) in absolute DMF (8 ml) is added at RT. After 1 hour at RT this reaction mixture is poured onto H2O (100 ml) and extracted 3 times with CH2Cl2 (60 ml). The combined organic phases are dried with Na2SO4, concentrated by rotary evaporation and the residue is purified by flash chromatography (90 g silica gel, CH2Cl2MeOH=9/1). Yield: 2.53 g (5.29 mmol, 88%)
Reaction SMILES: [C:1]([N:20]1[C:24]2[N:25]=[CH:26][CH:27]=[C:28]([C:29]([NH2:31])=O)[C:23]=2[CH:22]=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>C1COCC1.[Cl-].[Na+].O>[C:1]([N:20]1[C:24]2[N:25]=[CH:26][CH:27]=[C:28]([C:29](=[S:41])[NH2:31])[C:23]=2[CH:22]=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)c1ccnc2c1cnn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: NC(=S)c1ccnc2c1cnn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 80 °C

Procedure:
A solution of 1-tritylpyrazolo[5,4-b]pyridine-4-carboxamide (2.843 g, 7.029 mmol) in THF (50 mL) was treated with Lawesson's reagent (2.843 g, 7.029 mmol) at RT under nitrogen. The resulting yellow solution was allowed to heat at 80° C. for 4 hours and then treated with brine and extracted with EtOAc (2×). The organics were dried (Na2SO4), filtered, concentrated and purified by column chromatography (2% MeOH/DCM) to give the product as a yellow foam (quantitative yield). 1H NMR (DMSO, 400 MHz) δ 7.18-7.30 (16H, m), 8.28 (1H, m), 8.40 (1H, s), 10.34 (1H, br s); MS (ES+) 421.16
Reaction SMILES: Br[C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[N:14]=1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:12][C:13]1[N:14]=[C:15]([C:2]2[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][CH:9]=[CH:10][N:11]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1cccnc1Br
Reactant: CC1(C)OB(c2cccc(Cl)n2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cccnc1-c1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.49 g (0.70 mmol) of (Ph3P)2PdCl2 is added under argan to a solution of 3.0 g (13.9 mmol) of methyl 2-bromonicotinate in 10 ml of dioxane and the mixture is stirred for 30 min at room temperature. Thereafter, 3.33 g (13.78 mmol) of 2-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, 5.76 g (41.68 mmol) of K2CO3 and 11 ml of H2O are added in succession to the mixture, and the mixture is stirred for 6 hours under reflux and subsequently allowed to stand overnight at room temperature (RT). For work-up, the reaction mixture is poured into 150 ml of H2O and extracted repeatedly with CH2Cl2. The combined organic phases are dried over Na2SO4 and subsequently concentrated. The crude product thus obtained is purified by chromatography on silica gel using heptane/ethyl acetate (7:3) as the mobile phase. This gives 2.50 g (72%) of product as a colorless oil; 1H NMR (CDCl3) δ 8.70 (dd, 1H), 8.15 (dd, 1H), 7.95 (dd, 1H), 7.80 (dd, 1H), 7.40 (dd, 1H), 7.37 (dd, 1H), 3.90 (s, 3H, COOMe).
Reaction SMILES: C(Cl)(Cl)Cl.[CH3:5][CH:6]([OH:8])[CH3:7].C[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>>[C:5]1([CH:6]([OH:8])[C:7]#[C:14][CH2:13][CH2:12][CH2:11][CH3:10])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)O
Reactant: CCCCCC
Solvent: ClC(Cl)Cl
Product: CCCCC#CC(O)c1ccccc1

Procedure:
A colorless oil. [α]D25−18.1 (c 1.3, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.54-7.52 (m, 2H), 7.38-7.28 (m, 3H), 5.43 (d, J=5.6 Hz, 1H), 2.26 (td, J=7.2, 2.0 Hz, 2H), 2.13 (d, J=5.6 Hz, 1H), 1.55-1.36 (m, 4H), 0.898 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 141.2 (C), 128.3 (CH×2), 127.9 (CH), 126.5 (CH×2), 87.3 (C), 79.9 (C), 64.5 (CH), 30.5 (CH2), 21.8 (CH2), 18.3 (CH2), 13.4 (CH3); IR (neat) 3397, 3031, 2958, 2933, 2873, 2227, 1950, 1884, 1809, 1603, 1494, 1455, 1135, 1002, 698 cm−1; HRMS calculated for C13H16O 188.1201, found 188.1192. Chiral HPLC analysis: Chiralcel OD-H, 2-propanol/hexane (10:90), 1.0 mL/min, uv 254 nm; tR=11.0 min (87.5%), 13.8 min (12.5%), 75% ee.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:12]1([S:17]([C:20]2[CH:21]=[C:22]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37][CH2:38][C@@H:39]([C:41]3[CH:46]=[CH:45][C:44]([OH:47])=[C:43]([CH2:48][OH:49])[CH:42]=3)[OH:40])[CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13]1>CC(O)C>[CH:12]1([S:17]([C:20]2[CH:21]=[C:22]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37][CH2:38][C@@H:39]([C:41]3[CH:46]=[CH:45][C:44]([OH:47])=[C:43]([CH2:48][OH:49])[CH:42]=3)[OH:40])[CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13]1.[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O-:11])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)c1ccc(Cl)cc1
Agent: O=S(=O)(c1cccc(CCCCOCCCCCCNC[C@H](O)c2ccc(O)c(CO)c2)c1)C1CCCC1
Solvent: CC(C)O
Product: O=S(=O)([O-])c1ccc(Cl)cc1

Procedure:
4-Chlorobenzene sulfonic acid (19 mg) was added to a solution of 4-{(1R)-2-[(6-{4-[3-(cyclopentylsulfonyl)phenyl]butoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol (55 mg) (dissolved by gentle warming) in propan-2-ol (0.5 ml) at 21°. After a few minutes crystals had separated out. These were collected, and rinsed with propan-2-ol to give crystals of the title compound, δ (DMSO-d6) 9.40 (1H,s), 8.42 (2H, br s), 7.72-7.67 (2H, m), 7.62-7.55 (4H, m), 7.38 (2H, m), 7.32 (1H, d, J=2 Hz), 7.05 (1H, dd, J 2,8 Hz), 6.75 (1H, d, J=8 Hz), 5.97 (1H, br s), 5.00 (1H, v br s), 4.76 (1H, br d, J=9 Hz), 4.49 (2H, s), 3.75 (1H m), 3.32 (4H, partially obscured t), 3.10-2.87 (4H, 2m), 2.71 (2H, t, J=7 Hz), 1.90-1.25 (20H, m).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:8]([NH:10][C@H:11]([C:16]([CH2:18][C:19]([NH2:24])([CH3:23])[C:20]([NH2:22])=[O:21])=[O:17])[CH2:12][C:13](=[O:15])[OH:14])=[O:9])[CH2:4][CH2:5][S:6][CH3:7].[C:25]([O:29][C:30]([NH:32][C@H:33]([C:44](N[C@H](C(N[C@H](C(N[C@@H](C(N)=O)C)=O)CC(=O)O)=O)CCSC)=[O:45])[CH2:34][C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[NH:37][CH:36]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>O>[C:25]([O:29][C:30]([NH:32][C@H:33]([C:44]([NH:2][C@H:3]([C:8]([NH:10][C@H:11]([C:16]([CH2:18][C:19]([NH2:24])([CH3:23])[C:20]([NH2:22])=[O:21])=[O:17])[CH2:12][C:13](=[O:14])[OH:15])=[O:9])[CH2:4][CH2:5][S:6][CH3:7])=[O:45])[CH2:34][C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[NH:37][CH:36]=1)=[O:31])([CH3:27])([CH3:28])[CH3:26]
Reactant: CSCC[C@H](N)C(=O)N[C@@H](CC(=O)O)C(=O)CC(C)(N)C(N)=O
Reactant: CSCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@H](C)C(N)=O
Agent: Cl
Solvent: O
Product: CSCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)CC(C)(N)C(N)=O

Procedure:
When an equivalent quantity of L-methionyl-L-aspartyl-2-amino-2-methylpropionamide hydrochloride is substituted for the L-methionyl-L-aspartyl-D-alanine amide hydrochloride of Example 6, and the procedure detailed therein substantially repeated, there is obtained N-t-butoxycarbonyl-L-tryptophanyl-L-methionyl-L-aspartyl-2-amino-2-methylpropionamide containing 1/3 mole of water of hydration per mole. This compound is represented by the following formula. ##STR15##Elemental analysis of this compound shows C: 54.45%; H: 6.69%; N: 12.69% and S: 4.96%. Theory is C: 54.36%; H: 6.71%; N: 13.11% and S: 5.00%.
Reaction SMILES: [F:1][C:2]1([F:28])[C:8]([CH3:10])([CH3:9])[O:7][CH2:6][C:5](=O)[NH:4][C@@:3]1([C:13]1[CH:18]=[C:17]([C:19]#[C:20][C:21]2[N:22]=[C:23]([CH3:26])[S:24][CH:25]=2)[CH:16]=[CH:15][C:14]=1[F:27])[CH3:12].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1>O1CCOCC1>[F:1][C:2]1([F:28])[C:8]([CH3:10])([CH3:9])[O:7][CH2:6][C:5](=[S:38])[NH:4][C@@:3]1([C:13]1[CH:18]=[C:17]([C:19]#[C:20][C:21]2[N:22]=[C:23]([CH3:26])[S:24][CH:25]=2)[CH:16]=[CH:15][C:14]=1[F:27])[CH3:12]
Reactant: Cc1nc(C#Cc2ccc(F)c([C@@]3(C)NC(=O)COC(C)(C)C3(F)F)c2)cs1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: Cc1nc(C#Cc2ccc(F)c([C@@]3(C)NC(=S)COC(C)(C)C3(F)F)c2)cs1
Yield: 94.6 %

Procedure:
The reaction of (R)-6,6-difluoro-5-[2-fluoro-5-(2-methyl-thiazol-4-ylethynyl)-phenyl]-5,7,7-trimethyl-[1,4]oxazepan-3-one (178 mg, 436 μmol) with Lawesson's reagent (182 mg, 436 μmol) in 1,4-dioxane (8 ml) yielded the (R)-6,6-difluoro-5-[2-fluoro-5-(2-methyl-thiazol-4-ylethynyl)-phenyl]-5,7,7-trimethyl-[1,4]oxazepan-3-thione (175 mg, 94% yield) as a light yellow foam. MS (ISP): m/z=425.1 [M+H]+ and 427.1 [M+2+H]+.