Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][CH:9]=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:2]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[N-:30]=[N+:31]=[N-:32].[Na+]>ClCCl.C(Cl)(Cl)Cl.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][CH:9]=[C:10]([C:12]([N:30]=[N+:31]=[N-:32])=[O:14])[N:11]=2)[CH:2]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)c1csc(-c2cccnc2)n1
Agent: CC(C)COC(=O)Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NC(=O)c1csc(-c2cccnc2)n1
Reaction time: 1 h
Yield: 40 %

Procedure:
A suspension of 2-(3-pyridyl)-thiazole-4-carboxylic acid (0.824 g, 4 mmol) in dichloromethane-chloroform (30 ml-15 ml) was treated with triethylamine (0.75 ml, 0.5 g, 5 mmol) and then iso-butyl chloroformate (0.65 ml, 0.68 g, 5 mmol). After 1 h the mixture was evaporated to dryness and the residue suspended in THF (30 ml) and a solution of sodium azide (0.46 g, 7 mmol) in water (10 ml) was added. After 1 h, the mixture was concentrated (rotary evaporator) and partitioned between dichloromethane and brine. The organic extract was washed with half-saturated brine, dried, and evaporated. Trituration with petroleum ether, filtration, and drying in vacuo (CAUTION--no heating) afforded the title compounds as a brown solid (0.37 g, 40%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=[C:5]2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[N:32]1([CH2:31][CH2:30][NH:29][C:11]([C:9]2[CH:10]=[C:5]3[N:4]=[C:3]([NH:14][C:15]4[S:16][C:17]5[CH:23]=[C:22]([O:24][C:25]([F:27])([F:28])[F:26])[CH:21]=[CH:20][C:18]=5[N:19]=4)[N:2]([CH3:1])[C:6]3=[N:7][CH:8]=2)=[O:13])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: NCCN1CCOCC1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)cnc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCN3CCOCC3)cnc21
Yield: 29.3 %

Procedure:
3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (2-morpholin-4-yl-ethyl)-amide (28 mg) was prepared by following General Procedure F starting from 3-methyl-2-(6-trifluoromethoxy-benzo-thiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (75 mg), 4-(2-aminoethyl)morpholine (26 mg), HBTU (83 mg), and DIEA (48 uL). LC/MS: m/z 466.8. 1H NMR (DMSO-d6, 400 MHz): δ 12.39 (bs, 1H), 8.48 (bs, 1H), 8.09 (s, 1H), 7.94 (d, 1H), 7.81-7.66 (m, 1H), 7.51 (d, 1H), 7.35 (d, 1H), 3.83-3.23 (m, 11H), 2.51-2.48 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([C:10]3([C:17](=[S:20])[NH:18][CH3:19])[CH2:15][CH2:14][CH2:13][CH2:12][C:11]3=[O:16])=[CH:6][N:5]2[CH:21]=1.[BH4-].[Na+].O>CO>[OH:16][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][C:10]1([C:7]1[CH:8]=[CH:9][C:4]2[N:5]([CH:21]=[C:2]([CH3:1])[N:3]=2)[CH:6]=1)[C:17](=[S:20])[NH:18][CH3:19]
Reactant: CNC(=S)C1(c2ccc3nc(C)cn3c2)CCCCC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNC(=S)C1(c2ccc3nc(C)cn3c2)CCCCC1O
Reaction time: 1 h
Yield: 40.7 %

Procedure:
3.03 g of 1-(2-methylimidazo[1,2-a ]pyridin-6-yl)-N-methyl-2-oxocyclohexanecarbothioamide was suspended in 30 ml of methanol. The obtained suspension was cooled with ice, followed by the addition of 0.15 g of sodium borohydride. The obtained mixture was stirred for one hour, followed by the addition of 50 ml of water. The insoluble matter was recovered by filtration and recrystallized from ethanol and then from acetonitrile to give 1.24 g of the title compound (white powder) as a single diastereomer (yield: 41%).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[C:15]2[S:14][C:13]([NH:16][C:17]([NH:19][CH2:20][CH3:21])=[O:18])=[N:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)(C)C.[OH-].[K+].CN(C=O)C.CO>CCCCCCC.CO>[C:6]([C:7]1[C:15]2[S:14][C:13]([NH:16][C:17]([NH:19][CH2:20][CH3:21])=[O:18])=[N:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)#[CH:5]
Reactant: CCNC(=O)Nc1nc2cccc(C#C[Si](C)(C)C)c2s1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCCC
Solvent: CO
Solvent: CN(C)C=O
Product: C#Cc1cccc2nc(NC(=O)NCC)sc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.3 %

Procedure:
A mixture of 1-(7-trimethylsilylacetylenyl-2-benzothiazolyl)-3-ethylurea 2 (0.050 g, 0.16 mmol) and 1M aqueous KOH solution (0.16 mL, 0.16 mmol, 1.0 eq) in 1.5 mL of 2/1 mixture of DMF/MeOH was stirred at room temperature for about 2 hours. The mixture was taken up in 10 mL MeOH and the precipitation was filtered off. The mother liquid was concentrated and purified by prep HPLC to give the desired compound 0.006 g (15%). LC/MS 246 (M+1); LC retention time 2.77 min.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.Cl[C:9]1[N:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][N:10]=1.C(=O)([O-])[O-].[K+].[K+].CO.C(Cl)Cl>CN(C=O)C.CCOC(C)=O>[CH2:15]([C:12]1[CH:11]=[N:10][C:9]([N:1]2[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]2)=[N:14][CH:13]=1)[CH2:16][CH3:17]
Reactant: OC1CCNCC1
Reactant: CCCc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1cnc(N2CCC(O)CC2)nc1
Temperature: 110 °C
Yield: 72.3 %

Procedure:
A suspension of piperidin-4-ol (12 g, 119 mmol), 2-chloro-5-propylpyrimidine (20.44 g, 131 mmol) and potassium carbonate (49.2 g, 356 mmol) in DMF (100 mL) was heated at 110° C. for 12 h. The mixture was diluted with EtOAc (250 ml) and washed three times with water, dried over Na2SO4, and concentrated to give a yellow oil. The oil was purified by flash chromatography (SiO2, O-10% MeOH/CH2Cl2) to yield product (19 g, 86 mmol, 72.4% yield) as yellow solid. MS (ESI) 222.2 (M+1).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([NH2:8])=[S:7])[CH2:3][CH2:2]1.C[O-].[Na+].[C:12]([CH2:14][C:15](OCC)=[O:16])#[N:13]>C(O)C>[NH2:13][C:12]1[N:5]([CH2:4][CH:1]2[CH2:3][CH2:2]2)[C:6](=[S:7])[NH:8][C:15](=[O:16])[CH:14]=1
Reactant: NC(=S)NCC1CC1
Reactant: CCOC(=O)CC#N
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: Nc1cc(=O)[nH]c(=S)n1CC1CC1
Reaction time: 0.08 h
Yield: 56.2 %

Procedure:
To 1-cyclopropylmethyl-2-thiourea (0.60 g, 4.6 mmol) in ethanol (10 mL) was added sodium methoxide (0.26 g, 4.8 mmol) and, after 5 minutes, ethyl cyanoacetate (0.50 mL, 4.6 mmol). The resulting mixture was heated to reflux for 2 h and 40 minutes followed by evaporation of the solvent under reduced pressure and treatment of the resulting yellow solid with 2M aqueous acetic acid (10 mL) giving a white solid. The solid was collected by filtration and washed with 2M aqueous acetic acid (10 mL), stirred with ethanol (10 mL) followed by evaporation and drying under reduced pressure, giving the title compound (0.51 g, 56%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:14][O:15][CH:16]=2)=[CH:7][CH:6]=1)=[O:4]>CO.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:16][O:15][CH2:14][CH2:13][N:12]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1ccc(C2=COCCN2C(=O)OC(C)(C)C)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1ccc(C2COCCN2C(=O)OC(C)(C)C)cc1
Reaction time: 18 h
Yield: 94.9 %

Procedure:
To a mixture of tert-butyl 5-(4-(methoxycarbonyl)phenyl)-2H-1,4-oxazine-4(3H)-carboxylate (50 mg, 0.156 mmol) in methanol (3 ml) was added Pd(OH)2/C (25 mg). The mixture was stirred under a hydrogen for 18 hrs. The mixture was filtered and concentrated to give the title compound as a yellow oil (47.6 mg, 95%). Data was identical to that described below.
Reaction SMILES: ClCCl.[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][NH2:13])=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]>O>[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][NH:13][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:8][CH:7]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1ccc(NN)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(NNC(=O)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 50 ml of dichloromethane and 2.76 g of free 4-methoxyphenyl-hydrazine there are added first 2.2 g of triethylamine and then, dropwise, at a temperature of from 0° to 5°, 2.65 g of pivaloyl chloride. The reaction mixture is stirred for 12 hours at room temperature and then discharged into water. The aqueous mixture is extracted with dichloromethane, the extract is concentrated and the residue is recrystallised from toluene/pentane, yielding N-(4-methoxyphenyl)-N′-pivaloyl-hydrazine which melts at from 126° to 127°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].[CH2:18]([O:20][C:21]([C:23]1[C:24]2[S:32][CH:31]=[C:30]([CH2:33]Br)[C:25]=2[C:26]([Cl:29])=[N:27][CH:28]=1)=[O:22])[CH3:19]>C1COCC1.CN(C=O)C.O>[CH2:18]([O:20][C:21]([C:23]1[C:24]2[S:32][CH:31]=[C:30]([CH2:33][O:11][C:3]3[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=3[CH3:1])[C:25]=2[C:26]([Cl:29])=[N:27][CH:28]=1)=[O:22])[CH3:19]
Reactant: CCOC(=O)c1cnc(Cl)c2c(CBr)csc12
Reactant: Cc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnc(Cl)c2c(COc3cc([N+](=O)[O-])ccc3C)csc12
Temperature: 50 °C
Reaction time: 10 h

Procedure:
A mixture of 2-methyl-5-nitrophenol (960 mg, 6.07 mmol) (Avocado) and potassium carbonate powder (913 mg, 6.61 mmol) in dry THF (20 mL) and DMF (10 mL) was stirred at 50° C. for 15 minutes before a solution of 3-bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (1.997 g, 5.969 mmol) (from Example 1 supra) in THF (20 mL) was added. The reaction was stirred at 50° C. for 10 hours and the resulting precipitate was collected. The filtrate was concentrated to give more precipitate. The combined solid was stirred in water (30 mL), filtered, washed with water and dried overnight to give 4-chloro-3-(2-methyl-5-nitro-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white solid. (Yield 1.647 g, 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:12]=[C:11]([CH2:22][OH:23])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+].CCOC(C)=O>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[N:12]=[C:11]([CH:22]=[O:23])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(-n2nc(CO)cc2-c2ccc(Cl)c(Cl)c2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(-n2nc(C=O)cc2-c2ccc(Cl)c(Cl)c2)cc1
Reaction time: 3 h
Yield: 94.4 %

Procedure:
To a stirred solution of [5-(3,4-dichlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-methanol (Example 1 Step C, 1.0 g, 2.9 mmol) in CH2Cl2 (13 mL) under N2 was added Dess-Martin periodinane (2.1 g, 4.9 mmol) at rt. After 3 h, Na2S2O3 (5.0 g, 20 mmol) dissolved in saturated NaHCO3 (25 mL) and EtOAc (25 mL) were added, and the mixture was stirred until the layers were clear. The layers were separated, and the aqueous phase was extracted with EtOAc (3×15 mL). The combined organic extracts were dried over Na2SO4 and filtered, and the solvent was removed under reduced pressure to afford 0.95 g (96%) of the crude aldehyde, which was used without further purification. HPLC: Rt=10.3 (Method A). 1H NMR (400 MHz, CDCl3): 9.98 (s, 1H), 7.32 (s, 1H), 7.30 (d, J=2.3 Hz, 1H), 7.19-7.16 (m, 2H), 6.95 (s, 1H), 6.91 (dd, J=8.1, 2.3 Hz, 1H), 6.88-6.84 (m, 2H), 3.78 (s, 3H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:9][C:10]#[N:11].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>CCOCC>[NH2:11][CH2:10][CH2:9][CH:8]([O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCC(CC#N)OC1CCCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CCCCCC(CCN)OC1CCCCO1
Temperature: 25 °C
Yield: 95.7 %

Procedure:
A solution of 3-(tetrahydro-2H-pyran-2-yloxy)caprylonitrile (4.05 g., 18 millimole) in dry ether (10 ml.) is added dropwise to a stirred suspension of lithium aluminum hydride (0.76 g., 20 millimole) in dry ether (90 ml.) maintained under a nitrogen atmosphere. Upon completion of the addition, the reaction mixture is stirred and heated at reflux for 16 hours. After cooling to 25° C., the reaction mixture is treated successively with water (1 ml.), and 5% aqueous sodium hydroxide (3 ml.) added dropwise with caution, affording a fine suspension which is cooled to and maintained at 0°-5° C. for 30 minutes, and filtered. In vacuo evaporation of the solvent leaves the title compound as a pale yellow oil (3.95 g., 95%), pmr (CDCl3) δ0.88 (3H, t), 2.79 (2H, m) and 4.68 (H, bs).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:23](O)=[O:24])=[CH:21][N:22]=2)[CH2:14][C@H:13]1[O:26][CH3:27])=[O:10].CN([C:31]([O:35][N:36]1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.CON>CC(N(C)C)=O.CCOC(C)=O>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:23]([NH:36][O:35][CH3:31])=[O:24])=[CH:21][N:22]=2)[CH2:14][C@H:13]1[O:26][CH3:27])=[O:10]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CO[C@@H]1CN(c2ncc(C(=O)O)s2)CC[C@@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Agent: CON
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CONC(=O)c1cnc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)s1
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
Cis(±)2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2 -yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-1,3-thiazole-5-carboxylic acid (Example 35; 100 mg) was dissolved in anhydrous DMA (2 ml). HATU (97 mg), HOAT (31 mg), DIEA (41 μl) were added and the mixture was stirred for 30 min. N-Methoxyamine hydrochloride (19.3 mg) was added followed by DIEA (41 μl), and the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc, washed with H2O, 20% citric acid solution, H2O, sat. NaHCO3, H2O, brine and dried over Na2SO4. The organic phase was concentrated in vacuo to give the title compound as an off-white solid (82 mg). MS (ES)(MH+): 462, 460 for C17H21Cl2N5O4S; NMR: 1.64 (m, 2H), 1.85 (m, 1H), 2.05 (s, 3H), 2.83 (m, 1H), 3.33 (m, 5H), 3.73 (s, 3H), 4.07 (m, 1H), 4.38 (m, 2H), 7.24 (d, 1H), 7.74 (s, 1H), 11.39 (s, 1H), 12.05 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C(O)C.O.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>[O:30]1[CH2:31][CH2:32][N:27]([C:24]2[CH:25]=[CH:26][C:21]([C:2]3[CH:3]=[CH:4][C:5]4[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=4[CH:18]=3)=[CH:22][CH:23]=2)[CH2:28][CH2:29]1
Reactant: [O-]B([O-])Oc1ccc(N2CCOCC2)cc1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2S(=O)(=O)CC1
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COC(=O)C1=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc2S(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
Under argon atmosphere, a mixture of methyl 7-bromo-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.7 g), 4-morpholinophenyl borate (481 mg) and potassium carbonate (0.59 g) in toluene/ethanol/water (20/2/2 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (0.12 g), and the mixture was refluxed for 20 hours and cooled. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and precipitated solid was recrystallized from ethyl acetate/hexane to give yellow crystals of methyl 7-(4-morpholinophenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (617.6 mg).
Reaction SMILES: [CH:1]1([C:4]2[C:9]3[N:10]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:11]([C@@H:13]([NH:15][C:16]4[N:24]=[CH:23][N:22]=[C:21]5[C:17]=4[N:18]=[CH:19][N:20]5C4CCCCO4)[CH3:14])=[N:12][C:8]=3[CH:7]=[CH:6][C:5]=2[F:37])[CH2:3][CH2:2]1.Cl>CO.O1CCOCC1>[CH:1]1([C:4]2[C:9]3[N:10]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:11]([CH:13]([NH:15][C:16]4[N:24]=[CH:23][N:22]=[C:21]5[C:17]=4[N:18]=[CH:19][NH:20]5)[CH3:14])=[N:12][C:8]=3[CH:7]=[CH:6][C:5]=2[F:37])[CH2:3][CH2:2]1
Reactant: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c(C3CC3)c2n1-c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2ccc(F)c(C3CC3)c2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.4 %

Procedure:
To a mixture of [(S)-1-(7-cyclopropyl-6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]-[9-(tetrahydropyran-2-yl)-9H-purin-6-yl]amine (20 mg, 0.04 mmol) in MeOH (2 mL) was added 4N HCl in dioxane (0.25 mL) and the reaction mixture stirred at RT for 30 min. The volatiles were removed under reduced pressure and the resulting residue purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18 on a 20 min gradient 10-90%, 0.1% HCO2H in acetonitrile/water) to afford 198 (8 mg, 48%). LCMS (Method K): RT 3.74 and 3.81 min [M+H]+ 414.1. 1H NMR (DMSO-d6, 400 MHz): δ 12.89 (1H, br s), 8.19-7.97 (2H, m), 7.90-7.30 (7H, m), 7.04-6.95 (1H, dd, J=11.67, 8.76 Hz), 5.29 (1H, br s), 1.52 (3H, d, J=6.81 Hz), 1.28-1.18 (1H, m), 0.43-0.29 (2H, m), 0.25-0.08 (2H, m)
Reaction SMILES: [CH:1]([O:4][C:5](=[O:34])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([NH2:33])=[CH:14][C:15]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:16]=2[CH:32]=1)([CH3:3])[CH3:2].[C:35]([NH:38][C:39]1[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1)(=[O:37])[CH3:36]>>[CH:1]([O:4][C:5](=[O:34])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([NH:33][S:45]([C:42]2[CH:41]=[CH:40][C:39]([NH:38][C:35](=[O:37])[CH3:36])=[CH:44][CH:43]=2)(=[O:47])=[O:46])=[CH:14][C:15]2[N:19]=[C:18]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:17]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:16]=2[CH:32]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)CCCCCOc1cc2c(cc1N)nc(-c1ccccc1)n2-c1ccccc1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2cc3nc(-c4ccccc4)n(-c4ccccc4)c3cc2OCCCCCC(=O)OC(C)C)cc1

Procedure:
6-[(5-Amino-1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanoic acid isopropyl ester was reacted according to general operating instructions 13 with 4-(acetylamino)benzenesulfonic acid chloride.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]([OH:20])=[O:19].[I:21]C(F)(F)F>O1CCCC1.CCCCCC>[I:21][C:17]1[S:13][C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH:16]=1
Reactant: FC(F)(F)I
Reactant: O=C(O)c1cccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: O=C(O)c1ccc(I)s1
Temperature: 0 °C

Procedure:
The title compound has been described by Schick, J. W., et al., J. Am. Chem. Soc. 70:286 (1948), and was prepared according to the following procedure. A 25 ml (62.5 mmoles) volume of a 2.5M hexane solution of n-butyllithium was slowly added by syringe to a cooled (dry ice/2-propanol) 100 ml tetrahydrofuran solution of 9.0 ml (64.2 mmoles) of diisopropylamine. The solution was maintained below -60° C. during n-butyllithium addition. After addition, the cooling bath was removed and the solution allowed to reach room temperature (22° C.), and then cooled again below -60° C. To the cooled reaction vessel, 3.2 g (25.0 mmol) of 2-thiophenecarboxylic acid dissolved in 100 ml of tetrahydrofuran was slowly added. Thirty minutes after complete addition of 2-thiophenecarboxylic acid, approximately 17.2 g (87.8 mmoles) of iodotrifluoromethane was condensed into the reaction. After 5 minutes the cooling bath was removed and the reaction warmed to 0° C. and quenched with 50 ml of water. The basic aqueous solution was washed with 500 ml of diethyl ether. The ether solution was extracted with 50 ml of 1N sodium hydroxide and the two aqueous solutions were combined and washed with ether. The basic solution was acidified and extracted three times with 100 ml of diethyl ether. Drying of the organic solution with anhydrous magnesium sulfate followed by filtration and concentration gave a crude solid product. Partial purification was achieved by reprecipitation of the solid product from hot aqueous ethanol to give 3.79 g of slightly impure desired product as a mixture of dark red solid and yellow crystals. Recrystallization of the solid mixture gave 2.18 g (8.58 mmoles, 34% yield) of pure title compound as light yellow needles, m.p. 132°-134° C (hexanes).
Reaction SMILES: [CH2:1]([CH2:13][NH2:14])[CH2:2][C:3]([P:9]([OH:12])([OH:11])=[O:10])([P:5]([OH:8])([OH:7])=[O:6])[OH:4].O.[OH-].[Na+:17]>C(O)C>[CH2:1]([CH2:13][NH2:14])[CH2:2][C:3]([P:5]([O-:7])([OH:8])=[O:6])([P:9]([OH:12])([OH:11])=[O:10])[OH:4].[Na+:17]
Reactant: NCCCC(O)(P(=O)(O)O)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NCCCC(O)(P(=O)([O-])O)P(=O)(O)O
Temperature: 25 °C

Procedure:
A 250 ml flask was fitted with a mechanical stirrer, a thermometer, a dropping funnel, and a reflux condenser. The flask was charged with alendronic acid monohydrate (5 g, 0.019 mol) and aqueous ethanol. The aqueous ethanolic sodium hydroxide was added dropwise to the suspension of alendronic acid monohydrate in aqueous ethanol for 15 minutes at reflux with vigorously stirring. The mixture was then refluxed for additional 15 hours. The mixture was then cooled to room temperature with stirring. The solid was filtered, washed with absolute ethanol, then with absolute ethyl ether, and dried overnight in a vacuum oven (10-15 mm Hg, ambient temperature) to give 5.2 g of alendronate sodium, having crystalline Form H.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17](C3CCC3)=[O:18])[C@@H:13]([OH:23])[C@H:12]2[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:3]=1.[CH3:40][O:41]C(Cl)=O>>[CH3:40][O:41][C:17](=[O:18])[NH:16][C@H:14]1[CH2:15][C@@H:11]([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][C:2]([Cl:1])=[N:3][C:4]=3[NH:25][CH2:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@H:12]([OH:24])[C@@H:13]1[OH:23]
Reactant: O=C(N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O)C1CCC1
Reactant: COC(=O)Cl
Product: COC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O

Procedure:
This compound is prepared analogously to cyclobutanecarboxylic acid {(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-amide (Intermediate K) by replacing cyclobutanecarboxylic acid chloride with methylchloroformate.