Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1)[C:6]([CH3:8])=[O:7]>C1C=CC=CC=1>[CH2:5]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:3])=[O:14])=[CH:11][CH:10]=1)[C:6]([CH3:8])=[O:7]
Reactant: CC(=O)Cc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC(=O)Cc1ccc(C(=O)Cl)cc1

Procedure:
Thionyl chloride (1.45 ml) was added to 4-acetonylbenzoic acid (3.56 g) in benzene and the mixture refluxed for 1 hour. Benzene was evaporated to give the title compound as a yellow oil, 2.61 g, (bp 135°-140°/0.5 mm). γ(CDCl3) 7.78 (3H, s), 6.17 (2H, s), 2.63 (2H, d, J=9 Hz), 1.88 (2H, d, J=9 Hz).
Reaction SMILES: [OH-].[Na+:2].[CH2:3]([CH2:15][NH2:16])[CH2:4][C:5]([P:11]([OH:14])([OH:13])=[O:12])([P:7]([OH:10])([OH:9])=[O:8])[OH:6]>C(O)C.O>[CH2:3]([CH2:15][NH2:16])[CH2:4][C:5]([P:7]([O-:9])([OH:10])=[O:8])([P:11]([OH:14])([OH:13])=[O:12])[OH:6].[Na+:2]
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
Reaction time: 15 h
Yield: 96 %

Procedure:
A 250 ml flask was fitted with a mechanical stirrer, a thermometer, and a reflux condenser. The flask was charged with 41.1 ml of a solution of sodium hydroxide in ethanol (0.49N, 20.1 mmol), 8.9 ml of ethanol, water (0 to 40 mol. eq., according to the crystal form desired), and 5 g (20.1 mmol) of anhydrous alendronic acid. The reaction mixture was boiled with vigorous stirring for about 15 hours until the of pH of the liquid phase remained constant (approx. pH 7). After cooling of the reaction mixture to ambient temperature, the solid material was filtered, washed with absolute ethanol, and dried overnight in a vacuum oven (10-15 mmHg, ambient temperature) to give 96-99% sodium alendronate having the following crystal forms: crystal Form D, when 0-4 (preferably 0-2) mol. eq. water were used; crystal Form F, when 5-8 (preferably 6-7) mol. eq. water were used; crystal Form E, when 9-15 (preferably 12) mol. eq. water were used; and crystal Form G, when 15-40 (preferably 25-35) mol. eq. water were used. The monosodium salt was confirmed by atomic absorption and by measuring the pH of a 0.5% aqueous solution of the salt (approx. pH 4.4).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[O:11][CH3:12].[C:13]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)([OH:15])=[O:14]>C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.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>[CH3:12][O:11][C:3]1[C:4]([N+:8]([O-:10])=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=1[C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([C:13]([OH:15])=[O:14])[CH:21]=1
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: COc1c(Br)cccc1[N+](=O)[O-]
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: C1COCCO1
Product: COc1c(-c2cccc(C(=O)O)c2)cccc1[N+](=O)[O-]
Temperature: 105 °C
Yield: 197.4 %

Procedure:
1-Bromo-2-methoxy-3-nitro-benzene 1c (23.25 g, 0.10 mol), 3-carboxyphenylboronic acid (19.5 g, 0.117 mol) and tetrakis(triphenylphosphine)palladium (8.86 g, 7.7 mol) were dissolved in a solvent mixture of 100 mL of 2 N aqueous sodium carbonate and 500 mL of 1,4-dioxane. The reaction mixture was heated to reflux at 105° C. for 43 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was concentrated under reduced pressure and then 300 mL of 6 N hydrochloric acid and 400 mL of ethyl acetate were added. The aqueous layer was extracted with ethyl acetate (200 mL×2). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain the title compound 2′-methoxy-3′-nitro-biphenyl-3-carboxylic acid 1d (53.93 g) as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH:7]([CH3:8])[CH2:6][CH2:5][CH:4]([CH3:9])[C:3]1=[O:10].[CH3:12][C:13]1([CH3:22])[C@@H:18]([CH3:19])[CH2:17][CH2:16][C@H:15]([CH3:20])[C:14]1=[O:21].[CH3:23]C1(C)[C@H](C)CC[C@@H](C)C1=O>>[CH3:11][C:2]1([CH3:1])[C@@H:7]([CH3:8])[CH2:6][CH2:5][C@H:4]([CH3:9])[C@@:3]21[O:10][CH2:12]2.[CH3:22][C:13]1([CH3:12])[C@H:18]([CH3:19])[CH2:17][CH2:16][C@@H:15]([CH3:20])[C@:14]21[O:21][CH2:23]2
Reactant: CC1CCC(C)C(C)(C)C1=O
Reactant: C[C@H]1CC[C@H](C)C(C)(C)C1=O
Reactant: C[C@@H]1CC[C@@H](C)C(C)(C)C1=O
Product: C[C@@H]1CC[C@@H](C)[C@]2(CO2)C1(C)C
Product: C[C@H]1CC[C@H](C)[C@@]2(CO2)C1(C)C

Procedure:
Prepared according to the general method described, starting from 2,2,3,6-tetramethyl-1-cyclohexanone (mixture trans/cis: 85/15%) under the conditions described in published European patent application No. 0 374 509. The analytical data for this epoxide are described therein. When using as starting product (+)-(3S,6S)-2,2,3,6-tetramethyl-1-cyclohexanone ([α]20D =+52.2°) or, respectively (-)-(3R,6R)-2,2,3,6-tetramethyl-1-cyclohexanone ([α]20D =-50.7°), there were obtained the optically active isomers of the above-mentioned epoxide, i.e., (+)-(3S,5S,8S)-4,4,5,8-tetramethyl-1-oxaspiro[2.5]octane ([α]20D =+36.0°) or, respectively (-)-(3R,5R,8R)-4,4,5,8-tetramethyl-1-oxaspiro[2.5]octane ([α]20D =-35.1°). The analytical data of these compounds are also described in said European patent application.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9](CCCCCCCCCCCCCCC)[C:5]=1[C:6](Cl)=[O:7])[CH3:2].[NH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[C:31]([C:37]([F:40])([F:39])[F:38])[CH:30]=1.C(N(CC)CC)C>ClCCl>[C:33]([C:32]1[CH:35]=[CH:36][C:29]([NH:28][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[O:3][CH2:1][CH3:2])=[CH:30][C:31]=1[C:37]([F:38])([F:39])[F:40])#[N:34]
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: CCCCCCCCCCCCCCCc1cccc(OCC)c1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1ccccc1C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1

Procedure:
2-ethoxy-6-pentadecyl-benzoyl chloride was condensed with 4-Amino-2-trifluromethyl benzonitrile in dichloromethane in presence of triethylamine as acid scavenger to yield N-(4-Cyano-3-trifluoromethyl-phenyl)-2-ethoxy-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([C:18]3[O:22][N:21]=[C:20]([CH3:23])[N:19]=3)[O:12]2)=[C:4]([NH:24][CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[N:3]=1.[CH3:30][N:31]1[CH:35]=[C:34]([CH2:36][CH2:37][NH2:38])[N:33]=[CH:32]1.CS(C)=[O:41]>>[CH:18]([OH:22])=[O:41].[CH2:26]([CH:25]([NH:24][C:4]1[N:3]=[C:2]([NH:38][CH2:37][CH2:36][C:34]2[N:33]=[CH:32][N:31]([CH3:30])[CH:35]=2)[N:10]=[C:9]2[C:5]=1[N:6]=[CH:7][N:8]2[C@H:11]1[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([C:18]2[O:22][N:21]=[C:20]([CH3:23])[N:19]=2)[O:12]1)[CH2:28][CH3:29])[CH3:27]
Reactant: Cn1cnc(CCN)c1
Reactant: CS(C)=O
Reactant: CCC(CC)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](c2nc(C)no2)[C@@H](O)[C@H]1O
Product: CCC(CC)Nc1nc(NCCc2cn(C)cn2)nc2c1ncn2[C@@H]1O[C@H](c2nc(C)no2)[C@@H](O)[C@H]1O
Product: O=CO
Temperature: 92.5 °C

Procedure:
Intermediate 11 (0.069 g, 0.163 mmol) and 2-(1-methyl-1H-imidazol-4-yl)ethylamine (0.102 g, 0.815 mmol) were dissolved in DMSO (0.03 ml) and heated at 85-100° C. under nitrogen for 7 days, a further portion of 2-(1-methyl-1H-imidazol-4-yl)ethylamine (0.102 g, 0.815 mmol) was added after the first 5 days. The product was purified by Autoprep. HPLC to give the title compound after freeze drying as a beige solid (0.013 g). LC/MS system A Rt=3.32 min, m/z=512MH+.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][NH:4][P:5]1(=[S:14])[O:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[O:6]1.C(N(CC)CC)C.Cl[S:24][N:25]([CH3:29])[C:26]([F:28])=[O:27]>O1CCCC1.CCOCC>[CH3:29][N:25]([S:24][N:4]([CH2:3][CH:2]([CH3:15])[CH3:1])[P:5]1(=[S:14])[O:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[O:6]1)[C:26]([F:28])=[O:27]
Reactant: CC(C)CNP1(=S)Oc2ccccc2O1
Reactant: CN(SCl)C(=O)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)CN(SN(C)C(=O)F)P1(=S)Oc2ccccc2O1
Reaction time: 1.5 h

Procedure:
A solution of N-(2-methylpropyl)-2-thioxo-1,3,2-benzodioxaphosphol-2-amine (17.2 g, 70.8 mmol) and triethylamine (9.8 ml, 70.8 mmol) in tetrahydrofuran (50 ml) is added dropwise over 10 minutes to a solution of N-chlorothio(methyl)carbamoyl fluoride (10.2 g, 70.8 mmol) in tetrahydrofuran (50 ml) cooled in an ice bath. After the addition the mixture is stirred for 1.5 hours at 0°, diluted with ether (200 ml), washed with ice cold water, dried over sodium sulfate and concentrated under reduced pressure. The residue shows identical absorptions in the ir and pmr spectra for νC=O and N--CH3 as obtained for the carbamic fluoride II'' of Example 5. This crude carbamoyl fluoride product is suitable for reaction with methyl N-hydroxyethanimidothioate as in Example 5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23]([OH:25])=O)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[N:38]1C(C)=CC=C[C:39]=1C.CN.O1CCCC1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:26][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23](=[O:25])[NH:38][CH3:39])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCC(=O)O)n2)cc1Cl
Reactant: Cc1cccc(C)n1
Agent: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=O)CCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.8 %

Procedure:
To a solution containing 3-{3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-propionic acid (prepared in example 9, 50 mg, 0.11 mmol) in methylene chloride (2 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (59 μL, 0.12 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (17 μL, 0.14 mmol) was added to the solution at 0° C. After 1 h, a 2.0 M solution of methylamine in tetrahydrofuran (59 μL, 0.11 mmol) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(2-methylcarbamoyl-ethyl)-1H-pyrazol-3-yl]-propionamide (11 mg, 21%) as a white solid: ESI-LRMS m/e calcd for C22H29ClN4O4S [M+] 480.2, found 481.4 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.09-1.20 (m, 2H, CH2), 1.46-1.96 (m, 8H, 4×CH2), 2.17-2.29 (m, 1H, CH), 2.62 (t, J=6.3 Hz, 2H, COCH2), 2.75 (d, J=4.9 Hz, 3H, CONCH3), 3.27 (s, 3H, SO2CH3), 3.55 (t, J=7.6 Hz, 1H, CH), 4.31 (t, J=6.3 Hz, 2H, NCH2), 5.48 (brm, 1H, NH), 6.58 (d, J=2.3 Hz, 1H, Ar), 7.30 (d, J=2.3 Hz, 1 H, Ar), 7.46 (dd, Jo=8.2, Jm=1.6 Hz. 1H, Ar), 7.60 (d, Jm=1.6 Hz, 1H, Ar), 7.88 (s, 1 H, NH), 8.09 (d, Jo=8.2 Hz, 1H, Ar).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>C1COCC1.O.C(=O)(O)[O-].[Na+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([CH:13]3[CH2:14][CH2:15][N:16]([C:32](=[O:34])[CH3:33])[CH2:17][CH2:18]3)=[N:10][C:9]=2[C:19]2[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2[nH]c(C3CCNCC3)nc2-c2ccncc2)cc1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CCC(c2nc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.1 %

Procedure:
To a stirring solution of 4-[5-(4-fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-yl]piperidine (0.76 mmol,0.30 g) in THF (5 mL) was added triethylamine (2.7 mmol,0.27 g) and acetyl chloride (0.91 mmol,71.5 mg) and the reaction stirred at room temperature overnight. The reaction was diluted with water (50 mL) and saturated sodium bicarbonate (10 mL) and the aqueous phase extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over anhydrous sodium sulfate, and the solvent evaporated under reduced pressure. The residue was chromatographed over silica, eluting with 2.5% to 5% MeOH:CH2Cl2. The product containing fractions were combined and evaporated to give a yellow oil. This oil was crystallized from diethyl ether to give 75 mg of the title compound as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][NH2:13])=[CH:7][CH:6]=2.Br[C:15]1[C:16]([NH2:22])=[N:17][CH:18]=[C:19]([Br:21])[N:20]=1.CCN(C(C)C)C(C)C>C(O)C>[Br:21][C:19]1[N:20]=[C:15]([NH:13][CH2:12][C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]=[CH:3][C:2]([Br:1])=[CH:11]3)[C:16]([NH2:22])=[N:17][CH:18]=1
Reactant: NCc1ccc2ncc(Br)cc2c1
Reactant: Nc1ncc(Br)nc1Br
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Br)nc1NCc1ccc2ncc(Br)cc2c1
Temperature: 120 °C

Procedure:
A microwave tube was charged with (3-bromoquinolin-6-yl)methanamine (237 mg, 1.0 mmol), 3,5-dibromopyrazin-2-amine (253 mg, 1.0 mmol), DIPEA (0.6 mL) and 5 mL of ethanol. The tube was heated at 120° C. under microwave irradiation for 15 h. After cooling, the solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with DCM/methanol gradient to afford the title compound. LCMS (method E): [MH]+=406/408/410, tR=5.803 min.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.[CH3:12][O:13][CH2:14][CH:15]1[CH2:19][CH2:18][CH2:17][N:16]1[C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23].CCN(C(C)C)C(C)C.O>CS(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[C:20]([N:16]3[CH2:17][CH2:18][CH2:19][CH:15]3[CH2:14][O:13][CH3:12])[CH:21]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2ncsc2n1
Reactant: COCC1CCCN1c1cccc(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: COCC1CCCN1c1cccc(Nc2nc(Cl)nc3scnc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.1 %

Procedure:
A mixture of 5,7-dichlorothiazolo[5,4-d]pyrimidine (170 mg, 0.83 mmol), 3-(2-(methoxymethyl)pyrrolidin-1-yl)aniline (170 mg, 0.83 mmol) and DIEA (214 g, 1.66 mmol) in 15 mL of DMSO was stirred at room temperature overnight. 100 mL of water were added, the mixture was extracted with ethyl acetate (3×30 mL). The organic layer was washed with water (2×30 mL) and brine (30 mL), concentrated under reduced pressure to give 5-chloro-N-(3-(2-(methoxymethyl)pyrrolidin-1-yl)phenyl)thiazolo[5,4-d]pyrimidin-7-amine (200 mg, 64%) as a yellow solid. LC-MS: 376 [M+H]+, tR=1.75 min.
Reaction SMILES: [H-].[Na+].CCCC(C)C.[Br:9][C:10]1[CH:11]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:13][CH:14]=1.Br[CH2:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[N+:29]([O-:31])=[O:30]>CN(C)C(=O)C>[Br:9][C:10]1[CH:11]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:13]([CH2:21][C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[N+:29]([O-:31])=[O:30])[CH:14]=1
Reactant: CCOC(=O)c1cc(Br)c[nH]1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCCC(C)C
Product: CCOC(=O)c1cc(Br)cn1Cc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Wash 60% mineral oil suspended sodium hydride (1.2 equiv; 1.1 g, 27.52 mmoles) with a small amount of iso-hexane (×2). Suspend in N,N-dimethylacetamide (15 mL) and chill in an ice-bath. Add ethyl 4-bromo-1H-pyrrole-2-carboxylate (5.0 g, 22.93 mmoles) portionwise over 15 minutes allowing gas evolution to subside between additions. Stir at room temperature for 15 minutes to give a brown solution. Add 2-(bromomethyl)-4-chloro-1-nitro-benzene (1.15 equiv; 6.61 g, 26.37 mmoles) in portions over 15 minutes and stir the resulting purple solution at room temperature for 2.5 h. Cool in an ice-bath and quench with water (10 mL). Partition between 1M hydrochloric acid (100 mL) and EtOAc (300 mL). Wash the organic layer with water (2×100 mL) then brine. Dry over Na2SO4 and decolorize with activated charcoal. Filter through celite and evaporate to give ethyl 4-bromo-1-(5-chloro-2-nitrobenzyl)-1H-pyrrole-2-carboxylate as a an orange oil (9.1 g, quantitative). 1H-NMR (CDCl3) δ: 8.12 (1H, d), 7.40 (1H, dd), 7.07 (1H, d), 6.92 (1H, d), 6.53 (1H, d), 5.87 (2H, s), 4.17 (2H, q), 1.25 (3H, t).
Reaction SMILES: CON(C)[C:4]([CH:6]1[O:11][CH2:10][CH2:9][N:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7]1)=[O:5].[CH2:20]([Mg]Br)[CH2:21][CH2:22][CH3:23]>O1CCCC1>[CH2:12]([N:8]1[CH2:9][CH2:10][O:11][CH:6]([C:4](=[O:5])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:7]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CON(C)C(=O)C1CN(Cc2ccccc2)CCO1
Reactant: CCCC[Mg]Br
Solvent: C1CCOC1
Product: CCCCC(=O)C1CN(Cc2ccccc2)CCO1
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
Compound 82 is prepared from 2 (0.87 g, 3.28 mmol) in anhydrous tetrahydrofuran (30 mL) and commercially available (Aldrich) n-butyl magnesium bromide (2M solution in THF, 5 mmol, 2.5 mL, 1.5 eq) following General Procedure 1. After stirring for 1 hour further n-butyl magnesium bromide (2M solution in THF, 1.6 mmol, 0.8 mL) is added and stirring continued for 30 minutes. The reaction is quenched by addition of ammonium chloride solution (30 mL) followed by EtOAc. The organic phases are combined, dried over magnesium sulphate and the solvent is removed in vacuo to give 82 (0.82 g, 96%). MW 261.37; C16H23NO2; LCMS (6 minute method): m/z 262.4 [M+H]+, RT 2.34 mm.
Reaction SMILES: [C:1]([N:5]1[CH2:27][CH2:26][CH2:25][CH2:24][C:8]2[C:9]([Br:23])=[C:10]3[C:19]4[CH:18]=[C:17](Br)[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:28])([CH3:4])([CH3:3])[CH3:2].[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](B(O)O)[CH:30]=1.C([O-])([O-])=O.[K+].[K+].COCCOC>O>[C:1]([N:5]1[CH2:27][CH2:26][CH2:25][CH2:24][C:8]2[C:9]([Br:23])=[C:10]3[C:19]4[CH:18]=[C:17]([C:31]5[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=5)[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:28])([CH3:2])([CH3:3])[CH3:4]
Reactant: OB(O)c1cccnc1
Reactant: COc1cc2c(cc1Br)-c1c(Br)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1cc2c(cc1-c1cccnc1)-c1c(Br)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Temperature: 90 °C
Yield: 73.5 %

Procedure:
A mixture of 250 mg of 25a, 72 mg of pyridine-3-boronic acid, 135 mg of K2CO3 and 5 ml of degassed 90% aqueous DME was heated under N2 for 16 h at 90° C. The reaction was then cooled and diluted with water, and the product was extracted with ethyl acetate. The organic extract was washed with water, dried and concentrated, and the remainder was chromatographed over silica gel (using a gradient of heptane/ethyl acetate as eluent). The product isolated was triturated with diethylether, to provide 183 mg of 25b; NMR (CDCl3) δ 8.85, 8.56, 7.91, and 7.35 (4×m, 4, pyridyl-H), 8.37 and 6.87 (2×s, 2, Ar—H), 4.45 and 3.40-3.90 (br.m, 4, 2×CH2), 3.05 (bm, 2, CH2), 2.60 (br.m, 2, CH2), 1.90 and 1.70 (2×br.m, 4, 2×CH2), 1.58 (s, 9, tertC4H9).
Reaction SMILES: Cl.[NH:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][NH2:8].[C:9]([C:13]1[CH:22]=[CH:21][C:16]([CH2:17][N:18]=[C:19]=[S:20])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>ClCCl>[C:9]([C:13]1[CH:22]=[CH:21][C:16]([CH2:17][NH:18][C:19]([NH:8][CH2:7][C:3]2[NH:2][CH:6]=[CH:5][CH:4]=2)=[S:20])=[CH:15][CH:14]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)c1ccc(CN=C=S)cc1
Reactant: NCc1ccc[nH]1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CNC(=S)NCc2ccc[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
(1H-pyrrol-2-yl)methylamine hydrochloride (60 mg) prepared according to the same procedure as described in Step 2 was dissolved in dichloromethane (2 ml) and to the solution was added 4-t-butylbenzylisothiocyanate (155 mg), followed by stirring at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure and the obtained residue was column-chromatographed (ethyl acetate/hexane=1/3) to yield the compound 17-1 (120 mg, 65%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.Cl.[NH2:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:18][CH2:17]1.C(N(CC)CC)C>C(O)(C)C>[N+:8]([C:7]1[C:2]([NH:15][C@H:16]2[CH2:17][CH2:18][C@H:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:20][CH2:21]2)=[C:3]2[S:13][CH:12]=[CH:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Reactant: CCOC(=O)C[C@H]1CC[C@H](N)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CCOC(=O)C[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CC1
Temperature: 100 °C

Procedure:
A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (97 mg, 0.45 mmol), ethyl (trans-4-aminocyclohexyl)acetate hydrochloride (from Activate Scientific, 120 mg, 0.54 mmol) and triethylamine (0.19 mL, 1.4 mmol) in isopropyl alcohol (4 mL) was heated at 100° C. for 1 h. The mixture was concentrated to give the desired product to be used in the next step directly. LCMS calculated for C17H22N3O4S (M+H)+: m/z=364.1. Found: 364.1.
Reaction SMILES: N.[CH3:2][CH:3]([OH:9])/[CH:4]=[CH:5]/[CH:6]([OH:8])[CH3:7].C([O:13][C:14]1[CH:15]=[C:16]([C:23]([Cl:25])=[O:24])[CH:17]=[C:18]([CH:22]=1)[C:19]([Cl:21])=[O:20])(=O)C>O1CCCC1>[CH3:2][CH:3]([OH:9])/[CH:4]=[CH:5]/[CH:6]([OH:8])[CH3:7].[OH:13][C:14]1[CH:22]=[C:18]([C:19]([Cl:21])=[O:20])[CH:17]=[C:16]([CH:15]=1)[C:23]([Cl:25])=[O:24]
Reactant: CC(=O)Oc1cc(C(=O)Cl)cc(C(=O)Cl)c1
Agent: CC(O)/C=C/C(C)O
Agent: N
Solvent: C1CCOC1
Product: O=C(Cl)c1cc(O)cc(C(=O)Cl)c1
Reaction time: 2 h

Procedure:
To a solution of methanolic ammonia (20 mL, 1 N), polymer (126) dissolved in 5 mL tetrahydrofuran is added and the solution is stirred for two hours. The polymer was then precipitated in 100 mL of cold 1 N hydrochloric acid and collected by filtration. The polymer was then dried under high vacuum and was found to have a molecular weight of ˜5,000 g/mol by GPC.
Reaction SMILES: C(C1N=C(N2CCOCC2)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.[C:28]([C:32]1[N:33]=[C:34](Cl)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29].Cl.[F:51][C:52]1([F:59])[C:56]([F:58])([F:57])[CH2:55][NH:54][CH2:53]1>>[C:28]([C:32]1[N:33]=[C:34]([N:54]2[CH2:55][C:56]([F:58])([F:57])[C:52]([F:59])([F:51])[CH2:53]2)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: FC1(F)CNCC1(F)F
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: Cl
Product: CC(C)(C)c1nc(N2CC(F)(F)C(F)(F)C2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3,3,4,4-tetrafluoropyrrolidine hydrochloride and isolated as light-yellow gum (12.6 mg, 60%). MS (m/e): 443.4 (MH+).