Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:5]=[C:4]([NH:14][S:15]([CH2:18][CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)(=[O:17])=[O:16])[C:3]=1[O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][CH3:38].[CH3:39][O-:40].[Na+]>CO>[CH3:39][O:40][C:2]1[N:7]=[C:6]([C:8]2[N:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:5]=[C:4]([NH:14][S:15]([CH2:18][CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)(=[O:17])=[O:16])[C:3]=1[O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][CH3:38]
Reactant: C[O-]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2cccnn2)nc1NS(=O)(=O)CCc1cccc2ccccc12
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1Oc1c(NS(=O)(=O)CCc2cccc3ccccc23)nc(-c2cccnn2)nc1OC
Temperature: 60 °C
Reaction time: 72 h
Yield: 95 %

Procedure:
To a solution of N-[6-chloro-5-(2-methoxyphenoxy)-2-(3-pyridazinyl )-4-pyrimidinyl]-2-(1-naphthyl)ethanesulfonamide (0.088 g, 0.17 mmol) (Preparation 14) in methanol (5 ml) was added sodium methoxide (25% w/v in methanol, 1.0 ml). The mixture was stirred vigorously for 72 hours at 60° C. and then quenched with aqueous hydrochloric acid (2 M, 1 ml). Ice-cold water (2 ml) was added and a white precipitate formed. The resultant mixture was partitioned between water (5 ml) and dichloromethane (3×10 ml). The combined organic extracts were washed with water (3×10 ml), dried (magnesium sulfate) and concentrated under vacuum to give the title compound as a yellow solid (95% pure by HPLC). (0.065 g).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15](=[O:24])[CH2:16][O:17][C@H:18]1[CH2:22][CH2:21][C@H:20]([NH2:23])[CH2:19]1)([CH3:13])([CH3:12])[CH3:11].Cl[C:26]1[C:27]2[C:34]([C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=3)=[C:33]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[O:32][C:28]=2[N:29]=[CH:30][N:31]=1.O>CN(C=O)C>[C:10]([O:14][C:15](=[O:24])[CH2:16][O:17][C@H:18]1[CH2:22][CH2:21][C@@H:20]([NH:23][C:26]2[C:27]3[C:34]([C:35]4[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=4)=[C:33]([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[O:32][C:28]=3[N:29]=[CH:30][N:31]=2)[CH2:19]1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)CO[C@H]1CC[C@H](N)C1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(N[C@@H]4CC[C@H](OCC(=O)OC(C)(C)C)C4)c23)cc1
Temperature: 100 °C

Procedure:
Add 0.86 ml (5 2 mmol) of diisopropylethylamine to a mixture of 560.4 mg of (+/−)-cis/trans-[(3-aminocyclopentyl)oxy]acetic acid tert-butyl ester (crude product, approx. 2.60 mmol) and 964.3 mg (2.86 mmol) of 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine in 2.0 ml of DMF. Heat the reaction mixture to 100° C. for 6 h. After cooling, add water and extract with dichloromethane. Wash the organic phase with satd. sodium hydrogencarbonate solution and satd. sodium chloride solution, dry over sodium sulphate and concentrate under reduced pressure. After drying under high vacuum, purify the product mixture by preparative RP-HPLC (eluent: acetonitrile/water gradient) and separate it into the cis/trans isomers.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[C:25](=O)[CH3:26]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:25]([C:16]2[CH:17]=[CH:18][C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:15]=2)[CH3:26])=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc2ccccc2c1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Product: Cc1noc(-c2ccc(Br)cc2)c1NC(C)c1ccc2ccccc2c1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 1-naphthalen-2-yl-ethanone.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](=[N:13][O:14][CH2:15][CH2:16][OH:17])[CH3:12].O[C:19]1[CH:51]=[CH:50][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[N:26]([C:30]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]2=[O:49])=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](=[N:13][O:14][CH2:15][CH2:16][O:17][C:19]1[CH:51]=[CH:50][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[N:26]([C:30]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]2=[O:49])=[CH:21][CH:20]=1)[CH3:12]
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=NOCCO)c1ccc2ccccc2n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=NOCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)c1ccc2ccccc2n1
Yield: 87.4 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 461 mg of 2-[1-(2-quinolyl)-ethylideneaminooxy]ethanol (prepared as described in Preparation 14), 716 mg of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 525 mg of triphenylphosphine and 348 mg of diethyl azodicarboxylate, 911 mg of the title compound were obtained as a foam-like solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:9]=[C:8]([NH:10][CH:11]2[CH2:13][CH2:12]2)[CH:7]=[C:6](Cl)[N:5]=1)[CH3:2].C[O-].[Na+].[CH3:18][SH:19]>CO.C(Cl)Cl>[CH2:1]([NH:3][C:4]1[N:9]=[C:8]([NH:10][CH:11]2[CH2:13][CH2:12]2)[CH:7]=[C:6]([S:19][CH3:18])[N:5]=1)[CH3:2]
Reactant: CCNc1nc(Cl)cc(NC2CC2)n1
Reactant: CS
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCNc1nc(NC2CC2)cc(SC)n1

Procedure:
31.8 g (0.15 mol) of 2-ethylamino-4-cyclopropylamino-6-chloropyrimidine and 30.6 g of 30 percent strength methanolic sodium methylate solution (0.17 mol) in 25 g of methanol are first introduced into a bomb tube. 8.6 g of gaseous methylmercaptan (0.18 mol) are passed in, whilst cooling. The bomb tube is sealed and is heated to 100° for 24 hours. When the contents of the tube have cooled they are concentrated on a rotary evaporator to give an oil, the latter is taken up in methylene chloride and the solution is extracted with water. After drying over sodium sulphate, filtering and evaporating, the methylene chloride solution gives a yellow oil which crystallises slowly. When recrystallised from methanol-water, 27.3 g of colourless crystals of melting point 75°-6° are obtained.
Reaction SMILES: [Br:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][C:12]([CH3:15])([CH3:14])[O:11][CH2:10][C:9]=2[CH:16]=1)[OH:4].N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CN(C=O)C>[Br:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][C:12]([CH3:14])([CH3:15])[O:11][CH2:10][C:9]=2[CH:16]=1)[O:4][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC1(C)OCc2cc([C@@H](O)CBr)ccc2O1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC1(C)OCc2cc([C@H](CBr)O[Si](C)(C)C(C)(C)C)ccc2O1
Reaction time: 18 h

Procedure:
To the product of step (d) (10 g, 34.8 mmol) and imidazole (4.7 g, 69.7 mmol) dissolved in 100 mL DMF was added tert-butyldimethylsilyl chloride (5.78 g, 38.3 mmol). The reaction mixture was stirred for 18 hours. The reaction mixture was then partitioned between 200 mL of saturated sodium chloride and 200 mL of diethyl ether. The aqueous layer was extracted with 200 mL of diethyl ether. The organic layers were then combined, washed with saturated sodium chloride (3×100 mL), dried over MgSO4 and concentrated. The product was purified by silica gel chromatography, eluting with hexanes followed by 5% ethyl acetate in hexanes. The desired fractions were combined and concentrated to give the title compound as an oil.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH3:19][CH:20]([SH:22])[CH3:21]>CN(C=O)C>[CH:20]([S:22][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5])([CH3:21])[CH3:19]
Reactant: CC(C)S
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Sc1ccc([N+](=O)[O-])cc1C=O
Temperature: 55 °C

Procedure:
2-chloro-5-nitrobenzaldehyde (2.99 g, 16.1 mmol), potassium carbonate (2.45 g, 17.7 mmol) and propane-2-thiol (1.35 g, 17.7 mmol) were dissolved in 10.0 ml, DMF in a 50 mL, round-bottomed flask under dry nitrogen, topped with a reflux condenser. The reaction mixture was heated to 55° C. for 24 h. After cooling the mixture was added to 150 mL of saturated potassium carbonate solution. The yellow-brown solid was filtered, washed with water and further purified by chromatography on silica gel using 10:1 petroleum ether 60-80 and ether as eluent. Yield: 1.81 g, 50%, yellow solid. 1H NMR (200 MHz, CDCl3): δ 1.46 (d, J=6.9 Hz, 6H), 3.67 (septet, J=6.9 Hz, 1H), 7.55 (d, J=8.7 Hz, 1H), 8.32 (dd, J=2.5, 8.7 Hz, 1H), 8.66 (d, J=2.5 Hz, 1H), 10.3 (s, 1H) ppm. 13C NMR (50 MHz, CDCl3): δ 22.5, 36.6, 127.2, 127.4, 127.9, 133.4, 144.7, 150.8, 189.1.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([S:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[CH3:21])=[O:4].C(OC(=O)C)(=[O:24])C.OO>ClCCl>[Br:1][CH2:2][C:3]([C:5]1[C:6]([CH3:21])=[CH:7][C:8]([S:12]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[O:24])=[CH:9][C:10]=1[CH3:11])=[O:4]
Reactant: COc1ccc(Sc2cc(C)c(C(=O)CBr)c(C)c2)cc1
Reactant: CC(=O)OC(C)=O
Agent: OO
Solvent: ClCCl
Product: COc1ccc(S(=O)c2cc(C)c(C(=O)CBr)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.2 %

Procedure:
A mixture of 2-bromo-1-(4-(4-methoxyphenylthio)-2,6-dimethylphenyl)ethanone (500.0 mg, 1.3 mmol, 1.0 equiv), acetic anhydride (0.14 mL, 1.5 mmol, 1.1 equiv), 30% hydrogen peroxide (55.86 mg, 1.6 nm 101, 1.2 equiv) and silica gel (273.75 mg, 230-400 mesh) in dichloromethane (10.0 mL) was stirred at room temperature for 16 h. The solution was concentrated under reduced pressure, and the residue was re-dissolved in EtOAc (50 mL). The solution was washed with saturated aqueous NaHCO3 (30 mL), dried over MgSO4(s), and concentrated under reduced pressure to give 2-bromo-1-(4-(4 methoxyphenylsulfinyl)-2,6-dimethylphenyl)ethanone (235.4 mg, 0.6 mmol) as pale yellow oil in 48% yield: 1H NMR (DMSO-d6, 500 MHz) δ 7.65 (d, J=8.8 Hz, 2 H), 7.41 (s, 2 H), 7.09 (d, J=8.8 Hz, 2 H), 4.78 (s, 2 H), 3.79 (s, 3 H), 2.21 (s, 6 H).
Reaction SMILES: Cl.[CH2:2]([O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=[NH:12])=[CH:9][CH:8]=1)[CH2:3][CH2:4][CH3:5].C([O:18][CH:19]=[C:20]([C:26](OCC)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22])C.C[O-].[Na+].CO.[Na]>CO>[CH2:24]([O:23][C:21]([C:20]1[C:19]([OH:18])=[N:12][C:11]([C:10]2[CH:14]=[CH:15][C:7]([O:6][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:8][CH:9]=2)=[N:13][CH:26]=1)=[O:22])[CH3:25]
Reactant: CCCCOc1ccc(C(=N)N)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCOc1ccc(-c2ncc(C(=O)OCC)c(O)n2)cc1
Yield: 69.2 %

Procedure:
4-Butyloxybenzamidine hydrochloride (II) (22.9 g, 0.1 mol) and diethyl ethoxymethylenemalonate (III) (23.8 g, 0.1 mol) were suspended in methanol (100 ml), followed by agitating the suspension while keeping it at 10° C., dropwise adding a sodium methoxide-methanol solution, separately prepared by reacting sodium (2.5 g, 0.11 mol) with methanol (200 ml), then agitating the mixture for 2.5 hours, distilling off methanol under reduced pressure, gradually adding 6N-hydrochloric acid till the solution reached a pH of 4, filtering the resulting white precipitate, washing the precipitate with a small quantity of methanol and drying the precipitate to obtain ethyl-2-(4-butyloxyphenyl)-4-hydroxy-5-pyrimidinecarboxylate (IV) (21.9 g) (yield: 69% based on compound (II)).
Reaction SMILES: [CH2:1]([C@H:8]([NH:12]C(=O)OC(C)(C)C)[CH:9]([OH:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCOCC1>[NH2:12][C@@H:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:9]([OH:11])[CH3:10]
Reactant: CC(O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: C1COCCO1
Product: CC(O)[C@@H](N)Cc1ccccc1
Temperature: 20 °C
Reaction time: 16 h
Yield: 87.2 %

Procedure:
The process is performed as in Example 3, starting with 17.6 g of tert-butyl (1S)-1-benzyl-2-hydroxypropylcarbamate in 145 cm3 of dioxane and 61 cm3 of 6.5N hydrochloric dioxane, stirring for 16 hours at a temperature in the region of 20° C. After an identical work-up, 9.56 g of (3S)-3-amino-4-phenyl-2-butanol are obtained in the form of an orange-colored oil as a mixture of the two diastereoisomers (80/20). (Rf=0.25 in a 40/5/0.5 by volume mixture of dichloromethane/methanol/aqueous ammonia, on a Merck 60F254R silica plate).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:13](CC2C=CC(OC)=CC=2)[C:14]2[CH:15]=[C:16]([CH:25]=[CH:26][CH:27]=2)[C:17]([NH:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[O:18])[C:5]2[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=2)[N:7]=1.[NH2:37][C:38]1[CH:39]=[CH:40][C:41]([CH3:48])=[C:42]([NH:44][C:45](=[O:47])[CH3:46])[CH:43]=1.OP(O)(O)=O>O.CO>[C:45]([NH:44][C:42]1[CH:43]=[C:38]([NH:37][C:2]2[CH:3]=[C:4]([NH:13][C:14]3[CH:15]=[C:16]([CH:25]=[CH:26][CH:27]=3)[C:17]([NH:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[O:18])[C:5]3[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=3)[N:7]=2)[CH:39]=[CH:40][C:41]=1[CH3:48])(=[O:47])[CH3:46]
Reactant: CC(=O)Nc1cc(N)ccc1C
Reactant: COc1ccc(CN(c2cccc(C(=O)NCCN(C)C)c2)c2cc(Cl)nn3c(C#N)cnc23)cc1
Agent: O=P(O)(O)O
Solvent: O
Solvent: CO
Product: CC(=O)Nc1cc(Nc2cc(Nc3cccc(C(=O)NCCN(C)C)c3)c3ncc(C#N)n3n2)ccc1C

Procedure:
Example 253 was prepared from 253D and N-(5-amino-2-methylphenyl)acetamide following the procedure as described in Example 6. HPLC: Rt=3.110 min. (YMC S5 ODS (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.2% H3PO4). Solvent A: (10% MeOH, 90% H2O, 0.2% H3PO4). Gradient, start % B=0, final % B=100, gradient time 4 min., hold at 100% 1 min., flow rate 4 mL/min.). MS (ES): m/z=512.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.04 (1H, br. s.), 9.52-9.58 (2H, m), 9.21 (1H, s), 8.94 (1H, t, J=5.52 Hz), 8.18 (1H, s), 7.87 (1H, s), 7.59-7.63 (2H, m), 7.44-7.54 (2H, m), 7.06 (1H, d, J=8.28 Hz), 6.81-6.85 (1H, m), 3.59 (3H, q, J=5.69 Hz), 3.24 (2H, q, J=5.86 Hz), 2.73-2.84 (6H, m), 2.08 (3H, s), 1.98 (3H, s).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][Br:10])=[CH:5][C:4]=1[C:11]#[N:12].BrN1[C:18](=[O:19])CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.CC1C=CC(C)=CC=1OC>C(Cl)(Cl)(Cl)Cl>[Br:10][CH2:9][C:6]1[CH:5]=[C:4]([C:11]#[N:12])[C:3]([CH2:2][Br:1])=[CH:8][C:7]=1[O:19][CH3:18]
Reactant: N#Cc1cc(CBr)ccc1CBr
Reactant: O=C1CCC(=O)N1Br
Agent: COc1cc(C)ccc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(CBr)c(C#N)cc1CBr

Procedure:
These monomers are commercially available or can be prepared by a simple modification. A very suitable monomer is α,α'-dibromo-2-cyano-p-xylene (see formula V of FIG. 2), which can be prepared by refluxing a mixture of 2,5-dimethylbenzonitryl, N-bromosuccinimide and benzoyl peroxide in carbon tetrachloride for several hours. The solid formed is recrystallized from a mixture of petroleum ether and toluene and subsequently dried under a vacuum. Another suitable monomer is α,α'-dibromo-2-methoxy-p-xylene (see formula VI of FIG. 2), which can be prepared by refluxing a mixture of 2,5-dimethylanisol, N-bromosuccinimide and benzoyl peroxide in carbon tetrachloride in a nitrogen atmosphere for several hours. The solid formed is recrystallized from hexane and subsequently dried under a vacuum.
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=[NH:19])[NH:17][OH:18])=[CH:12][CH:11]=1)(=[O:9])=[O:8])C.[CH2:21]([N:23]([CH2:26][C:27]1[S:31][C:30]([C:32](O)=O)=[CH:29][C:28]=1[CH3:35])[CH2:24][CH3:25])[CH3:22].Cl>[Li+].[OH-].CO>[CH2:21]([N:23]([CH2:26][C:27]1[S:31][C:30]([C:32]2[O:18][N:17]=[C:16]([C:13]3[CH:12]=[CH:11][C:10]([S:7]([NH:6][CH2:5][C:4]([OH:3])=[O:20])(=[O:8])=[O:9])=[CH:15][CH:14]=3)[N:19]=2)=[CH:29][C:28]=1[CH3:35])[CH2:24][CH3:25])[CH3:22]
Reactant: CCOC(=O)CNS(=O)(=O)c1ccc(C(=N)NO)cc1
Reactant: CCN(CC)Cc1sc(C(=O)O)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(S(=O)(=O)NCC(=O)O)cc3)no2)cc1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 1.8 %

Procedure:
{4-[5-(5-Diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-benzenesulfonylamino}-acetic acid ethyl ester (98 mg) is obtained starting from [4-(N-hydroxycarbamimidoyl)-benzenesulfonylamino]-acetic acid ethyl ester (233 mg, 0.774 mmol) and 5-diethylaminomethyl-4-methyl-thiophene-2-carboxylic acid (160 mg, 0.704 mmol) according to Method A; LC-MS: tR=0.57 min; [M+1]+=493.17. This material (98 mg, 199 μmol) is dissolved in 2 N aq. LiOH (25 mL) and methanol (25 mL). The mixture is stirred at rt for 20 h before it is acidified by adding 1 N aq. HCl and extracted twice with EA. The combined organic extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by prep. HPLC to give the title compound (6 mg) as a white solid; LC-MS: tR=0.50 min; [M+1]+=465.02.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:10]([CH:11]=[O:12])=[C:4]2[CH:3]=1.[C:21]([Mg]Br)#[CH:22].C(=O)(O)[O-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:10]([CH:11]([OH:12])[C:21]#[CH:22])=[C:4]2[CH:3]=1
Reactant: C#C[Mg]Br
Reactant: COc1ccc(-c2nn3ccc(Cl)cc3c2C=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CC(O)c1c(-c2ccc(OC)cc2)nn2ccc(Cl)cc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 106.9 %

Procedure:
To a cold (-78° C.) suspension of 5-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridine-3-carbaldehyde (0.90 g, 3.14 mmol) in tetrahydrofuran (50 mL) was added ethynylmagnesium bromide (7.5 mL, 0.5 M in tetrahydrofuran, 3.77 mmol) dropwise. The reaction mixture was stirred at −78° C. for 1 hour, then at room temperature for 4 hours. The resultant solution was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with water and brine and the combined organics were dried over magnesium sulfate. Filtration and concentration provided 1-[5-chloro-2-(4methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-propyn-1-ol (1.05 g, 100%) as a white solid. 1H NMR (CDCl3) δ 8.40 (d, 1H), 8.05 (s, 1H), 7.72 (d, 2H), 7.05 (d, 2H), 6.80 (dd, 1H), 5.78 (s, 1H), 3.91 (s, 3H), 2.74 (s, 1H), 2.53 (s, 1H); MS m/z 313 (M+1).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:15](Cl)([Cl:17])=[O:16]>CCCCCC1C=C(O)C2[C@@H]3C=C(C)CC[C@H]3C(C)(C)OC=2C=1.C1(C)C=CC=CC=1>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:15]([Cl:17])=[O:16])[CH2:4][CH2:3]1
Reactant: O=C(Cl)Cl
Reactant: CC1CCNCC1
Agent: CCCCCc1cc(O)c2c(c1)OC(C)(C)[C@@H]1CCC(C)=C[C@@H]21
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC1CCN(C(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
9 g (90.75 mmol) of 4-methylpiperidine and 13.9 ml (100 mol) of triethylamine were dissolved in 100 ml of THC and, at −30° C., 54.9 ml (100 mmol) of phosgene in toluene (20 percent) were added, and the mixture was stirred for 2.5 h, during which it warmed to room temperature. The reaction mixture was concentrated, the residue was mixed with methylene chloride and filtered off, and the filtrate was concentrated. The crude product (12.7 g) was reacted without further purification.
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:5](=[C:7]([Cl:12])[CH:8]=[C:9]([Cl:11])[CH:10]=1)[OH:6].[CH:14]([Mg]Cl)([CH3:16])[CH3:15]>C1COCC1>[Cl:12][C:7]1[C:5]([OH:6])=[C:4]([C:3](=[O:13])[CH:14]([CH3:16])[CH3:15])[CH:10]=[C:9]([Cl:11])[CH:8]=1
Reactant: CC(C)[Mg]Cl
Reactant: COC(=O)c1cc(Cl)cc(Cl)c1O
Solvent: C1CCOC1
Product: CC(C)C(=O)c1cc(Cl)cc(Cl)c1O
Temperature: -40 °C
Reaction time: 0.75 h

Procedure:
Methyl-3,5-dichlorosalicylate (prepared according to Ahmed et al., Medicinal Chemistry 2008, 4, 298-308, which is expressly incorporated by reference herein; 2.0 g, 9.0 mmol) was dissolved in dry THF (30 mL), cooled to −40° C. and treated in portions with isopropyl magnesium chloride, 2.0 M in THF; 10 mL, 20 mmol). The mixture was stirred at −20 to −40° C. for 45 min, warmed to 25° C. and stirred for 4 h. The excess reagent was quenched by addition of satd NH4Cl (10 mL). The mixture was diluted with EtOAc (50 mL) and the pH was adjusted to ˜1 by addition of 1 M HCl. The organic phase was washed with satd NaCl solution (20 mL), dried (Na2SO4) and evaporated. The residue was purified by reverse-phase high-performance liquid chromatography (RP-HPLC) with 70% acetonitrile to give the purified ketone (1.1 g): mp: 102-104° C. 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J=2.5 Hz, 1H), 7.57 (d, J=2.4 Hz, 1H), 3.54 (dt, J=13.6, 6.8 Hz, 1H), 1.26 (d, J=6.8 Hz, 6H); EIMS m/z 232.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15](#[N:18])[CH2:16][OH:17].C(=O)([O-])O.[Na+].Cl>O.CC(C)=O>[N+:12]([C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[C:6]([F:8])=[CH:7][C:2]=1[O:17][CH2:16][C:15]#[N:18])([O-:14])=[O:13]
Reactant: N#CCO
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(F)cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: N#CCOc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 4.5 h
Yield: 84.6 %

Procedure:
To a mixture of 1,5-difluoro-2,4-dinitrobenzene (2 g), acetone (20 g) and 50% aqueous glycolonitrile solution (1.2 g), a solution of sodium hydrogen carbonate (0.9 g) in water (18 g) was dropwise added at 27° to 30° C. in 5 minutes, and stirring was continued at 27° to 41° C. for 4.5 hours. After completion of the reaction, the reaction mixture was poured into 1% hydrochloric acid, extracted with ethyl acetate and concentrated. The precipitated crystals were collected by filtration and dried to give 2,4-dinitro-5-fluorophenoxyacetonitrile (2.0 g; yield, 83.0%).
Reaction SMILES: [CH2:1]1[CH:6]2[CH2:7][C:8]3([C:10]([OH:12])=O)[CH2:9][CH:2]1[CH2:3][CH:4]3[CH2:5]2.O=S(Cl)[Cl:15]>C1(C)C=CC=CC=1>[CH2:5]1[CH:4]2[C:8]3([C:10]([Cl:15])=[O:12])[CH2:9][CH:2]([CH2:1][CH:6]1[CH2:7]3)[CH2:3]2
Reactant: O=C(O)C12CC3CC(CC1C3)C2
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)C12CC3CC(CC1C3)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Noradamantane carboxylic acid (4.99 g, 30.1 mmol) and SOCl2 (5 mL, 69 mmol) in toluene (5 mL) were heated to 65° C. until vigorous evolution of gas commenced. The heating bath was removed for 5-10 minutes until gas evolution had moderated. Heating the reaction again at 65° C. was resumed for 2 hours. The reaction was cooled to room temperature, the volatiles removed in vacuo and toluene added and evaporated (2×) to remove excess SOCl2. The crude acid chloride was used without further purification.
Reaction SMILES: [OH:1][C:2]1([CH2:17][C:18]#[N:19])[C:6]2=[C:7]3[CH2:13][CH2:12][O:11][C:8]3=[N:9][CH:10]=[C:5]2[CH2:4][CH:3]1[CH:14]([CH3:16])[CH3:15].N.C(O)C>C(O)C.[Co]>[NH2:19][CH2:18][CH2:17][C:2]1([OH:1])[C:6]2=[C:7]3[CH2:13][CH2:12][O:11][C:8]3=[N:9][CH:10]=[C:5]2[CH2:4][CH:3]1[CH:14]([CH3:15])[CH3:16]
Reactant: CC(C)C1Cc2cnc3c(c2C1(O)CC#N)CCO3
Agent: [Co]
Agent: N
Solvent: CCO
Product: CC(C)C1Cc2cnc3c(c2C1(O)CCN)CCO3
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of (8-hydroxy-7-isopropyl-1,6,7,8-tetrahydro-2H-cyclopenta[d]furo[2,3-b]pyridin-8-yl)acetonitrile (440 mg, 1.70 mmol) in ethanol (12 mL) were added Raney cobalt (4 g) and 2M ammonia/ethanol solution (6 mL), and the mixture was stirred at room temperature for 4 hr under a hydrogen atmosphere. The catalyst was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (446 mg, yield 100%).