Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:21](F)=[CH:20][C:5]2=[N:6][C:7]3[N:8]([O:18][CH3:19])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.O.CS(O)(=O)=O.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>CS(C)=O>[F:1][C:2]1[C:21]([N:33]2[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]2)=[CH:20][C:5]2=[N:6][C:7]3[N:8]([O:18][CH3:19])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1
Reactant: COn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Reactant: CN1CCNCC1
Agent: CS(=O)(=O)O
Solvent: O
Solvent: CS(C)=O
Product: COn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCN(C)CC4)cc3nc21
Temperature: 20 °C
Yield: 46.9 %

Procedure:
A suspension of 0.93 g of 7,8-difluoro-1-methoxy-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine- 3-carboxylic acid in 0.6 g of 1-methylpiperazine and 20 cm3 of dimethyl sulphoxide is heated at a temperature close to 80° C. for 5 minutes. After cooling to about 20° C., the reaction mixture is poured into 30 cm3 of water, 1.5 cm3 of 2N methanesulphonic acid are added and the product is drained and washed with 3 times 5 cm3 of water. After recrystallizing from 30 cm3 of dimethylformamide containing 30% of ethanol, 0.55 g of 7-fluoro-1-methoxy-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is obtained in the form of a brown solid melting at 270° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:16])[CH2:12][C:13]([OH:15])=O)=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].[N:17]1[CH:22]=[CH:21][C:20]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]([NH2:33])[CH3:32])=[CH:27][C:26]=2[C:34]([F:37])([F:36])[F:35])=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:16])[CH2:12][C:13]([NH:33][CH:31]([C:28]2[CH:29]=[CH:30][C:25]([O:24][CH2:23][C:20]3[CH:19]=[CH:18][N:17]=[CH:22][CH:21]=3)=[C:26]([C:34]([F:37])([F:35])[F:36])[CH:27]=2)[CH3:32])=[O:15])=[CH:8][CH:9]=1)(=[NH:3])[NH2:2]
Reactant: N=C(N)c1ccc(NC(=O)CC(=O)O)cc1
Reactant: CC(N)c1ccc(OCc2ccncc2)c(C(F)(F)F)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)CC(=O)Nc1ccc(C(=N)N)cc1)c1ccc(OCc2ccncc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
134.1 mg (0.4 mmol) of N-(4-carbamimidoyl-phenyl)-malonamic acid*trifluoro-acetic acid salt (intermediate 4) was dissolved in absolute DMF and to this solution 118.5 mg (0.4 mmol) of the amine from step 2, 509 mg (0.8 mmol) 1-propane-phoshonic-acid-anhydride and 51.7 mg (0.4 mmol) N,N-diisopropy-ethyl-amine were added. After stirring for 24 h at ambient temperature the reaction mixture was filtered, evaporated to dryness and purified by preparative HPLC. Yield 45 mg (18%), colourless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:7]([CH:8]=[O:9])[C:6]([OH:11])=[CH:5][CH:4]=1.Br[CH2:13][C:14]([O:16][CH3:17])=[O:15]>>[CH:8]([C:7]1[CH:10]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[O:11][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:9]
Reactant: COc1ccc(O)c(C=O)c1
Reactant: COC(=O)CBr
Product: COC(=O)COc1ccc(OC)cc1C=O
Yield: 86 %

Procedure:
In the same manner as in Reference Example 1, 5-methoxysalicylaldehyde was reacted with methyl bromoacetate to yield methyl 2-formyl-4-methoxyphenoxyacetate (yield 86%), which was then recrystallized from acetone-hexane to yield colorless prisms having a melting point of 74° to 75° C.
Reaction SMILES: C1(C2C=CC([CH:8]=[O:9])=CC=2)CC1.Br[C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[C:18]([CH3:23])([CH3:22])[CH2:17][CH2:16]2.[Li]CCCC.CN(C=O)C>>[CH3:22][C:18]1([CH3:23])[C:19]2[C:15](=[CH:14][C:13]([CH:8]=[O:9])=[CH:21][CH:20]=2)[CH2:16][CH2:17]1
Reactant: CC1(C)CCc2cc(Br)ccc21
Reactant: O=Cc1ccc(C2CC2)cc1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: CC1(C)CCc2cc(C=O)ccc21
Yield: 93 %

Procedure:
The title compound was synthesized in analogy to 4-cyclopropyl benzaldehyde (described in example S53) using 5-bromo-1,1-dimethylindan [synthesized in analogy to a procedure described in Org. Prep. Proc. Int. 10:123-131 (1978)] (270 mg, 1.20 mmol), nBuLi (833 μl, 1.6M solution in hexane, 1.33 mmol) and DMF (173 μl, 2.22 mmol). The isolated residue was purified by flash column chromatography (1:9 ether:pentane) to give 1,1-dimethylindan-5-carbaldehyde (195 mg, 93%) as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ 9.96 (s, 1H), 7.71-7.69 (m, 2H), 7.28 (m, 1H), 2.95 (apt t, J=7.0 Hz, 2H), 1.98 (apt t, J=7.0 Hz, 2H), 1.95 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[CH:6]2.Cl[C:21]1[N:26]=[CH:25][N:24]=[C:23]([C:27]([N:29]2[C:37]3[C:32](=[CH:33][C:34]([F:38])=[CH:35][CH:36]=3)[CH2:31][CH2:30]2)=[O:28])[CH:22]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:38][C:34]1[CH:33]=[C:32]2[C:37](=[CH:36][CH:35]=1)[N:29]([C:27]([C:23]1[N:24]=[CH:25][N:26]=[C:21]([N:17]3[CH2:18][CH2:19][CH:14]([C:7]4[C:8](=[O:13])[NH:9][C:10]5[C:5]([CH:6]=4)=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=5)[CH2:15][CH2:16]3)[CH:22]=1)=[O:28])[CH2:30][CH2:31]2
Reactant: O=C(c1cc(Cl)ncn1)N1CCc2cc(F)ccc21
Reactant: COc1ccc2[nH]c(=O)c(C3CCNCC3)cc2c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2[nH]c(=O)c(C3CCN(c4cc(C(=O)N5CCc6cc(F)ccc65)ncn4)CC3)cc2c1

Procedure:
25 mg (70 μmol) 6-methoxy-3-piperidin-4-yl-1H-quinolin-2-one, 20 mg (70 μmol) (6-chloro-pyrimidin-4-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone and 50 μL (0.29 mmol) DIPEA were stirred in 2 mL DMF overnight at RT. Then the reaction mixture was diluted with DMF and purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[CH:6]([CH:9]=[CH:10][N:11]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:12](Cl)=[O:13])([CH3:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:6]([CH:9]=[CH:10][N:11]([C:15]([CH3:17])([CH3:16])[CH3:18])[C:12]([N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1)=[O:13])([CH3:8])[CH3:7]
Reactant: c1cn[nH]c1
Reactant: CC(C)C=CN(C(=O)Cl)C(C)(C)C
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)C=CN(C(=O)n1cccn1)C(C)(C)C
Temperature: 40 °C
Reaction time: 10 h
Yield: 64.4 %

Procedure:
27.2 g (0.2 mole) of pyrazole, 1 g of 4-dimethylaminopyridine and 40.6 g (0.2 mole) of N-(2-isopropylvinyl)-N-tert.-butylcarbamyl chloride are added in succession to a suspension of 42 g of potassium carbonate in 150 ml of dry methylene chloride at 20° C. The mixture is stirred for 10 hours at 40° C., after which the resulting precipitate is filtered off under suction and washed with 200 ml of methylene chloride. The filtrate is washed with three times 80 ml of water, dried over Na2SO4 and evaporated down under reduced pressure, and the oil which remains is evaporated down under reduced pressure. 30.3 g of 1-(N-(2-isopropylvinyl)-N-tert.-butylcarbamyl)-pyrazole are obtained as a colorless liquid of boiling point 104°-105° C./0.3 mbar and nD 1.4828 (Compound No. 3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[CH2:14][CH2:13]1)[N:8]([C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[O:36][CH3:37])[CH:7]2[CH2:38][C:39]([OH:41])=[O:40].S(=O)(=O)(O)O.[CH3:47]O>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[CH2:13][CH2:14][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[CH2:16][CH2:17]1)[N:8]([C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[O:36][CH3:37])[CH:7]2[CH2:38][C:39]([O:41][CH3:47])=[O:40]
Reactant: COc1cccc(N2CCN(C3=Nc4c(F)cccc4C(CC(=O)O)N3c3cc(C(F)(F)F)ccc3OC)CC2)c1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: CCO
Product: COC(=O)CC1c2cccc(F)c2N=C(N2CCN(c3cccc(OC)c3)CC2)N1c1cc(C(F)(F)F)ccc1OC
Yield: 81.8 %

Procedure:
(±)-{8-Fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-(2-methoxy-5-trifluoromethylphenyl)-3,4-dihydroquinazolin-4-yl}acetic acid (148 g) is dissolved in methanol (1480 g), then concentrated sulphuric acid (21.5 ml) is added. The mixture is stirred under reflux for 6 h, then cooled and concentrated to ca. one third of the original volume in vacuo. Water (400 ml) and dichloromethane (400 ml) are added, then the phases are separated. The organic phase is extracted with saturated sodium hydrogencarbonate solution (two times 375 ml, diluted with 300 ml of water), dried over sodium sulphate and concentrated to give a foamy residue. This is dissolved twice in succession in ethanol (400 ml each) and concentrated, and subsequently dried in vacuo for 18 h using entraining nitrogen. A total of 124 g of methyl {8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate are thus obtained as an amorphous solid, corresponding to 81.9% of theory.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[C:10]([CH:11]([CH3:13])[CH3:12])[C:3]=12.[CH3:14][O:15][C:16]1[N:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C(C1C2C(=NC=CC=2C2C=CSC=2)NN=1)(C)C>>[CH:11]([C:10]1[C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[C:19]2[CH:20]=[N:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)[NH:8][N:9]=1)([CH3:13])[CH3:12]
Reactant: COc1ccc(B(O)O)cn1
Reactant: CC(C)c1n[nH]c2nccc(Cl)c12
Agent: CC(C)c1n[nH]c2nccc(-c3ccsc3)c12
Product: COc1ccc(-c2ccnc3[nH]nc(C(C)C)c23)cn1
Yield: 60 %

Procedure:
According to Example 1(4), a crude product of 3-isopropyl-4-(6-methoxypyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine was prepared using compound (6b) instead of compound (1c) and using 6-methoxypyridin-3-yl-boronic acid instead of quinoline-3-boronic acid and was used in the subsequent reaction without being purified. According to Example 1(5), compound (18a) (the second stage yield: 60%) was prepared using 3-isopropyl-4-(thiophen-3-yl)-1H-pyrazolo[3,4-b]pyridine instead of compound (1d).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([C:14]([NH:16][C@:17]2([C:22]([OH:24])=O)[CH2:19][C@H:18]2[CH:20]=[CH2:21])=[O:15])[C:11]2=[N:25][NH:26][CH:27]=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:40]1([S:43]([NH2:46])(=[O:45])=[O:44])[CH2:42][CH2:41]1.C1CCN2C(=NCCC2)CC1>ClCCCl>[CH:40]1([S:43]([NH:46][C:22]([C@@:17]2([NH:16][C:14]([CH:12]3[CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9][C:10]4=[CH:27][NH:26][N:25]=[C:11]34)=[O:15])[CH2:19][C@H:18]2[CH:20]=[CH2:21])=[O:24])(=[O:45])=[O:44])[CH2:42][CH2:41]1
Reactant: NS(=O)(=O)C1CC1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)C1CN(C(=O)OC(C)(C)C)Cc2c[nH]nc21)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCCl
Product: C=C[C@@H]1C[C@]1(NC(=O)C1CN(C(=O)OC(C)(C)C)Cc2c[nH]nc21)C(=O)NS(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of acid 8b (47.0 mg, 0.125 mmol) and CDI (22.3 mg, 0.150 mmol) in dry DCE (1.0 mL) was stirred at rt for 8 h. The cyclopropyl sulfonamide 9b (18.2 mg, 0.150 mmol) and DBU (22.8 mg, 0.150 mmol) were sequentially added and the mixture stirred at rt for 48 h. The solvent was evaporated and the residue diluted with EtOAc (2 mL). The mixture was washed sequentially with 0.5 M HCl (2×), deionized H2O and brine. The EtOAc solution was dried over MgSO4, filtered through a Celite plug capped with a layer of MgSO4 and concentrated. The crude product was purified via a SiO2 column (CH2Cl2, 25% EtOAc/hexanes then 50% EtOAc/hexanes) to give compound 104 as an ivory solid; 3:2 mixture of diastereomers, 27 mg, 45% (3:2 mixture of diastereomers), MS m/z 478.1 (APCI−, M−1).
Reaction SMILES: C1C=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])C2=CC=1)=[O:8].[C:14]([OH:17])(=[O:16])[CH3:15]>[OH-].[OH-].[Pd+2]>[CH3:5][C:7]([CH2:9][C:10]([CH2:15][C:14]([OH:17])=[O:16])=[O:11])=[O:8]
Reactant: CC(=O)O
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Agent: [Pd+2]
Agent: [OH-]
Product: CC(=O)CC(=O)CC(=O)O
Temperature: 25 °C

Procedure:
Compound 77 (0.302 g, 0.44 mmol) was dissolved in glacial acetic acid (20 mL). Pd(OH)2 (80 mg) was added and the mixture was charged with H2 (160 psi) in a Parr hydrogenator and stirred over night at room temperature. The reaction was found to be complete according to TLC (product stains bright purple after staining with ninhydrin). Pd(OH)2 was filtered off and the solvent was removed in vacuo to afford the pure product 78 as the triacetate salt.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1.[C:15]([O:19][C:20]([NH:22][C@@H:23]1[CH2:27][CH2:26][C@:25]([CH:31]([CH3:33])[CH3:32])([C:28](O)=[O:29])[CH2:24]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH:31]([C@:25]1([C:28]([N:9]2[CH2:8][CH2:7][C:6]3[C:11](=[CH:12][C:3]([C:2]([F:1])([F:13])[F:14])=[CH:4][CH:5]=3)[CH2:10]2)=[O:29])[CH2:26][CH2:27][C@@H:23]([NH:22][C:20](=[O:21])[O:19][C:15]([CH3:17])([CH3:16])[CH3:18])[CH2:24]1)([CH3:33])[CH3:32]
Reactant: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: FC(F)(F)c1ccc2c(c1)CNCC2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[C@]1(C(=O)N2CCc3ccc(C(F)(F)F)cc3C2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 36 h
Yield: 54.7 %

Procedure:
To a solution of 7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline (1.7 g, 8.45 mmol) of Step B-4, (1S,3R)-3-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopentanecarboxylic acid (2.75 g, 10.14 mmol) of Step A-4,4-dimethylaminopyridine (0.70 g, 5.73 mmol), and N,N-diisopropylethylamine (7.0 mL, 40.2 mmol) in methylene chloride (30.0 mL) was added bromotris(pyrrolydino)phophonium hexafluorophosphate (5.119 g, 10.98 mmol). After being stirred for 36 h at room temperature, the solution was concentrated in vacuo. The residue was purified by column chromatography on silica eluting with 20% ethyl acetate/hexanes to give 2.1 g (55%) of desired product. MS calculated for C24H33F3N2O3: (M+H)+455; found 355 (M−Boc+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][C:9]([OH:11])=[O:10].[OH-].[Na+].[CH2:14]([O:21][C:22](Cl)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1.O>[CH2:14]([O:21][C:22]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][C:9]([OH:11])=[O:10])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCCOCCOCC(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COCCOCCNC(=O)OCc1ccccc1
Reaction time: 2.5 h

Procedure:
A suspension of 6.7 g (12.5 mmol) of 2-[2-(aminoethoxy)ethoxy]-acetic acid in 30 ml of THF and 10 ml of water is adjusted to pH 10 with 2N NaOH, and reacted dropwise with 1.95 ml of chloroformic acid benzyl ester (Fluka, Buchs, Switzerland). While the mixture is being stirred for 2.5 h, the pH is maintained between 9 and 9.5 by 2N NaOH. After concentration of the reaction mixture under reduced pressure, the resulting aqueous phase is washed twice with ethyl acetate, adjusted to pH 1.8 with 2N sulfuric acid and extracted 3 times with ethyl acetate. The combined organic phases are then washed with water and brine, dried and concentrated under reduced pressure. The title compound so obtained is further used without being further purified. TLC Rf (ethyl acetate/acetic acid: 9/1)=0.39.
Reaction SMILES: N([O-])=O.[Na+].[N+:5]([C:8]1[CH:14]=[C:12](N)[C:11]([CH3:15])=[CH:10][C:9]=1[CH3:16])([O-:7])=[O:6].[ClH:17]>O.[Cu]Cl>[Cl:17][C:12]1[CH:14]=[C:8]([N+:5]([O-:7])=[O:6])[C:9]([CH3:16])=[CH:10][C:11]=1[CH3:15]
Reactant: Cl
Reactant: Cc1cc(C)c([N+](=O)[O-])cc1N
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(C)c([N+](=O)[O-])cc1Cl
Reaction time: 1 h
Yield: 47 %

Procedure:
A solution of sodium nitrite (7.2 g, 0.1 mol) in water (20 mL) was added dropwise over 45 min at <5° C. to a stirred suspension of 5-nitro-2,4-xylidine (16.6 g, 0.1 mol) in conc. hydrochloric acid (300 mL). After complete addition the reaction was stirred at <5° C. for 1 h then a solution of copper(I)chloride (16.0 g, 0.16 mol) in conc. hydrochloric acid (50 mL) was added dropwise over 20 min at <5° C. (CARE: effervescence at first). The reaction was then warmed from 0° C. to room temperature and stirred for 18 h. The mixture was then carefully poured into water (1 L) and extracted with ethyl acetate (3×300 mL). The combined organic extracts were dried (magnesium sulfate), filtered and the solvent removed under vacuum to leave a crude oil. The oil was purified by flash column chromatography (SiO2; heptane) to give the product as a yellow oil (8.8 g, 47%). IR νmax (film)/cm−1 3103, 2985, 2935, 2863, 2744, 2432, 1610, 1572, 1518, 1480, 1454, 1384, 1346, 1286, 1266, 1244, 1197, 1166, 1157, 1107, 1036, 982, 894, 842, 759, 746, 725, 704, 646 and 602; NMR δH (400 MHz; CDCl3) 8.01 (1H, s), 7.20 (1H, s), 2.56 (3H, s), 2.41 (3H, s).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@@H:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C@@H:3]1[C:11]([OH:13])=O.[NH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1>>[CH3:14][C:2]1([CH3:1])[C@@H:4]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@H:3]1[C:11]([NH:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: CC1(C)[C@@H](C(=O)O)[C@@H]1c1ccccc1
Reactant: Nc1ccncc1
Product: CC1(C)[C@@H](C(=O)Nc2ccncc2)[C@@H]1c1ccccc1
Yield: 93.4 %

Procedure:
2,2-Dimethyl-trans-3-phenylcyclopropanecarboxylic acid (250 mg, 1.31 mmol) and 4-aminopyridine (123 mg, 1.31 mmol) were reacted as described under General Procedure D to furnish the title compound (326 mg, 93%) as a white foam. 1H NMR (300 MHz, CDCl3) δ 8.48-8.45 (m, 2H), 8.35 (br s, 1H), 7.63-7.60 (m, 2H), 7.31-7.16 (m, 5H), 2.87 (d, J=5.7 Hz, 1H), 1.96 (d, J=5.7 Hz, 1H), 1.40 (s, 3H), 0.97 (s, 3H). ESIMS m/z [M+H]+ 267.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][N:5]([S:21](=[O:31])(=[O:30])[NH:22]C(OC(C)(C)C)=O)[C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.FC(F)(F)C(O)=O.ClCCl>>[CH3:1][O:2][C:3](=[O:32])[CH2:4][N:5]([S:21](=[O:30])(=[O:31])[NH2:22])[C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)CN(c1c(F)cccc1OCc1ccccc1)S(=O)(=O)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CN(c1c(F)cccc1OCc1ccccc1)S(N)(=O)=O

Procedure:
A solution of N-(t-butoxycarbonylsulfamoyl)-N-(2-benzyloxy-6-fluorophenyl)glycine methyl ester (980 mg, 2.09 mmol) 10 mL of trifluoroacetic acid:dichloromethane(1:1) is stirred at RT for 15 min. The solvent is removed under reduced pressure and the residue chromatographed on an Isco Companion (80 g silica gel cartridge, 30-60% gradient of hexane/ethyl acetate) to give N-sulfamoyl-N-(2-benzyloxy-6-fluorophenyl)glycine methyl ester. MS (M−1)−: 367 NMR (CDCl3): δ 7.41 (m, 5H), 7.25 (m, 1H), 2.21 (m, 2H), 5.13 (d, 2H, J=5.0 Hz), 5.02 (br s, 2H), 4.39 (dd, J=32 and 19 Hz, 2H), 3.70 (s, 3H).
Reaction SMILES: [CH3:1][Si:2]([CH3:8])([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].[OH-].[K+].[CH:11]#[CH:12]>CS(C)=O>[CH:11]([O:6][CH2:5][CH2:4][CH2:3][Si:2]([CH3:8])([CH3:7])[CH3:1])=[CH2:12]
Reactant: C#C
Reactant: C[Si](C)(C)CCCO
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: C=COCCC[Si](C)(C)C
Yield: 96 %

Procedure:
In a similar manner to Example 1, 25 g (0.19 mol) of 3-(trimethylsilyl)propanol, 2.5 g of KOH and 25 g of DMSO were reacted at 80° C. with acetylene. 3-(Trimethylsilyl)propyl vinyl ether was obtained in 96% yield.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2([OH:17])[CH2:16][CH2:15][C:10]3(OCC[O:11]3)[CH2:9][CH2:8]2)=[N:4][CH:3]=1.Cl.[OH-].[Na+]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[S:6][C:5]([C:7]2([OH:17])[CH2:8][CH2:9][C:10](=[O:11])[CH2:15][CH2:16]2)=[N:4][CH:3]=1
Reactant: OC1(c2ncc(Br)s2)CCC2(CC1)OCCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1CCC(O)(c2ncc(Br)s2)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
The product of Step 2 (15 g, 46.8 mmol) was diluted with THF (10 mL). HCl (6 N, 78 mL) was added and stirred at 60° C. for 3 h. The reaction was cooled to RT and NaOH (6 N, 78 mL) was added. The reaction was diluted with EtOAc. The layers were separated and the aqueous layer back extracted with EtOAc (2×). The combined organic layers were dried (MgSO4) and evaporated. The residue was diluted with EtOAc to transfer and concentrated to ˜20 mL where hexanes (60 mL) was added drop wise. The slurry was cooled to room temperature, stirred for 1 h then filtered, washed with hexanes (2×15 mL) and dried to afford 4-(5-bromo-1,3-thiazol-2-yl)-4-hydroxycyclohexanone (11.25 g, 40.8 mmol, 87% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]1([S:18]([O-:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Na+].CN(C)C=O>O>[NH2:1][C:2]1[CH:7]=[C:6]([S:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:20])=[O:19])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=S([O-])c1ccccc1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(S(=O)(=O)c2ccccc2)ccc1[N+](=O)[O-]

Procedure:
2.0 g. of 2 amino-4-chloro-1-nitrobenzene and 5.0 g. sodium benzene-sulfinate in 20 ml. dimethylformamide is heated at reflux for 3 hours. The mixture is cooled, diluted with water and the product filtered off to give 2-amino-1-nitro-4-phenylsulfonylbenzene.
Reaction SMILES: Cl.[F:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([C:11]2[CH:16]=[C:15]([C:17]3[CH2:21][CH:20]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[O:19][N:18]=3)[N:14]=[C:13]([CH3:28])[N:12]=2)=[O:10])=[CH:5][C:4]=1[O:31][CH3:32].[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl.O>[F:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([C:11]2[CH:16]=[C:15]([C:17]3[CH2:21][CH:20]([CH:22]4[CH2:23][CH2:24][N:25]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:26][CH2:27]4)[O:19][N:18]=3)[N:14]=[C:13]([CH3:28])[N:12]=2)=[O:10])=[CH:5][C:4]=1[O:31][CH3:32]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(CNC(=O)c2cc(C3=NOC(C4CCNCC4)C3)nc(C)n2)ccc1F
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: COc1cc(CNC(=O)c2cc(C3=NOC(C4CCN(S(C)(=O)=O)CC4)C3)nc(C)n2)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
To a cold solution of N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide hydrochloride (0.1 g, 0.215 mmol, Preparation #K.1) and TEA (0.141 g, 1.4 mmol, Sd Fine Chem) in DCM (10 mL) was added methane sulfonyl chloride (0.032 g, 0.28 mmol, Spectrochem). The reaction mixture was slowly warmed to RT and stirred for about 0.5 h. The reaction mixture was diluted with water (10 mL) and the product extracted with DCM (2×20 mL). The combined organic layers were washed with water (1×25 mL) followed by brine (1×50 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude material obtained was purified using silica gel column chromatography eluted in 60% EtOAc-hexane. Relevant fractions containing the required compound were combined and evaporated to dryness under reduced pressure to afford N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(1-(methylsulfonyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide as light pale yellow solid 0.065 g (55%): 1H NMR (400 MHz, DMSO): δ 9.501-9.469 (t, J=6.4 Hz, 1H), 8.144 (s, 1H), 7.179-7.135 (m, 2H), 6.901-6.890 (m, 1H), 4.730-4.692 (m, 1H), 4.483-4.467 (d, J=6.4 Hz, 2H), 3.815 (s, 3H), 3.617-3.587 (d, J=12 Hz, 2H), 3.517-3.489 (m, 2H), 2.848 (s, 3H) 2.755 (s, 3H), 2.699-2.639 (m, 2H), 1.896-1.864 (m, 1H), 1.740-1.711 (m, 2H), 1.323-1.236 (m, 2H). LC/MS (Table 1, Method c) Rt=4.71 min MS m/z: 506 (M+H)+.