Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6]O.[C:8]([OH:17])(=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14]>C1(C)C=CC=CC=1>[CH3:6][O:16][C:8](=[O:17])[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)CCCCC(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: COC(=O)CCCCC(C)C
Yield: 95 %

Procedure:
2 g concentrated sulfuric acid were added to a solution of 32 g (1 mol) methanol and 144 g (1 mol) "isooctanoic acid" (isomeric mixture from Ruhrchemie A. G. Oberhausen) in 200 ml toluene and heated to boiling with hater separation until the equimolar amount of water separates (about 2 hours). After cooling it was washed with water and then with 10% sodium bicarbonate solution. The solvent was distilled off under reduced pressure. The remaining end-product after distillation over a 15 cm Vigreux column gave 150 g (95%) isooctanoic acid methylester as an easily mobile liquid with a fruity smell.
Reaction SMILES: ClC1C(OC2C=CC(F)=CC=2F)=CN=C(S(C)(=O)=O)N=1.CN1C=C(B2OC(C)(C)C(C)(C)O2)C2CCCCC=2C1=O.[F:42][C:43]1[CH:71]=[C:70]([F:72])[CH:69]=[CH:68][C:44]=1[O:45][C:46]1[C:47]([C:56]2[C:65]3[CH2:64][CH2:63][CH2:62][CH2:61][C:60]=3[C:59](=[O:66])[N:58]([CH3:67])[CH:57]=2)=[N:48][C:49](S(C)(=O)=O)=[N:50][CH:51]=1.[CH2:73]([S:75]([NH2:78])(=[O:77])=[O:76])[CH3:74]>>[F:42][C:43]1[CH:71]=[C:70]([F:72])[CH:69]=[CH:68][C:44]=1[O:45][C:46]1[C:47]([C:56]2[C:65]3[CH2:64][CH2:63][CH2:62][CH2:61][C:60]=3[C:59](=[O:66])[N:58]([CH3:67])[CH:57]=2)=[N:48][C:49]([NH:78][S:75]([CH2:73][CH3:74])(=[O:77])=[O:76])=[N:50][CH:51]=1
Reactant: Cn1cc(-c2nc(S(C)(=O)=O)ncc2Oc2ccc(F)cc2F)c2c(c1=O)CCCC2
Reactant: CCS(N)(=O)=O
Agent: CS(=O)(=O)c1ncc(Oc2ccc(F)cc2F)c(Cl)n1
Agent: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2c(c1=O)CCCC2
Product: CCS(=O)(=O)Nc1ncc(Oc2ccc(F)cc2F)c(-c2cn(C)c(=O)c3c2CCCC3)n1

Procedure:
The title compound of Example 149, step 3 was reacted with the title compound of Example 163, step 3 in a manner similar to Example 163, step 4 and the resulting 4-[5-(2,4-difluorophenoxy)-2-methylsulfonylpyrimidin-4-yl]-2-methyl-5,6,7,8-tetrahydroisoquinolin-1-one was treated with EtSO2NH2 instead of MeSO2NH2 in a manner similar to Example 163, step 5 to give the title compound. 1H NMR (DMSO-d6, 400 MHz): δ 8.38 (s, 1H), 7.61 (s, 1H), 7.35-7.31 (m, 1H), 7.04-6.95 (m, 2H), 3.41 (s, 3H), 3.30-3.20 (m, 2H), 2.42-2.40 (m, 2H), 2.32-2.30 (m, 2H), 1.61-1.51 (m, 4H), 1.18 (t, J=7.2 Hz, 3H). LCMS: 477.1 (M+H)+
Reaction SMILES: [C:1]1(OB=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([C:25]([NH:27][C:28]2[CH:40]=[C:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:38]=[CH:37][C:29]=2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:26])[CH:20]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:41]1([C:39]2[CH:38]=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[C:28]([NH:27][C:25]([C:21]3[CH:20]=[C:19]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:24]=[CH:23][N:22]=3)=[O:26])[CH:40]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=BOc1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(Cl)ccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(-c2ccccc2)ccn1
Temperature: 25 °C
Yield: 98.3 %

Procedure:
Phenylboranic acid (21 mg), tripotassium phosphate (69 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (1.2 mg), and palladium(II) acetate (1.3 mg) were added to a toluene (1.2 mL) solution of tert-butyl 2-(4-chloropyridine-2-carboxamido)-4-phenylbenzoate (60 mg), followed by heating to reflux under a nitrogen atmosphere for 3 hours. The reaction mixture was cooled to room temperature, and then phenylboranic acid (5.4 mg), tripotassium phosphate (16 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (1.2 mg), and palladium(II) acetate (1.3 mg) were added thereto, followed by heating to reflux under a nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, and then ethyl acetate and a 10% aqueous solution of citric acid were added thereto. The insoluble substance was removed by filtration. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 100-85% hexane/ethyl acetate] to obtain 65 mg of tert-butyl 4-phenyl-2-(4-phenylpyridine-2-carboxamido)benzoate as a colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[ClH:10]>[Pd]>[ClH:10].[NH2:1][C:2]1[NH:7][CH:6]([CH3:8])[CH2:5][CH:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(C)nc(N)n1
Agent: [Pd]
Agent: Cl
Product: CC1CC(C)NC(N)=N1

Procedure:
1 g 2-amino-4,6-dimethylpyrimidine was heated for 14 h in a hydrochloric acid environment (2 M HCl) with palladium on activated charcoal as a catalyst, with H2 fed in. Subsequent filtration, removal of the solvent and addition of diethyl ether yielded the 2-amino-4,6-dimethyl-1,4,5,6-tetrahydropyrimidine hydrochloride, which was recrystallized from i-propanol/diethyl ether and dried in a vacuum.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[C:13]([O:17][CH3:18])(=[O:16])[CH:14]=[CH2:15].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[OH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2](/[CH:15]=[CH:14]/[C:13]([O:17][CH3:18])=[O:16])[CH:11]=[CH:10]2
Reactant: C=CC(=O)OC
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1ccc2cc(O)ccc2c1
Reaction time: 15 h
Yield: 71.4 %

Procedure:
5 g (22.4 mmol) of 6-bromo-2-naphthol, 6 ml (67.2 mmol) of methyl acrylate, 100 mg (0.45 mmol) of palladium acetate and 25 ml of triethylamine were placed in a flask gassed with nitrogen. After the addition of 545 mg (1.79 mmol) of tri-(o-tolyl)-phosphine the reaction mixture was boiled under reflux overnight. After 15 hours the reaction was interrupted and the mixture was partitioned between ethyl acetate and water. The organic phase was back-washed three times with water and the aqueous phases were each individually back-washed twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate, filtered over Celite and evaporated completely in a vacuum. Chromatography on silica gel with toluene/ethyl acetate (3:2) and subsequent recrystallization from ethyl acetate gave 3.65 g of methyl (E)-3-(6-hydroxy-naphthalen-2-yl)-acrylate.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7](B3OC(C)(C)C(C)(C)O3)=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:20].[Br:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26](Br)[CH:27]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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>[Br:21][C:22]1[CH:27]=[C:26]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:2]([CH3:1])[C:3](=[O:20])[CH2:4]3)[CH:25]=[N:24][CH:23]=1
Reactant: CN1C(=O)Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: Brc1cncc(Br)c1
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: ClCCl
Solvent: COCCOC
Product: CN1C(=O)Cc2cc(-c3cncc(Br)c3)ccc21
Temperature: 120 °C

Procedure:
To 1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one (1.0 g, 3.66 mmol), prepared as described in Example 3a, was added 3,5-dibromopyridine (2.6 g, 11 mmol), 1,2-dimethoxyethane (10.0 mL), and 2 M aqueous sodium carbonate (4.00 mL, 8.0 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at, which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.11 mmol/g loading, (2.0 g, 0.220 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 120° C. for 3 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane, and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethanol-dichloromethane, 0 to 3.55%) to furnish 5-(5-bromo-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 303.0133 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 3.27 (s, 3H), 3.62 (s, 2H), 6.94 (d, J=8.1 Hz, 1H), 7.48 (s, 1H), 7.50 (d, J=8.1 Hz, 1H), 8.01 (t, J=1.9 Hz, 1H), 8.64 (d, J=2.0 Hz, 1H), 8.73 (d, J=1.6 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH:14]=[CH:13][C:12]=2[CH2:11]1.Cl.[N:28]1([CH2:34][CH2:35][O:36][C:37]2[CH:42]=[CH:41][C:40]([CH2:43][C:44](O)=[O:45])=[CH:39][CH:38]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]([CH:10]2[CH2:19][CH2:18][C:17]3[CH:16]=[C:15]([O:20][C:21](=[O:26])[C:22]([CH3:23])([CH3:25])[CH3:24])[CH:14]=[CH:13][C:12]=3[CH2:11]2)=[C:2]([NH:1][C:44](=[O:45])[CH2:43][C:40]2[CH:41]=[CH:42][C:37]([O:36][CH2:35][CH2:34][N:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]3)=[CH:38][CH:39]=2)[CH:7]=1
Reactant: O=C(O)Cc1ccc(OCCN2CCCCC2)cc1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N)c1
Agent: Cl
Product: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NC(=O)Cc2ccc(OCCN3CCCCC3)cc2)c1
Yield: 54.9 %

Procedure:
Synthesized from pivalic acid 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (100 mg) and [4-(2-piperidin-1-ylethoxy)phenyl]acetic acid hydrochloride (140 mg) according to an analogous synthetic method to Preparation Example 154,the title compound (93 mg) was obtained.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([N:19]=[N+]=[N-])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(P(CCCC)CCCC)CCC.C1C([N+]([O-])=O)=CC=C(O)C=1>C(#N)C>[CH2:11]([NH:19][C:8](=[O:10])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [N-]=[N+]=NCCc1ccccc1
Reactant: O=C(O)Cc1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=[N+]([O-])c1ccc(O)cc1
Solvent: CC#N
Product: O=C(Cc1ccccc1)NCCc1ccccc1
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
To an argon-blanketed solution of phenylacetic acid (69 mg, 0.51 mmol) in acetonitrile (3 mL) was added bis(trimethylsilyltrifluoroacetamide) (BSTFA, 400 μL, 1.51 mmol) via syringe. The mixture was stirred for 30 min. after which time solvent, unreacted starting material and the reaction by-products were removed at high vacuum. The colorless residue was redissolved in toluene (5 mL) and phenethyl azide (58 mg, 0.39 mmol) then freshly-distilled tri-n-butylphosphine (98 μL, 0.39 mmol) were added via syringe. While nitrogen evolution was still progressing, p-nitrophenol (55 mg, 0.40 mmol) was added in one portion, imparting a bright yellow color to the solution. The reaction was stirred at 65° C. for 48 h. The reaction mixture was partitioned between satd Na2CO3 solution and ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a yellow oil that was purified by flash chromatography (1:1 EtOAc/hexane) to yield 91 mg (98%) of the title compound as a white powder (mp 91-92° C., lit. mp 91-93° C.). Spectral data were identical to those reported in the literature.
Reaction SMILES: [CH3:1][C:2](=[N:4]O)[CH3:3].[C:6](Cl)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[N:9][CH:8]=1.CCOCC.C>N>[CH3:1][C:2]1[N:4]=[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[O:13][CH:3]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: CC(C)=NO
Agent: N
Solvent: CCOCC
Product: Cc1coc(-c2cccnc2)n1
Temperature: 120 °C

Procedure:
To 10 g (0.140 mol) of acetone oxime cooled to -10° C. neat nicotinoyl chloride (40 g, 0.280 mol) was added dropwise under a nitrogen atmosphere. A violent reaction occured and the mixture became quickly solid. The solid was heated to 120° C. for 3 h. After cooling the mixture was dissolved in ice water and ammonia. After addition of 300 ml of ether the mixture was treated with charcoal, filtered, and the ether phase separated. The aqueous phase was extracted with 2×200 ml of ether, and the combined organic phase dried over magnesium sulphate. Removal of solvent in vacuo gave crude 82 as a red oil. Yield: 3.9 g (0.024 mol, 17%).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:25]1[CH2:28][CH2:27][CH2:26]1>CN(C1C=CN=CC=1)C.CC#N>[N:25]1([S:21]([C:19]2[CH:18]=[CH:17][C:8]3[N:9]([CH2:10][CH:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6][C:7]=3[CH:20]=2)(=[O:23])=[O:22])[CH2:28][CH2:27][CH2:26]1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Reactant: C1CNC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CCC3)ccc2n1CC1CCOCC1

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (76 mg, 0.20 mmol), azetidine (34 uL, 26 mg, 0.50 mmol) and DMAP (82 mg, 0.67 mmol) in MeCN (5 mL). The crude product was purified by MPLC using Hex/EtOAc (1:2) on silica gel to give 37 mg (46% yield) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.52-1.65 (m, 4 H), 1.68 (s, 9 H), 1.99-2.13 (m, 2 H), 2.32-2.47 (m, 1 H), 3.32-3.43 (m, 2 H), 3.74-3.84 (m, 4 H), 3.90-4.01 (m, 2 H), 4.54 (d, J=7.42 Hz, 2 H), 7.92 (dd, J=8.79, 1.56 Hz, 1 H), 8.09 (d, J=8.79 Hz, 1 H), 8.15 (d, J=1.17 Hz, 1 H); MS (ESI) (M+H)+=392.0; Anal. Calcd for C20H29N3O3S+1.20 TFA+0.40 EtOAc+0.1H2O (556.60): C, 50.93; H, 5.94; N, 7.55. Found: C, 50.98; H, 5.68; N, 7.50.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][NH:27]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[CH3:31][N:32]([CH3:39])[CH2:33]/[CH:34]=[CH:35]/[C:36](O)=[O:37]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:36](=[O:37])/[CH:35]=[CH:34]/[CH2:33][N:32]([CH3:39])[CH3:31])=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CN(C)C/C=C/C(=O)O
Reactant: Nc1nccn2c([C@@H]3CCCN3)nc(-c3ccc(C(=O)Nc4ccccn4)cc3)c12
Product: CN(C)C/C=C/C(=O)N1CCC[C@H]1c1nc(-c2ccc(C(=O)Nc3ccccn3)cc2)c2c(N)nccn12
Yield: 46.6 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from the compound described in intermediate 2b and (E)-4-(dimethylamino)but-2-enoic acid, to afford the title compound (11.8 mg, 46.6%). Data: UPLC (C) Rt: 1.29 min; m/z 511.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:16]=[CH:17][C:18]([C:19]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:21])=[CH:22][CH:23]=1
Reactant: C1CCNC1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N2CCCC2)cn1
Yield: 98 %

Procedure:
As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64 mmol) was converted, using pyrrolidine instead of 2-aminoethyl isopropylether, to the title compound (229 mg, 98%) which was obtained as a colourless. MS: m/e=364.3 [M+H]|.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]([SH:8])=[N:6][N:7]=1.[H-].[Na+].FC(F)(F)S(O[CH2:17][P:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19])(=O)=O>C1COCC1>[CH3:1][S:2][C:3]1[S:4][C:5]([S:8][CH2:17][P:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19])=[N:6][N:7]=1
Reactant: CCOP(=O)(COS(=O)(=O)C(F)(F)F)OCC
Reactant: CSc1nnc(S)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(CSc1nnc(SC)s1)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-methylthio-1,3,4-thiadiazole-5-thiol (1 mmole) in THF (5 mL) was treated with sodium hydride (60%, 1.1 mmole) at 0° C. and the resulting mixture was stirred at room temperature for 30 min. The reaction was then cooled to 0° C. and treated with diethylphosphonomethyl trifluoromethanesulfonate (1.1 mmole). After stirring at room temperature for 12 h, the reaction was quenched with saturated ammonium chloride. Extraction and chromatography gave 2-methylthio-5-diethylphosphonomethylthio-1,3,4-thiadiazole as an oil.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:15]([C:22]1[CH:27]=[CH:26][C:25]([P:28](Cl)(Cl)=[O:29])=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[O:15]([C:22]1[CH:27]=[CH:26][C:25]([P:28]2(=[O:29])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH2:1][N:8]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:24][CH:23]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=P(Cl)(Cl)c1ccc(Oc2ccccc2)cc1
Reactant: c1ccc(CNc2ccccc2)cc1
Product: O=P1(c2ccc(Oc3ccccc3)cc2)c2ccccc2CN1c1ccccc1

Procedure:
The procedure of Example 1 was employed utilizing N-benzylaniline and 4-phenoxyphenyl phosphonic dichloride. The reaction of the dilithio compound and the 4-phenoxyphenyl phosphonic dichloride was conducted at 0° C. The crude product produced as a result of the chromatographic separation was distilled at 140° C. and the resulting residue was crystallilzed from diethyl ether to yield 1-(4-phenoxyphenyl)-2-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide as beige needles. A second crop was obtained to give a total yield of 0.75 g, 3% yield of 1-(4-phenoxyphenyl)-2-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide having a melting point of 207°-208° C. and the following analysis:
Reaction SMILES: [C:1]1([CH2:7][C:8](=[CH2:12])[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(O)CC>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][N:24]([CH2:12][CH:8]([CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:9]([OH:11])=[O:10])[CH2:23][CH2:22]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: C=C(Cc1ccccc1)C(=O)O
Solvent: CCCO
Product: COc1ccccc1N1CCN(CC(Cc2ccccc2)C(=O)O)CC1
Temperature: 25 °C
Yield: 18.3 %

Procedure:
2-(Phenylmethyl)propenoic acid (Mannich et al., Chem. Ber., 1922, 55, 3486) (2.00 g, 12.35 mmol) and 1-(2-methoxyphenyl)piperazine (2.37 g, 12.35 mmol) in propanol (25 mL) were boiled under reflux for 18 hours, cooled to room temperature, and evaporated in vacuo. The residue was triturated with acetone and diethyl ether to give 2-[[4-(2-methoxyphenyl)piperazinyl]methyl]-3-phenyl propanoic acid (0.80 g) as a colorless powder, mp. 155°-158° C.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[CH:32]1([C:35]2[C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][N:37]([CH3:49])[N:36]=2)[CH2:34][CH2:33]1>>[NH2:23][C@H:18]1[C@@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:39]3[C:35]([CH:32]4[CH2:34][CH2:33]4)=[N:36][N:37]([CH3:49])[CH:38]=3)[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c(C2CC2)n1
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Product: Cn1cc(-c2nc(C(=O)Nc3cnn(C)c3[C@@H]3CC[C@@H](N)[C@@H](F)CO3)cs2)c(C2CC2)n1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3R,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 100), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with 3-cyclopropyl-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole gave 253. 1H NMR (400 MHz, DMSO-d6) δ 9.76 (s, 1H), 8.27 (s, 1H), 8.20 (s, 1H), 7.81 (s, 1H), 5.02-4.76 (m, 2H), 4.16-3.90 (m, 2H), 3.80 (s, 3H), 3.76 (s, 3H), 3.29-3.16 (m, 1H), 2.41-2.30 (m, 1H), 2.18-2.09 (m, 1H), 1.86-1.74 (m, 2H), 1.66-1.58 (m, 1H), 1.02-0.90 (m, 2H), 0.89-0.80 (m, 2H). LCMS (ES+) m/z 460 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:9]2[C:13]([C:14](O)=[O:15])=[CH:12][C:11]([C:17]([F:20])([F:19])[F:18])=[N:10]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C(Cl)(=O)C([Cl:24])=O>CN(C)C=O.ClCCl>[Cl:1][C:2]1[C:3]([N:9]2[C:13]([C:14]([Cl:24])=[O:15])=[CH:12][C:11]([C:17]([F:20])([F:19])[F:18])=[N:10]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(O)c1cc(C(F)(F)F)nn1-c1ncc(Cl)cc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a 100 mL flask, 1-(3,5-dichloropyridin-2-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (0.40 g, 1.22 mmol), dichloromethane (10 mL) and oxalyl dichloride (0.31 g, 2.44 mmol) were added sequentially. After five drops of N,N-dimethyl formamide were added, a large amount of gas was released. After being stirred for 8 hours at room temperature, the reaction mixture was concentrated under reduced pressure. Then toluene (30 mL) was added, and was concentrated again under vacuum to give the product (0.42 g) as yellow solid in 100% yield.
Reaction SMILES: [NH2:1][C:2]1[C:11]2=[N:12][N:13]([CH2:30][CH2:31][CH3:32])[C:14]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]3C(=O)C4C(=CC=CC=4)C3=O)=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.O.NN>C(O)C>[NH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]1[N:13]([CH2:30][CH2:31][CH3:32])[N:12]=[C:11]2[C:10]=1[C:9]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:3]=[C:2]2[NH2:1]
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1CCCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: CCCn1nc2c(N)nc3ccccc3c2c1CCCCN
Temperature: 25 °C
Yield: 70 %

Procedure:
A mixture of 2-[4-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butyl]-1H-isoindole-1,3(2H)-dione (7.21 g, 16.9 mmol) and hydrazine hydrate (4.22 g, 84.3 mmol) in ethanol (400 mL) was heated at reflux for 2 hours. The resulting solution was allowed to cool to room temperature, filtered, and concentrated under reduced pressure to yield 3.52 g of 1-(4-aminobutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine as a yellow solid, mp 137-139° C.
Reaction SMILES: [CH:1]([N:3]=[C:4]=[O:5])=[CH2:2].[CH:6]1([OH:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>C(OCC)(=O)C>[CH:1]([NH:3][C:4](=[O:5])[O:12][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[CH2:2]
Reactant: C=CN=C=O
Reactant: OC1CCCCC1
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CCOC(C)=O
Product: C=CNC(=O)OC1CCCCC1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
69 parts of vinyl isocyanate and 89.5 parts of ethyl acetate are initially taken in a reaction vessel and are heated at 40° C. A mixture of 110 parts of cyclohexanol, 89.5 parts of ethyl acetate and 0.02% of dibutyltin dilaurate as the catalyst is added in the course of one hour, after which the mixture is allowed to continue reacting for a further 2 hours at 40° C. A pale yellow solution is obtained, from which, on cooling, the reaction product separates out in the form of crystals. Content of blocked isocyanate groups: 11.7%.