Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCCC1[N:7]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[N:8]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:30]1[C:31]([N:50]2[CH2:53][CH:52]([OH:54])[CH2:51]2)=[N:32][CH:33]=[C:34]([CH:49]=1)[C:35]([NH:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][C:45]([F:48])([F:47])[F:46])=[CH:40][CH:39]=1)=[O:36].C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl.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>[OH:54][CH:52]1[CH2:53][N:50]([C:31]2[C:30]([C:11]3[NH:7][N:8]=[CH:9][CH:10]=3)=[CH:49][C:34]([C:35]([NH:37][C:38]3[CH:39]=[CH:40][C:41]([O:44][C:45]([F:48])([F:47])[F:46])=[CH:42][CH:43]=3)=[O:36])=[CH:33][N:32]=2)[CH2:51]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC(O)C2)c(Br)c1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
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: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC(O)C2)c(-c2ccn[nH]2)c1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (209 mg, 0.752 mmol), K3PO4 (368 mg, 1.735 mmol) and Pd(PPh3)4 (33.4 mg, 0.029 mmol) were added to a mixture of 5-bromo-6-(3-hydroxyazetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 37.1, 250 mg, 0.578 mmol) in toluene (2.5 mL) in a vial, which was sealed, purged with argon and the RM was stirred at 110° C. for 3 h. The cooled mixture was treated with brine (25 mL) and extracted with EtOAc. The combined extracts were washed with brine (25 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The residue (100 mg, 0.199 mmol) was dissolved in DCM (0.5 mL), treated with TFA (0.3 mL, 3.89 mmol) and stirred at RT for 8 h. Aq. Na2CO3 (0.5 mL) was added and the solvent was evaporated off under reduced pressure to give a crude product which was purified by SFC (Column NH2, from 21% to 26% over 6 min) and lyophilized in water/MeCN to give the title product. UPLC-MS (Condition 3) tR=0.86 min, m/z=420.2 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 3.53-3.59 (m, 2H) 3.91-4.00 (m, 2H) 4.35-4.42 (m, 1H) 6.43 (d, J=1.88 Hz, 1H) 7.35 (d, J=8.66 Hz, 2H) 7.79 (br. s, 1H) 7.86 (d, J=9.03 Hz, 2H) 8.09 (d, J=2.07 Hz, 1H) 8.71 (d, J=2.07 Hz, 1H) 10.26 (s, 1H).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:8]([N:13]=1)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH3:4].NC1C=NC=CC=1N>>[CH2:1]([C:5]1[NH:13][C:12]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ncccc2[nH]1
Agent: Nc1ccncc1N
Product: CCCCc1nc2cnccc2[nH]1

Procedure:
The title compound was prepared according to the procedure described for the preparation of 2-butylimidazo[4,5-b]pyridine starting with 3,4-diaminopyridine. Yield: 3.69 g (92%) thick oil: 1H NMR (300 MHz, CDCl3) δ8.93 (s, 1H), 8.35 (d, 1H, J=6 Hz), 7.48 (d, 1H, J=6 Hz), 3.01 (t, 2H, J=7 Hz), 1.92-1.82 (m, 2H), 1.48-1.30 (m, 2H), 0.86 (t, 3H, J=7 Hz).
Reaction SMILES: O[C:2]1([CH2:26][O:27][CH2:28][CH3:29])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.CCN(S(F)(F)[F:36])CC>ClCCl>[F:36][C:2]1([CH2:26][O:27][CH2:28][CH3:29])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1
Reactant: CCOCC1(O)CCN(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)CC1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CCOCC1(F)CCN(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)CC1
Yield: 65 %

Procedure:
The title compound was prepared by reacting (S)—N-{3-[4-(4-hydroxy-4-ethoxymethyl piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.37 mmol) with DAST (4.10 mmol) in dichloromethane (10 ml) at a temperature 0° C. for one hour and by purifying the compound by silica gel column chromatography in 65% yield.
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-])=O)[C:5]([F:8])([F:7])[F:6]>CO.[Ni]>[CH3:1][CH:2]([CH3:18])[CH2:3][CH:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15])[C:5]([F:6])([F:7])[F:8]
Reactant: CC(C)C=C(c1ccccc1[N+](=O)[O-])C(F)(F)F
Agent: [Ni]
Solvent: CO
Product: CC(C)CC(c1ccccc1N)C(F)(F)F
Reaction time: 10 h

Procedure:
A solution of 2.98 g (12.9 mmol) 1-(3-methyl-1-trifluoromethyl-but-1-enyl)-2-nitrobenzene in 30 ml methanol is hydrogenated over Raney-Nickel (ethanol) at 100° C. and 150 bar for 10 hours. Then the catalyst is filtered off and the solvent removed in a water-jet vacuum. The obtained crude product is purified by column chromatography over silica gel (eluant: hexane/methylene chloride=1:2). Yield: 1.9 g 2-(3-methyl-1-trifluoromethyl-butyl)phenylamine in the form of a brown oil (1H-NMR).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:13][CH2:14][CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])([O-])=O.O.Cl>CCO>[CH2:19]([N:16]([CH2:17][CH3:18])[CH2:15][CH2:14][NH:13][C:5]1[C:4]([NH2:1])=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[CH:7][CH:6]=1)[CH3:20]
Reactant: CCN(CC)CCNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCN(CC)CCNc1ccc([N+](=O)[O-])cc1N
Temperature: 65 °C

Procedure:
N′-(2,4-Dinitro-phenyl)-N,N-diethyl-ethane-1,2-diamine 3a (0.63 g, 2.322 mmol) was dissolved in anhydrous EtOH (9 mL) in a 2 neck 100 mL argon purged flask. The reaction vessel was fitted with a condenser and dropping funnel and heated in an oil bath to 65° C. H2O (7.5 mL), EtOH (15 mL) and aqueous (NH4)2S (50 wt %, 1.064 g, 7.807 mmol) were charged to the dropping funnel and added to the hot reaction mixture dropwise over 30 minutes. The reaction was heated at 65-70° C. for 2 hours then cooled to room temperature overnight. Mixture was acidified by the addition of aqueous 1M HCl to adjust pH to 0-1. The reaction mixture was filtered to remove any insoluble material and the filtrate was concentrated under reduced pressure to remove EtOH. The resulting aqueous solution was basified by the addition of aqueous 2M ammonium hydroxide solution to adjust pH to 9-10. The aqueous solution was diluted with dichloromethane and transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with dichloromethane and the combined organic layers were washed with H2O, brine, and dried over magnesium sulphate, filtered and concentrated to afford a dark red oil. The product was purified using silica gel dry column chromatography with a solvent system of (5% 2M NH3 in methanol/95% dichloromethane) to afford an orange oil/solid 4a N1-(2-Diethylamino-ethyl)-4-nitro-benzene-1,2-diamine. Yield: 0.476 grams (84.5%). 1H NMR (DMSO) δ 0.96 (t, 6H, J=7.1), 2.52 (m, 4H), 2.62 (t, 2H, J=6.8), 3.24 (m, 2H), 5.09 (br s, 2H), 5.82 (br s, 1H), 6.49 (d, 1H, J=8.9), 7.42 (d, 1H, J=2.6), 7.53 (dd, 1H, J=8.9, 2.6); MS (ESI): 253 (MH+, 100%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:29]3[C:28]4[CH2:27][CH2:26][N:25]([C:30](=[O:36])[CH:31]=[CH:32][CH2:33][CH2:34][OH:35])[CH2:24][C:23]=4[S:22][C:21]=3[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C(N(CC)CC)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:29]3[C:28]4[CH2:27][CH2:26][N:25]([C:30](=[O:36])[CH:31]=[CH:32][CH2:33][CH2:34][O:35][S:45]([CH3:44])(=[O:47])=[O:46])[CH2:24][C:23]=4[S:22][C:21]=3[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(C=CCCO)N1CCc2c(sc3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCC=CC(=O)N1CCc2c(sc3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
In a 250 ml rb flask were placed 1-[4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenyl amino]-5,8-dihydro-6H-9-thia-1,3,7-triaza-fluoren-7-yl}-5-hydroxy-pent-2-en-1-one (1.00 g, 1.91 mmol) in THF (80 ml) and to the solution was added triethylamine (0.58 g, 5.74 mmol) (0.80 ml) followed by methanesulfonyl chloride (0.54 g, 4.79 mmol) at 0° C. The reaction mixture was stirred at room temperature overnight. THF was evaporated and to the residue was added water and small amount of methyl alcohol, sonicated. The precipitated off-white solid was filtered, washed with methyl alcohol and dried to provide 0.63 g of off-white solid. (55%) 1H-NMR (DMSO-d6) δ 8.601-8.585 (m, 1H), 8.394 (s, 1H), 8.196 (s, 1H), 7.906-7.864 (m, 1H), 7.769 (s, 1H), 7.584-7.564 (d, 1H), 7.523-7.501 (d, 1H), 7.388-7.357 (m, 1H), 7.239-7.216 (d, 1H), 6.765-6.703 (m, 2H), 5.280 (s, 2H), 4.957 (s, 1H), 4.843 (s, 1H), 4.366-4.337 (m, 2H), 3.940-3.860 (m, 2H), 3.255-3.189 (m, 6H), 2.655-2.626 (m, 2H). MS m/e 600.0 (M+H), RT=2.78 min
Reaction SMILES: [NH4+].[OH-].[NH2:3][C:4]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][C:7]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH:19]=2)=[O:9])=[C:6](Cl)[CH:5]=1.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>O1CCOCC1>[NH2:3][C:4]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][C:7]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH:19]=2)=[O:9])=[C:6]([N:30]2[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]2)[CH:5]=1
Reactant: Nc1cc(Cl)c(C(=O)Nc2ccc3scnc3c2)cc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CN1CCN(c2cc(N)c([N+](=O)[O-])cc2C(=O)Nc2ccc3scnc3c2)CC1
Temperature: 25 °C

Procedure:
A solution of the amide from above (2 mmol) in dioxane (4 mL) was reacted with aqueous NH4OH using the conditions described in Example 115. After the formation of 4-amino-N-benzothiazol-5-yl-2-chloro-5-nitrobenzamide was complete, the reaction mixture was charged with N-methylpiperazine (12 mmol). The contents were heated at reflux for 10 h, and the reaction mixture was cooled to RT. The contents were poured onto ice cold water with vigorous stirring. The solid formed was collected by filtration, washed with water, and dried in vacuo to provide the product, 4-amino-N-benzothiazol-5-yl-2-(4-methyl-piperazin-1-yl)-5-nitrobenzamide as a yellow solid.
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[Cl:11].[F:13][C:14]1[CH:27]=[CH:26][C:17]([O:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH:23]=[CH:22][O:21]2)=[CH:16][CH:15]=1>C(OCC)C.O=P(Cl)(Cl)Cl>[F:13][C:14]1[CH:15]=[CH:16][C:17]([O:18][CH2:19][C@@H:20]2[O:21][C@@H:22]([O:12][CH:3]([C:4]3[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=3[Cl:11])[CH2:2][Br:1])[CH2:23][CH2:24][CH2:25]2)=[CH:26][CH:27]=1
Reactant: OC(CBr)c1ccc(Cl)cc1Cl
Reactant: Fc1ccc(OCC2CCC=CO2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: Fc1ccc(OC[C@H]2CCC[C@H](OC(CBr)c3ccc(Cl)cc3Cl)O2)cc1

Procedure:
389 mg of α-bromomethyl-2,4-dichlorobenzyl alcohol and 300 mg of 2-(4-fluorophenoxymethyl)-3,4-dihydro-2H-pyran, prepared as described above, were dissolved in 10 ml of diethyl ether. A catalytic amount (2 drops) of phosphorus oxytrichloride was added to the resulting solution and the mixture allowed to react at room temperature for 4 days, after which it was treated and the product purified essentially as described in Example 34(a), to give 214 mg of the isomer of lesser polarity of trans-6-(4-fluorophenoxymethyl)-2-[2-bromo-1-(2,4-dichlorophenyl)ethoxy]tetrahydropyran, 211 mg of the isomer of greater polarity and 143 mg of a mixture of these isomers.
Reaction SMILES: [C:1]([NH2:16])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]CC.N[C:18](C)(C(O)C)[CH:19]([OH:21])[CH3:20]>>[CH3:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([NH:16][C:19]([OH:21])([CH3:20])[CH3:18])=[O:15]
Reactant: CC(O)C(C)(N)C(C)O
Reactant: CCCCCCCCCCCCCC(N)=O
Product: CCCCCCCCCCCC(=O)NC(C)(C)O

Procedure:
myristic acid amide of 3-amino-3-methyl-2,4-pentanediol.
Reaction SMILES: [Na].Cl[C:3]1[CH:8]=[C:7]([C:9]([C:11]2[CH:20]=[C:19]([CH3:21])[C:14]3[NH:15][C:16](=[O:18])[O:17][C:13]=3[CH:12]=2)=[O:10])[CH:6]=[C:5]([Cl:22])[N:4]=1.[C:23](=[O:26])([O-])O.[Na+]>C1COCC1>[CH2:23]([O:26][C:3]1[CH:8]=[C:7]([C:9]([C:11]2[CH:20]=[C:19]([CH3:21])[C:14]3[NH:15][C:16](=[O:18])[O:17][C:13]=3[CH:12]=2)=[O:10])[CH:6]=[C:5]([Cl:22])[N:4]=1)[C:11]1[CH:20]=[CH:19][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cc(C(=O)c2cc(Cl)nc(Cl)c2)cc2oc(=O)[nH]c12
Reactant: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)c2cc(Cl)nc(OCc3ccccc3)c2)cc2oc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.85 mL (3.85 mmol) sodium benzylate solution (1M in benzylalcohol) were added to 1.24 g (3.85 mmol) 6-(2,6-dichloro-pyridine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one in 50 mL THF and stirred overnight at RT. The reaction mixture was combined with saturated sodium hydrogen carbonate solution and extracted with EtOAc. The combined organic phases were dried and evaporated down i. vac.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]([OH:8])=[O:7].[CH3:9]OC(OC)(C)C.[ClH:16]>CO>[ClH:16].[CH3:9][O:7][C:6]([CH2:5][S:4][CH2:3][CH2:2][NH2:1])=[O:8]
Reactant: NCCSCC(=O)O
Reactant: COC(C)(C)OC
Agent: Cl
Solvent: CO
Product: COC(=O)CSCCN
Reaction time: 12 h

Procedure:
13.5 g of S-(β-aminoethyl)mercaptoacetic acid and 10.8 g of 2,2-dimethoxy propane are added, successively, to a solution of 7.3 g of gaseous hydrochloric acid in 20 cc of methanol. The solution is permitted to stand for 12 hours at ambient temperature. The flakes formed (17.5 g) are filtered and washed with ethyl acetate. Fusion point=100° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]2[N:14]=[CH:15][NH:16][CH:17]=2)=[C:11]([CH3:18])[O:10][N:9]=1.Cl[C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]2[N:14]=[CH:15][N:16]([C:20]3[N:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH:17]=2)=[C:11]([CH3:18])[O:10][N:9]=1
Reactant: Cc1onc(-c2ccccc2F)c1-c1c[nH]cn1
Reactant: Clc1ncccn1
Product: Cc1onc(-c2ccccc2F)c1-c1cn(-c2ncccn2)cn1
Yield: 65 %

Procedure:
As described for Example 36, 3-(2-fluoro-phenyl)-4-(1H-imidazol-4-yl)-5-methyl-isoxazole (100 mg, 0.41 mmol) using 2-chloropyrimidine instead of 4-fluoroacetophenone was converted to the title compound (86 mg, 65%) which was obtained as an off-white solid. MS: m/e=322.4 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[N:5]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@H:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[NH:9][C@@H:8]([CH3:20])[CH2:7]1)[CH3:2].N1C=CC=CC=1.Cl[C:36]([O:38][CH3:39])=[O:37].[OH-].[K+]>ClCCl.O>[CH3:39][O:38][C:36]([N:9]1[C:10]2[C:15](=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)[C@H:6]([N:5]([CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:4]([O:3][CH2:1][CH3:2])=[O:28])[CH2:7][C@@H:8]1[CH3:20])=[O:37]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)N(Cc1ccccc1)[C@@H]1C[C@H](C)Nc2cc(OC)c(OC)cc21
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)N(Cc1ccccc1)[C@@H]1C[C@H](C)N(C(=O)OC)c2cc(OC)c(OC)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.8 %

Procedure:
A solution of cis-benzyl-(6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic acid ethyl ester (Example 66) (111 mg, 0.29 mmol) in anhydrous dichloromethane (2 mL), was treated sequentially with anhydrous pyridine (1 mL), and methyl chloroformate (38 μL, 0.49 mmol). After stirring at room temperature overnight, water (10 mL) and an aqueous 10% KOH solution (10 mL) were added, and the mixture was extracted with ethyl acetate (3×10 mL). The combined organic phases were then washed with 1N HCl (2×10 mL), and then a saturated sodium bicarbonate solution (10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give 112 mg crude product. Purification by silica gel chromatography using 0-50% ethyl acetate/hexanes as eluent afforded the desired final product (12.6 mg, 10%): MS m/z 443 (M+ +1), 460 (M++ 18); 1H NMR (CDCl3) δ 7.02 (C8, s, 1H), 6.42 (C5, s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH2:13])[CH:7]=1.C[O:16][C:17](=O)[CH:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:31])=[CH:26][CH:25]=1)[C:19](=O)[CH2:20][CH3:21].O1CCOCC1>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:7]=1[C:17](=[O:16])[C:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([N:32]3[CH2:33][CH2:34][CH2:35][CH2:36]3)=[O:31])=[CH:26][CH:25]=1)=[C:19]([CH2:20][CH3:21])[NH:13]2
Reactant: COC(=O)COc1ccc(F)c(N)c1
Reactant: CCC(=O)C(Cc1ccc(C(=O)N2CCCC2)cc1)C(=O)OC
Solvent: C1COCCO1
Solvent: O
Product: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(C(=O)N2CCCC2)cc1
Temperature: 120 °C

Procedure:
A mixture of (3-amino-4-fluorophenoxy)acetic acid methyl ester (0.39 g), 3-oxo-2-[4-(pyrrolidine-1-carbonyl)benzyl]pentanoic acid methyl ester (1.0 g), polyphosphoric acid (2 g) and dioxane (20 mL) was heated at 120° C. for 18 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (9:1 by volume) to afford title compound, 0.25 g.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3]1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH:34]=[C:35]([C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1)[CH3:36]>CN(C=O)C.[Cu]I>[CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[N:6](/[CH:34]=[C:35](/[C:37]3[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=3)\[CH3:36])[C:5]=2[CH2:4][CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)CC3
Reactant: CC(=CBr)c1cccnc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CCN(C)CC2)c1cccnc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (200 mg, 0.934 mmol) was dissolved in DMF (6 mL), CuI (17.7 mg, 0.09 mmol), L-proline (21 mg, 0.18 mmol), K3PO4 (397 mg, 1.86 mmol) was added and stirred for 10 min. at RT. 3-(1-Bromoprop-1-en-2-yl)pyridine (222 mg, 1.12 mmol) was added dropwise and the reaction mixture was heated at 90° C. for 18 h. DMF was evaporated under reduced pressure, 10 mL water was added and the mixture extracted with ethyl acetate. The organic layer was dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by column chromatography to 180 mg of the desired compound. 1HNMR (CD3OD, TFA salt) δ (ppm): 9.10 (s, 1H), 8.80 (s, 1H), 8.70 (d, 1H), 8.0 (t, 1H), 7.36 (s, 2H), 7.08 (m, 2H), 3.80 (m, 2H), 3.40 (m, 4H), 3.20 (m, 2H), 3.05 (s, 3H), 2.42 (s, 3H), 1.05 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][CH:11]=O.C1(P(=[CH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10]/[CH:11]=[CH:32]/[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(CC=O)c(Cl)c1
Solvent: Cc1ccccc1
Product: COc1ccc(C/C=C/C(=O)OC(C)(C)C)c(Cl)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
To a solution of (2-chloro-4-methoxyphenyl)acetaldehyde (1.22 g) in toluene (30.0 mL) was added tert-butyl (triphenylphosphoranylidene)acetate (2.75 g), followed by stirring at 80° C. overnight. The reaction mixture was air-cooled to room temperature, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl (2E)-4-(2-chloro-4-methoxyphenyl)but-2-enoate (1.67 g).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N: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[CH2:29][CH2:28][S:27][CH2:26][CH2:25]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:16]=[CH:17][C:18]([C:19]([N:24]2[CH2:29][CH2:28][S:27][CH2:26][CH2:25]2)=[O:21])=[CH:22][CH:23]=1
Reactant: Cc1onc(-c2ccncn2)c1COc1ccc(C(=O)O)cn1
Reactant: C1CSCCN1
Product: Cc1onc(-c2ccncn2)c1COc1ccc(C(=O)N2CCSCC2)cn1
Yield: 70 %

Procedure:
As described for example 313b, 6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid (53 mg, 0.17 mmol) was converted, using thiomorpholine instead of isopropylamine, to the title compound (47 mg, 70%) which was obtained as a colourless gum. MS: m/e=398.1 [M+H]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].Cl[S:27]([C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33]([OH:35])=[O:34])(=[O:29])=[O:28]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:27]([C:30]4[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=4)[C:33]([OH:35])=[O:34])(=[O:29])=[O:28])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4cccc(C(=O)O)c4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 3-(chlorosulfonyl)benzoic acid as starting compounds. Instead of using the work-up procedure described for GP1, the following procedure is used. After the reaction has been quenched with 1 M aqueous sodium carbonate solution, the phases are separated and the aqueous phase is slightly acidified with aqueous hydrochloric acid.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([NH2:24])[CH3:23])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[OH:27][C@H:28]([C@@H:32]([OH:36])[C:33]([OH:35])=[O:34])[C:29]([OH:31])=[O:30]>>[OH:27][C@H:28]([C@@H:32]([OH:36])[C:33]([OH:35])=[O:34])[C:29]([OH:31])=[O:30].[F:26][C:2]([F:1])([F:25])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C@@H:22]([NH2:24])[CH3:23])=[CH:17][CH:16]=3)=[N:11]2)=[CH:8][CH:9]=1
Reactant: CC(N)Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Product: C[C@H](N)Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1

Procedure:
The title compound was prepared as described in Example 99 using 1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-2-amine (CB58) and (2R,3R)-2,3-dihydroxysuccinic acid and isolated as a white solid (0.70 g, 49%): mp 187-191° C.; 1H NMR 1H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 8.08 (dd, J=8.6, 3.6 Hz, 4H), 7.63 (dt, J=8.1, 1.0 Hz, 2H), 7.49 7.32 (m, 2H), 3.81 (s, 2H), 3.47 (dt, J=8.5, 6.2 Hz, 1H), 3.01 (dd, J=13.4, 5.5 Hz, 1H), 2.74 (dd, J=13.4, 8.7 Hz, 1H), 1.13 (d, J=6.4 Hz, 3H) (OH and NH2 not observed).