Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:19]=1)[NH:7][C:8](=[O:18])[CH2:9][N:10]=[C:11]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:20]([O:24][CH3:25])(=[O:23])[CH:21]=[CH2:22].C(N(CC)CC)C>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:18]=[C:8]1[NH:7][C:6]2[CH:19]=[C:2](/[CH:22]=[CH:21]/[C:20]([O:24][CH3:25])=[O:23])[CH:3]=[CH:4][C:5]=2[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][CH2:9]1
Reactant: C=CC(=O)OC
Reactant: O=C1CN=C(c2ccccc2)c2ccc(Br)cc2N1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc2c(c1)NC(=O)CN=C2c1ccccc1
Yield: 32.9 %

Procedure:
Title compound 354 (400 mg, 1.28 mmol), methyl acrylate (132 mg, 1.54 mmol), Pd2(dba)3 (16 mg, 0.038 mmol), POT (24 mg, 0.07 mmol) and triethylamine (0.446 mL, 3.2 mmol) were mixed in DMF (15 mL). The mixture was degassed with nitrogen for 5 minutes and the reaction mixture was heated to 100 oC for 2 hours. The DMF was removed and the residue was partitioned between ethyl acetate and water. The 2 layers were split and the aqueous layer was extracted with 2 other portions of ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated. The crude product was purified by flash chromatography (50% to 65% ethyl acetate in hexanes) to afford title compound 355 (135 mg, 33%) as a light yellow solid. 1H NMR (DMSO-d6) δ (ppm): 10.56 (s, 1H), 7.77 (d, J=8.4 Hz, 2H), 7.68 (d, J=16.0 Hz, 1H), 7.58-7.54 (m, 1H), 7.49 (d, J=8.4 Hz, 2H), 7.24 (d, J=6.4 Hz, 2H), 7.16 (td, J=7.5, 1.0 Hz, 1H), 6.70 (d, J=16.2 Hz, 1H), 4.12 (s, 2H), 3.72 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:6]([O:15][CH3:16])=[CH:7][C:8]([OH:14])=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1)([CH3:4])[CH3:3].[Br:17]Br.O>C(Cl)Cl>[Br:17][C:7]1[C:8]([OH:14])=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:6]=1[O:15][CH3:16]
Reactant: COc1cc(O)c(C(C)=O)cc1C(C)(C)C
Reactant: BrBr
Solvent: ClCCl
Solvent: O
Product: COc1c(C(C)(C)C)cc(C(C)=O)c(O)c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
To a solution of 10.7 g (48.1 mmol) of 1-[5-(1,1-dimethylethyl)-2-hydroxy-4-methoxyphenyl]ethanone in 250 ml of methylene chloride was added 8.11 g (50.7 mmol) of bromine. The reaction mixture was stirred at ambient temperature for 2 hours. Water (500 ml) was added. The organic phase was separated, washed with saturated aqueous sodium bicarbonate, dried and evaporated. The residue was filtered through 150 g of silica gel using 10:90 (v/v) ether:hexane as eluent. There was obtained 8.70 g (28.8 mmol, 60%) of 1-[3-bromo-5-(1,1-dimethylethyl)-2-hydroxy-4-methoxyphenyl]ethanone as white crystals after crystallization from hexane; mp 69°-71° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([CH3:16])([CH3:15])[C:10]([O:12]CC)=[O:11].[OH-].[Na+].Cl>O1CCOCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([CH3:16])([CH3:15])[C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)C(C)(C)Cc1ccccc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(Cc1ccccc1Br)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.8 %

Procedure:
A solution of the crude ester (482 mg) in dioxane (2 mL) was combined with aqueous sodium hydroxide (20%, 4 mL) and stirred at room temperature for 2 hrs. The reaction mixture was diluted with ethyl acetate and the aqueous fraction was acidified to pH 2 with conc. hydrochloric acid. After extraction with ethyl acetate, the combined organic fractions were dried over sodium sulfate and concentrated under vacuum to give 121 mg (47% yield for two steps) of 3-(2-bromophenyl)-2,2-dimethylpropanoic acid as a white solid. The crude carboxylic acid was used in the next step without further purification: MS m/z: 255.0 (M−1).
Reaction SMILES: [N:1]1[C:11]2[C:10](=O)[CH2:9][CH2:8][C:7](=[O:13])[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[I:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][NH2:23])=[CH:18][CH:17]=1.[K+].[Br-]>>[I:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][N:23]=[C:10]2[CH2:9][CH2:8][C:7](=[O:13])[NH:6][C:5]3[CH:4]=[CH:3][CH:2]=[N:1][C:11]2=3)=[CH:18][CH:17]=1
Reactant: O=C1CCC(=O)c2ncccc2N1
Reactant: NNc1ccc(I)cc1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: O=C1CCC(=NNc2ccc(I)cc2)c2ncccc2N1

Procedure:
Prepared according to general procedure A from 176 mg (1.0 mmol) 5H-pyrido[3,2-b]azepine-6,9(7H,8H)-dione and 257 mg (1.5 mmol) (4-iodophenyl)hydrazine hydrochloride. Recrystallization from ethanol afforded an orange solid. Yield: 248 mg (63%); m.p. 204-205° C.; IR (KBr): 3211 cm−1 (NH), 2964/2900 cm−1 (CH-aliph.), 1691 cm−1 (C═O); 1H-NMR (DMSO-d6, 400 MHz): δ (ppm)=2.55-2.59 (m, 2H, azepine-CH2, part of AA′XX′-system), 3.01-3.04 (m, 2H, azepine-CH2, part of AA′XX′-system), 7.02-7.06 (m, 2H, arom. H), 7.37-7.44 (m, 2H, arom. H), 7.50-7.54 (m, 2H, arom. H), 8.41 (dd, 1H, 4.5/1.7 Hz, arom. H), 9.51 (s, 1H, NH), 9.82 (s, 1H, NH); C15H13IN4O (392.20).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]3[CH:13]=[CH:14][C:15]([C:17]4[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[N:18]=4)=[CH:16][C:9]=23)=[CH:4][CH:3]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]3[CH:13]=[CH:14][C:15]([C:17]4[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[N:18]=4)=[CH:16][C:9]=23)=[CH:4][CH:3]=1
Reactant: Nc1nccc(-c2ccc3noc(-c4ccc(Cl)cc4)c3c2)n1
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)Nc1nccc(-c2ccc3noc(-c4ccc(Cl)cc4)c3c2)n1
Temperature: 100 °C
Yield: 30 %

Procedure:
To a suspension of 4-[3-(4-chlorophenyl)-benzo[c]isoxazol-5-yl]-pyrimidin-2-ylamine in toluene (1.5 mL) at room temperature, was added acetic anhydride (0.5 mL). The mixture was heated at 100° C. for 3 hours. The reaction mixture was diluted with water (6 mL) and the precipitate filtered then washed with toluene (2×6 mL). Purification was achieved by silica gel chromatography (4:1 ethyl acetate/hexane then 2% methanol/dichloromethane), followed by a 5% aqueous sodium bicarbonate wash (1×50 mL) to give the title compound as a yellow solid (12 mg, 30% yield). 1H NMR (500 MHz, d6-DMSO) δ 10.62 (s, 1H), 8.85 (s, 1H), 8.75 (d, 1H), 8.31 (d, 1H), 8.25 (d, 2H), 8.02 (d, 1H), 7.85 (d, 1H), 7.75 (d, 2H), 2.3 (s, 3H) ppm. LC-MS (ES+) m/e=365.13 (M+H).
Reaction SMILES: [N:1]#[N:2].C(OC([NH:13][C@@H:14]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C@H:15]([OH:31])[CH2:16][C@@:17]1([C:28]([NH2:30])=[O:29])[CH2:21][CH2:20][CH2:19][N:18]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=O)C1C=CC=CC=1>C(O)C.[Pd]>[N:1]#[N:2].[NH2:13][C@@H:14]([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C@H:15]([OH:31])[CH2:16][C@@:17]1([C:28]([NH2:30])=[O:29])[CH2:21][CH2:20][CH2:19][N:18]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NC(=O)[C@]1(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2ccccc2)CCCN1c1ccccc1
Agent: [Pd]
Agent: N#N
Solvent: CCO
Product: NC(=O)[C@]1(C[C@@H](O)[C@@H](N)Cc2ccccc2)CCCN1c1ccccc1
Yield: 94.6 %

Procedure:
A solution of 0.45 g of N2 -[3(S)-(benzyloxyformamido)-2(R)-hydroxy-4-phenylbutyl]-N1 -phenyl-L-prolinamide in 20 ml of ethanol was hydrogenated over 10% palladium-on-carbon for 4 hours to give 0.315 g of N2 -[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N1 -phenyl-L-prolinamide in the form of a white solid: MS: m/e 354 [M+]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([O:13][C:14]2[CH:19]=[C:18](Cl)[N:17]=[C:16]([CH3:21])[N:15]=2)[C:9]([F:12])([F:11])[F:10])=[C:4]([N:22]2[CH:26]=[CH:25][C:24]([CH3:27])=[N:23]2)[CH:3]=1.[CH2:28]1[C:32]2([CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH2:31][C@@H:30]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[N:29]1[C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([O:13][C:14]2[N:15]=[C:16]([CH3:21])[N:17]=[C:18]([N:35]3[CH2:34][CH2:33][C:32]4([CH2:28][N:29]([C:43]([O:45][CH2:46][C:47]5[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=5)=[O:44])[C@H:30]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:31]4)[CH2:37][CH2:36]3)[CH:19]=2)[C:9]([F:12])([F:11])[F:10])=[C:4]([N:22]2[CH:26]=[CH:25][C:24]([CH3:27])=[N:23]2)[CH:3]=1
Reactant: Cc1ccn(-c2cc(Br)ccc2[C@@H](Oc2cc(Cl)nc(C)n2)C(F)(F)F)n1
Reactant: CCOC(=O)[C@@H]1CC2(CCNCC2)CN1C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Br)cc4-n4ccc(C)n4)C(F)(F)F)nc(C)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 90 °C

Procedure:
To a solution of (R)-4-(1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-6-chloro-2-methylpyrimidine (21 g) in dioxane (200 ml) was added (S)-2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (15 g) and Na2CO3 (14 g). The reaction was heated to 90° C. for 48 h, then cooled to RT, filtered, and concentrated in vacuo. Purification of the residue on normal phase column chromatography on silica gel (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as an off-white solid.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:21]=[CH:22][C:23]=3[O:24][CH3:25])[NH:14]C(=O)C(F)(F)F)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O.[OH-].[K+]>CO>[C:1]12([C:11]3[CH:12]=[C:13]([CH:21]=[CH:22][C:23]=3[O:24][CH3:25])[NH2:14])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: COc1ccc(NC(=O)C(F)(F)F)cc1C12CC3CC(CC(C3)C1)C2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(N)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 50 °C
Reaction time: 18 h

Procedure:
11.03 g (31.2 mmol) of 3-(1-adamantyl)4-methoxy -N-(trifluoroacetyl)aniline dissolved in 40 ml of methanol and 160 ml of water are treated with 7.12 g (51.5 mmol) of potassium hydroxide. The reaction medium is heated to 50° C. for 20 hours and then 80° C. for 18 hours. After evaporation to dryness, the residue is taken up with ethyl ether, the insoluble matter is filtered off and the filtrate is dried over magnesiumsulphate and evaporated. The solid is washed in hexane to yield, after drying, 7.44 g (93%) of 3-(1-adamantyl)-4-methoxyaniline, melting point 140°-141° C.
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)=[O:2].C(OC)(OC)[O:15]C>CO>[C:1]([C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)([OH:15])=[O:2]
Reactant: COC(OC)OC
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Solvent: CO
Product: O=C(O)C=Cc1ccc(C(=O)O)cc1
Temperature: 25 °C

Procedure:
A solution of 37.0 g of 4-formylcinnamic acid in 22 ml of trimethyl orthoformate and 600 ml of methanol was heated under reflux for 17 hrs. with stirring. At the end of this time, 100 ml of methanol was added and the reaction mixture was heated under reflux for an additional 5 hrs. and then allowed to cool to room temperature. The precipitate was collected, washed with methanol and dried at 75°-80° overnight to give 7.36 g of 4-carboxycinnamic acid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=O)[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[CH:26]1([CH2:29][NH2:30])[CH2:28][CH2:27]1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:18])([CH3:19])[C:15]([NH:30][CH2:29][CH:26]2[CH2:28][CH2:27]2)=[O:17])[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)O)c2c1N
Reactant: NCC1CC1
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)NCC3CC3)c2c1N

Procedure:
Prepared as in Example 24a from 3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoic acid (Example 47b) and cyclopropylmethanamine as a pale-yellow solid (80%). 1H NMR (400 MHz, DMSO-d6) δ 0.12-0.13 (m, 2H), 0.29-0.31 (m, 2H), 0.90 (m, 1H), 1.27 (s, 6H), 1.33 (t, J=8.0 Hz, 3H), 2.56 (s, 3H), 2.97 (t, J=8.0 Hz, 2H), 4.14 (s, 2H), 4.32 (q, J=8.0 Hz, 2H), 6.88 (d, J=8.0 Hz, 1H), 7.26 (d, J=4.0 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.91 (t, J=4.0 Hz, 1H), 8.11 (s, 2H). MS 400 (MH+).
Reaction SMILES: [C:1](Cl)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:19]([O:21][C:22](=[O:41])[CH2:23][N:24]([C:31](=[O:40])[C:32]1[CH:37]=[C:36]([NH2:38])[CH:35]=[C:34]([NH2:39])[CH:33]=1)[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:20]>>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][N:24]([CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:41])[C:31](=[O:40])[C:32]1[CH:37]=[C:36]([NH:38][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:35]=[C:34]([NH:39][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:33]=1)[CH3:30]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCOC(=O)CN(CC(=O)OCC)C(=O)c1cc(N)cc(N)c1
Product: CCCCCCCCCCCCCCCC(=O)Nc1cc(NC(=O)CCCCCCCCCCCCCCC)cc(C(=O)N(CC(=O)OCC)CC(=O)OCC)c1

Procedure:
The reaction of palmitoyl chloride with N-(3,5-diaminobenzoyl)-N-(2-ethoxy-2-oxoethyl)glycine ethyl ester as in Example 54 gave N-(2-ethoxy-2-oxoethyl)-N-[3,5-bis(1-oxohexadecylamino)benzoyl]glycine ethyl ester as an oil after chromatography on silica gel using 35% ethyl acetate-hexane.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[N:6]1([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:38]=[C:24]4[CH:25]=[CH:26][CH:27]=[C:28]([C:29]5[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=5)[C:32](O)=[O:33])[N:23]4[N:22]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1.[C:39]([NH:47][NH2:48])(=O)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(=O)([O-])O.[Na+]>>[C:40]1([C:39]2[O:33][C:32]([C:31]3[CH:30]=[C:29]([C:28]4[N:23]5[N:22]=[C:21]([NH:20][C:17]6[CH:16]=[CH:15][C:14]([O:13][CH2:12][CH2:11][N:6]7[CH2:10][CH2:9][CH2:8][CH2:7]7)=[CH:19][CH:18]=6)[N:38]=[C:24]5[CH:25]=[CH:26][CH:27]=4)[CH:37]=[CH:36][CH:35]=3)=[N:48][N:47]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(O)c1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Reactant: NNC(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc(-c2nnc(-c3cccc(-c4cccc5nc(Nc6ccc(OCCN7CCCC7)cc6)nn45)c3)o2)cc1
Temperature: 0 °C

Procedure:
Phosphorus oxychloride (5 ml) was added dropwise to 3-{2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-benzoic acid (50 mg, 0.113 mmol) and benzhydrazide (15 mg, 0.113 mmol). The solution was heated to reflux overnight. Once cooled the reaction mixture was added gradually to ice/water. The solution was basified with saturated aqueous sodium hydrogencarbonate and subsequently extracted twice with dichloromethane. The organics were combined, washed several times with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The product was purified by preparatory HPLC. LCMS RT: 2.80 min, MI: 544, Method: 2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:16]=[CH:15][C:14]3[C:9](=[C:10]([C:17]([O:19]C)=[O:18])[CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=1.[Li+].[OH-]>C1COCC1.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:16]=[CH:15][C:14]3[C:9](=[C:10]([C:17]([OH:19])=[O:18])[CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=1
Reactant: COC(=O)c1cccc2cnc(-c3cccnc3)nc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc2cnc(-c3cccnc3)nc12
Temperature: 50 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
A mixture of methyl 2-(pyridin-3-yl)quinazoline-8-carboxylate (3.5 g, 13.2 mmol) and LiOH (0.48 g, 19.8 mmol) in 1:1 THF/H2O (50 mL) was stirred at 50° C. for 2 hours. The solvent was removed in vacuo and water (20 mL) was added. Aqueous solution was adjusted to pH=3 with 1N aqueous hydrochloride solution. The mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried (Na2SO4), concentrated in vacuo, and purified by silica gel column chromatography (2.5% MeOH in CH2Cl2) to obtain 2-(pyridin-3-yl)quinazoline-8-carboxylic acid (3.0 g, 90% yield).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6]Br)=[CH:2]1.[CH3:8][C:9]1[CH:10]=[C:11]([CH:24]=[C:25]([CH3:28])[C:26]=1[OH:27])[C:12]([NH:14][CH2:15][C:16]1([N:21]([CH3:23])[CH3:22])[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:13]>>[CH3:28][C:25]1[CH:24]=[C:11]([CH:10]=[C:9]([CH3:8])[C:26]=1[O:27][CH2:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[C:12]([NH:14][CH2:15][C:16]1([N:21]([CH3:23])[CH3:22])[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:13]
Reactant: Cc1cc(C(=O)NCC2(N(C)C)CCCC2)cc(C)c1O
Reactant: BrCc1ccsc1
Product: Cc1cc(C(=O)NCC2(N(C)C)CCCC2)cc(C)c1OCc1ccsc1

Procedure:
Synthesised from 3-thienylmethyl bromide and 3,5-dimethyl-4-hydroxy-N-[(1-dimethylaminocyclopentyl)methyl]benzamide following the procedure as described in Example 10 (b). The crude product was purified by SPE chromatography. 1H NMR (CDCl3) δ: 1.41 (m, 2H), 1.65 (m, 4H), 1.83 (m, 2H), 2.27 (s, 6H), 2.31 (s, 6H), 3.44 (d, 2H, J˜2 Hz), 4.85 (s, 2H), 6.88 (s, 1H), 7.16 (m, 1H), 7.26 (m, 1H), 7.34 (m, 2H), 7.45 (s, 2H). LCMS m/z 387.0 (MH+; 98%).
Reaction SMILES: [C:1]1([C:7]2([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:11][C:10]3[CH:12]=[CH:13][C:14]([C:16](ON4C5C=CC=CC=5N=N4)=[O:17])=[CH:15][C:9]=3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>C(#N)C>[C:1]1([C:7]2([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[O:11][C:10]3[CH:12]=[CH:13][C:14]([C:16]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[O:17])=[CH:15][C:9]=3[O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1COCCN1
Reactant: O=C(On1nnc2ccccc21)c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Solvent: CC#N
Product: O=C(c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2)N1CCOCC1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a mixture of 1H-benzotriazol-1-yl 2,2-diphenyl-1,3-benzodioxole-5-carboxylate (300 mg, 0.689 mmol) in acetonitrile ( 2.0 mL) was added morpholine (100 mg, 1.15 mmol, 1.67 eq.) at 0° C. After 10 min, the cooling bath was removed and the reaction was stirred 3 h at 20° C. The reaction was partitioned between water and dichloromethane. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine and water and then dried in vacuo, affording the title compound (267 mg, quant.) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22](O)=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH2:58][C:59]1[CH:60]=[N:61][N:62]([CH3:79])[C:63]=1[N:64]1[CH2:70][CH2:69][CH:68]([F:71])[CH:67]([NH:72][C:73](=[O:78])[C:74]([F:77])([F:76])[F:75])[CH2:66][CH2:65]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([F:20])[C:14]=1[C:12]1[S:13][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[C:10]([C:22](=[O:23])[NH:58][C:59]2[CH:60]=[N:61][N:62]([CH3:79])[C:63]=2[N:64]2[CH2:65][CH2:66][CH:67]([NH:72][C:73](=[O:78])[C:74]([F:75])([F:76])[F:77])[CH:68]([F:71])[CH2:69][CH2:70]2)[N:11]=1
Reactant: Cn1ncc(N)c1N1CCC(F)C(NC(=O)C(F)(F)F)CC1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCC(F)C(NC(=O)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
To a solution of 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (784 mg, 2.2 mmol) in DCM (40 mL) was added PyBOP (1.46 g, 2.8 mmol) and the mixture stirred at room temperature for 30 min. A solution of N-(1-(4-Amino-1-methyl-1H-pyrazol-5-yl)-5-fluoroazepan-4-yl)-2,2,2-trifluoroacetamide (647 mg, 2.0 mmol) and DIPEA (0.59 mL, 3.4 mmol) in DCM (40 mL) was then added and the mixture was stirred at room temperature for 16 hr. The mixture was diluted with DCM (60 mL) and washed with water (30 mL). The organic layer was separated, passed through a phase separation cartridge and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave tert-butyl 2-(2,6-difluorophenyl)-4-(5-(4-fluoro-5-(2,2,2-trifluoroacetamido)azepan-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as an off-white solid (1.32 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=[O:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22][CH3:23])=[O:21].O>CC(C)=O>[OH:1][C:2]1[C:3]([C:9](=[O:11])[CH3:10])=[C:4]([O:8][CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CBr
Reactant: CC(=O)c1c(O)cccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)COc1cccc(O)c1C(C)=O
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a mixture of 2′,6′-dihydroxyacetophenone (6 g) and potassium carbonate (5.72 g) in acetone (20 mL) was added methyl bromoacetate (3.73 mL), and the mixture was stirred at room temperature for 5 days. To the reaction mixture was added water, and the precipitated crystals were collected by filtration. The crystals were washed with water and dried under reduced pressure to give the title compound (7.89 g).
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]([CH3:15])([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([I:14])[CH:9]=1)[CH2:5][OH:6].[Cl:16][CH2:17][C:18](Cl)=[O:19]>C(Cl)Cl>[Cl:16][CH2:17][C:18]([NH:3][C:4]([CH2:5][OH:6])([CH3:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([I:14])[CH:9]=1)=[O:19]
Reactant: CC(N)(CO)Cc1cccc(I)c1
Reactant: O=C(Cl)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(CO)(Cc1cccc(I)c1)NC(=O)CCl
Temperature: 35 °C

Procedure:
NaOH 1M aq. soln. (10 mL) followed by NaOH 32% (270 μL) were added to a 0° C. solution of rac-2-amino-3-(3-iodo-phenyl)-2-methyl-propan-1-ol H-6 (850 mg, 2.92 mmol) in DCM (10 mL). After 10 min a solution of chloroacetyl chloride (261 mL, 3.21 mmol) in DCM (10 mL) was added dropwise to the reaction mixture maintaining the temperature below 5° C. The resulting suspension was heated to 35° C. for 30 min after which complete formation of product was observed by LCMS. The layers were separated and the aqueous layer extracted with DCM (2×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated in vacuo to give the title compound that was used further without purification. LC-MS A: tR=0.79 min; [M(35Cl)+H]+=367.91.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].[N+:19]([O-])([OH:21])=[O:20]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([N+:19]([O-:21])=[O:20])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccccc12
Reactant: O=[N+]([O-])O
Product: CCOC(=O)c1cc2c(cn1)[nH]c1ccc([N+](=O)[O-])cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
1 g of β-carbolin-3-carboxylic acid ethyl ester is slowly introduced at room temperature into 20 ml of concentrated nitric acid (65%). After addition is complete, the solution is heated to 70°-75° C., whereupon a clear solution forms. After about 30 minutes, the solution becomes turbid. After a total stirring time of 1.5 hours at 70°-75° C., the solution is allowed to cool and the sediment is poured onto 100 g of ice. After filtering with suction, recrystallization from pyridine is carried out. 6-nitro-β-carbolin-3-carboxylic acid ethyl ester of melting point 320°-325° C. is isolated in 55% yield.