Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1NC=CN=1)(C1NC=CN=1)=O.[S:13]([N:17]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH2:18][C:19](O)=[O:20])(=[O:16])(=[O:15])[NH2:14]>C1COCC1>[CH3:32][O:31][C:29](=[O:30])[CH2:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[N:17]1[CH2:18][C:19](=[O:20])[NH:14][S:13]1(=[O:16])=[O:15]
Reactant: COC(=O)Cc1ccccc1N(CC(=O)O)S(N)(=O)=O
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: COC(=O)Cc1ccccc1N1CC(=O)NS1(=O)=O
Reaction time: 65 h

Procedure:
Carbonyl diimidazole (60 mg, 0.37 mmol) is added as solid to a solution of the title E compound, N-sulfamoyl-N-[2-(methoxycarbonylmethyl)-phenyl] glycine (112 mg, 0.37 mmol) in THF (5 mL). After 65 h, the solvent is removed by evaporation. The residue is taken up in EtOAc and washed with 1N aqueous HCl followed by brine. The organic solution is dried over anhydrous MgSO4, filtered and concentrated. This residue is then evaporated from diethyl ether to yield [2-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-acetic acid methyl ester as a white foam: [M−1]−=283.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][N:10]([CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][C:19]3=[O:23])[C:11]2=[O:14])=[CH:6][C:5]=1[N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])[CH2:26][CH2:25]1)([O-])=O.C(O)(=O)C>C(O)C.[Fe]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][N:10]([CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][C:19]3=[O:23])[C:11]2=[O:14])=[CH:6][C:5]=1[N:24]1[CH2:25][CH2:26][N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])[CH2:28][CH2:29]1
Reactant: Cc1ccccc1N1CCN(c2cc3c(cc2[N+](=O)[O-])C(=O)N(CCCN2CCCC2=O)CC3)CC1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccccc1N1CCN(c2cc3c(cc2N)C(=O)N(CCCN2CCCC2=O)CC3)CC1
Temperature: 75 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
In a 25 ml round-bottom flask equipped with a magnetic stir bar, the iron powder (204.00 mg, 3.65 mmol) was suspended in clean, dry ethanol (8.00 ml, 137.01 mmol) at room temperature under an inert nitrogen atmosphere. To this was added the 7-nitro-2-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-6-(4-o-tolyl-piperazin-1-yl)-3,4-dihydro-2H-isoquinolin-1-one 10c (71.80 mg, 0.15 mmol) dissolved in 1 ml of ethanol followed by the addition of acetic acid (2.00 ml, 34.94 mmol). The reaction mixture was warmed to 75° C. and was allowed to stir overnight. The reaction was cooled to room temperature and the mixture was filtered through Celite, washing with methanol. The collected solution was then concentrated under reduced pressure. The resultant ruby red oil was then diluted with 50 ml of ethyl acetate and the solution was neutralized with 30 ml of saturated NaHCO3 (aq) solution. The layers were then separated and the product was extracted from the aqueous using ethyl acetate (3×30 ml). The organic phases were combined, washed with brine (1×50 ml) and dried over Na2SO4. The solution was then decanted and the solvent was removed under reduced pressure. The product was then purified from the ruby red concentrate using silica gel column chromatography, eluting a gradient of 100% dichloromethane to 10% MeOH in dichloromethane. The product, 7-amino-2-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-6-(4-o-tolyl-piperazin-1-yl)-3,4-dihydro-2H-isoquinolin-1-one 10d (48.10 mg, 0.10 mmol), was isolated as an off-white solid and was carried forward without further purification. LCMS (m/e)=462 (M+H).
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=O.C1(=O)OC(=O)C=C1.N[C@H](C(O)=O)CCC(O)=O.NCC(O)=O.[NH:31]1[CH2:38][CH2:37]C[C@H:32]1[C:33](O)=[O:34].S(O)(=O)(C1C=CC(N)=CC=1)=O.NC1C=CC=C(C)C=1S(O)(=O)=O>>[C:4]1(=[O:6])[O:8][C:1](=[O:7])[CH:2]=[CH:3]1.[NH:31]1[CH2:32][CH2:33][O:34][CH2:37][CH2:38]1
Reactant: O=C(O)/C=C\C(=O)O
Reactant: O=C(O)[C@@H]1CCCN1
Agent: Cc1cccc(N)c1S(=O)(=O)O
Agent: NCC(=O)O
Agent: N[C@@H](CCC(=O)O)C(=O)O
Product: C1COCCN1

Procedure:
Examples of monomers which can provide structure units represented by Formula (A) include half amides of maleic acid, prepared by the reaction of maleic anhydride with glutamic acid, glycine or proline, or by the reaction of maleic anhydride with sulfanilic acid, amino toluene sulfonic acid, naphthylaminemonosulfonic acid or naphthylaminedisulfonic acid, and the half amides obtained by the reaction of maleic anhydride with morpholine or amino alkanoles.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:30]1[CH:31]=[CH:32][C:33]([NH:36][C:37]2[CH:38]=[N:39][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:41][CH:42]=2)=[N:34][CH:35]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C:30]3[CH:35]=[N:34][C:33]([NH:36][C:37]4[CH:38]=[N:39][C:40]([C:43]([F:45])([F:46])[F:44])=[CH:41][CH:42]=4)=[CH:32][CH:31]=3)=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: FC(F)(F)c1ccc(Nc2ccc(Br)cn2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)nc3)cc2)CC1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-piperidine-1 carboxylic acid tert-butyl ester (1.56 g, 4.1 mmol) and (5-Bromo-pyridin-2-yl)-(6-trifluoromethyl-pyridin-3-yl)-amine (1.28 g, 4.0 mmol) were dissolved in DME (8 mL) in a pressure vessel, and to the solution was added PdCl2dppf (100 mg, 0.12 mmol) and Na2CO3 (2.0M, 4.0 mL, 8.1 mmol). The mixture was sparged with nitrogen for 10 minutes, then the vessel was sealed and stirred at 80° C. for 18 hours. The mixture was partitioned between EtOAc and saturated aqueous NH4Cl, washed with brine, dried with magnesium sulfate, filtered, and concentrated via rotary evaporation. The crude material was purified via column chromatography on silica gel, eluting with a gradient of EtOAc/hexanes (10-50%) to obtain the target compound as a solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25 (br. s., 2H) 1.42 (s, 9H) 1.52 (qd, J=12.63, 4.55 Hz, 2H) 1.77 (m, 2H) 2.66-2.76 (m, 1H) 4.09 (m, 2H) 7.03 (d, J=8.59 Hz, 1H) 7.34 (d, J=8.34 Hz, 2H) 7.60 (d, J=8.08 Hz, 2H) 7.79 (d, J=8.84 Hz, 1H) 7.99 (dd, J=8.72, 2.65 Hz, 1H) 8.56 (d, J=2.53 Hz, 1H) 8.91 (d, J=2.53 Hz, 1H) 9.87 (s, 1H); MS (M+H)+499.3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([C:14]2[NH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22](B4OC(C)(C)C(C)(C)O4)=[CH:21][CH:20]=3)=[CH:17][N:18]=2)[CH:12]2[CH2:34][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:35]([O:39][C:40]([N:42]1[CH:47]([C:48]2[NH:49][C:50]([C:53]3[CH:58]=[CH:57][C:56](Br)=[CH:55][CH:54]=3)=[CH:51][N:52]=2)[CH:46]2[CH2:60][CH:43]1[CH2:44][CH2:45]2)=[O:41])([CH3:38])([CH3:37])[CH3:36].C(=O)(O)[O-].[Na+]>O.CCOC(C)=O.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>[C:35]([O:39][C:40]([N:42]1[CH:47]([C:48]2[NH:49][C:50]([C:53]3[CH:58]=[CH:57][C:56]([C:22]4[CH:21]=[CH:20][C:19]([C:16]5[NH:15][C:14]([CH:13]6[CH:12]7[CH2:34][CH:9]([CH2:10][CH2:11]7)[N:8]6[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N:18][CH:17]=5)=[CH:24][CH:23]=4)=[CH:55][CH:54]=3)=[CH:51][N:52]=2)[CH:46]2[CH2:60][CH:43]1[CH2:44][CH2:45]2)=[O:41])([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(Br)cc2)[nH]1
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
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: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5C6CCC(C6)N5C(=O)OC(C)(C)C)[nH]4)cc3)cc2)[nH]1
Temperature: 80 °C
Yield: 6.1 %

Procedure:
To the solution of 3-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (560 mg, 1.22 mmol) and 3-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (535 mg, 1.28 mmol) in 1,2-dimethoxyether (11 ml) and water (3.5 ml) was added sodium bicarbonate (343 mg, 4 mmol), followed by Pd(PPh3)4 (55 mg). The mixture was heated at 80° C. for 7 hours. The mixture was diluted with EtOAc, and was washed with water and brine, and was dried with sodium sulfate. Concentration and purification by flash column chromatography (DCM/MeOH) gave 4,4′-bis-[2-(2-tert-butoxycarbonyl-2-aza-bicyclo[2.2.1]hept-3-yl)-3H-imidazol-4-yl]-biphenyl (50 mg). m/z: 677.2 (M+H)+.
Reaction SMILES: O[C:2]([C:13]1[C:21]2[O:20][CH2:19][CH2:18][C:17]=2[C:16]([CH3:22])=[C:15]([NH:23]C(=O)OC(C)(C)C)[C:14]=1[CH3:31])([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:12])[CH3:11])=[CH:6][CH:5]=1)[CH3:3].Cl.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH:10]([C:7]1[CH:8]=[CH:9][C:4]([C:2]([C:13]2[C:21]3[O:20][CH2:19][CH2:18][C:17]=3[C:16]([CH3:22])=[C:15]([NH2:23])[C:14]=2[CH3:31])=[CH2:3])=[CH:5][CH:6]=1)([CH3:11])[CH3:12]
Reactant: Cc1c2c(c(C(C)(O)c3ccc(C(C)C)cc3)c(C)c1NC(=O)OC(C)(C)C)OCC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C=C(c1ccc(C(C)C)cc1)c1c(C)c(N)c(C)c2c1OCC2
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
To a solution of tert-butyl (7-(1-hydroxy-1-(4-isopropylphenyl)ethyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 223 (306 mg, 0.72 mmol) in ethyl acetate (5 mL) was added dropwise a solution of 4 N hydrochloric acid-ethyl acetate (5 mL) under ice-cooling, and the reaction solution was stirred for 30 minutes. The reaction solution was added to a saturated sodium hydrogen carbonate solution, which was extracted with ethyl acetate. The combined organic layer was washed with a saturated sodium hydrogen carbonate solution and a saturated brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to obtain 221 mg (yield: quantitative) of the title compound. Oily matter.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:18][CH3:19])=[N:15][C:16](I)=[C:10]2[CH:9]1[CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([F:28])[C:25]([Cl:29])=[C:24]([F:30])[CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].II>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:18][CH3:19])=[N:15][CH:16]=[C:10]2[CH:9]1[CH2:20][CH2:21][C:22]1[CH:23]=[C:24]([F:30])[C:25]([Cl:29])=[C:26]([F:28])[CH:27]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1nc(I)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1cc(F)c(Cl)c(F)c1
Agent: II
Solvent: C1CCOC1
Product: CCc1ncc2n1CCN(C(=O)OC(C)(C)C)C2CCc1cc(F)c(Cl)c(F)c1
Temperature: 25 °C

Procedure:
A cooled (−30° C.) solution of 8-[2-(4-chloro-3,5-difluoro-phenyl)-ethyl]-3-ethyl-1-iodo-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (1.790 g; 3.244 mmol) in anhydrous THF (90 ml) was treated dropwise with a solution of 1-Methylmagnesium bromide in THF (14.6 ml; 14.6 mmol; 4.5 eq.) until complete removal of the iodine substituent. The mixture was then quenched with water (10 ml), diluted with ether (100 ml), and was allowed to warm-up to rt. This solution was washed with brine (2×150 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. The crude was purified by FC (DCM/MeOH=15/1) to give the pure product 8-[2-(4-chloro-3,5-difluoro-phenyl)-ethyl]-3-ethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a yellow solid (1.150 g; 83%). LC-MS: tR=0.95 min.; [M+H]+=426.01 g/mol.
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH:8]=[CH:9][CH2:10][C:11]1(C(OC)=O)[C@H:15](/[CH:16]=[CH:17]/[CH:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][C@H:13](C(OC)=O)[C:12]1=[O:29])([O:3]C)=[O:2].[OH-].[Na+].Cl>O.CO.[Cl-].[Na+]>[OH:24][CH:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:17]=[CH:16][C@H:15]1[CH2:14][CH2:13][C:12](=[O:29])[C@H:11]1[CH2:10][CH:9]=[CH:8][CH2:7][CH2:6][CH2:5][C:1]([OH:3])=[O:2]
Reactant: CCCCCC(O)/C=C/[C@@H]1C[C@H](C(=O)OC)C(=O)C1(CC=CCCCC(=O)OC)C(=O)OC
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCCC(O)C=C[C@H]1CCC(=O)[C@H]1CC=CCCCC(=O)O

Procedure:
The cyclopentanonetriester of formula IV, dimethyl cis,trans-3-(6-carbomethoxy-2-hexenyl)-4-(3-hydroxy-1-octenyl)-2-oxo-1,3-cyclopentanedicarboxylate (11.2 g), described in Example 82, is heated to reflux for 1 hr. in a solution of sodium hydroxide (13.4 g) in 80 ml of water and 110 ml of methanol. The mixture is cooled, adjusted to pH 5 with 2 N HCl, diluted with saturated sodium chloride solution and extracted with ether. The ether extract is dried (Na2SO4) and concentrated to yield the title compound as a mixture of C15 epimers is separated by silica gel chromatography using hexane: chloroform: acetic acid: 10:20:1. The less polar epimer is designated epimer A, nmr (CDCl3) δ 1.05 (t, J=5, 3H), 4.20 (1H), 5.33-5.78 (1H), 6.38 (2H). The more polar epimer is designated epimer B, nmr (CDCl3) δ 1.05 (t, J=5, 3H) 4.18 (1H), 5.30-5.77 (1H), 6.74 (2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:13][CH2:12][C:5]2=[C:6]([C:9](O)=[O:10])[S:7][CH:8]=[C:4]2[CH2:3]1.Cl.[CH3:16][NH:17][O:18][CH3:19].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CS(C)=O>[CH3:19][O:18][N:17]([CH3:16])[C:9]([C:6]1[S:7][CH:8]=[C:4]2[CH2:3][C:2]([CH3:14])([CH3:1])[CH2:13][CH2:12][C:5]=12)=[O:10]
Reactant: CC1(C)CCc2c(csc2C(=O)O)C1
Reactant: CNOC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1scc2c1CCC(C)(C)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
To a solution of 5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (20 g, 95 mmol) in DMSO (150 mL) is added N,O-dimethylhydroxylamine hydrochloride (12.06 g, 124 mmol) and DIPEA (65 mL, 380 mmol), followed by TBTU (33.59 g, 105 mmol, dissolved in DMF (70 mL)). The reaction mixture is stirred at rt for 2 h before it is poured into water/ice and extracted twice with diethyl ether (2×100 mL). The organic extracts are washed with sat. aq. NaHCO3 solution, 10% aq. citric acid solution and brine, dried over Na2SO4, filtered, evaporated and dried to give 5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid methoxy-methyl-amide (23 g) as a brown oil; LC-MS: tR=1.01 min, [M+1]=254.14.
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:26]2[N:27]=[C:28]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[S:29][CH:30]=2)\[C:23](O)=[O:24])[CH2:19][CH2:18]1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:72][C@@H:73]1[C:76](=[O:77])[NH:75][C@@H:74]1[CH2:78][N:79]1[CH:83]=[C:82]([CH2:84][NH:85][C:86](=[O:92])[O:87][C:88]([CH3:91])([CH3:90])[CH3:89])[N:81]=[N:80]1>C(Cl)Cl.C(Cl)Cl.CN(C=O)C>[C:88]([O:87][C:86]([NH:85][CH2:84][C:82]1[N:81]=[N:80][N:79]([CH2:78][C@@H:74]2[C@H:73]([NH:72][C:23](=[O:24])/[C:22](=[N:21]\[O:20][C:17]3([C:15]([O:14][CH:1]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)=[O:16])[CH2:19][CH2:18]3)/[C:26]3[N:27]=[C:28]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:33])[S:29][CH:30]=3)[C:76](=[O:77])[NH:75]2)[CH:83]=1)=[O:92])([CH3:91])([CH3:89])[CH3:90]
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)O)cs1
Reactant: CC(C)(C)OC(=O)NCc1cn(C[C@H]2NC(=O)[C@H]2N)nn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCc1cn(C[C@H]2NC(=O)[C@H]2NC(=O)/C(=N\OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)c2csc(NC(=O)OC(C)(C)C)n2)nn1
Temperature: 25 °C
Reaction time: 1.3 h
Yield: 80.7 %

Procedure:
To a slurry of (Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (1.32 g, 2.46 mmol) in DCM (12 mL) at 0° C. was added DIPEA (1.08 mL, 6.16 mmol) followed by HATU (0.984 g, 2.59 mmol). The reaction mixture was warmed to room temperature and tert-butyl ((1-(((2R,3S)-3-amino-4-oxoazetidin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)carbamate (0.73 g, 2.5 mmol) was added as a solution in DCM:DMF (1.7:1, 9.6 mL). After stirring for 1.3 h, a color change from yellow to dark purple was observed, whereupon it was diluted with DCM, washed with water, brine, dried over sodium sulfate and concentrated in vacuo. The crude residue was purified by silica gel chromatography (EtOAc-Heptane, 0-90%), affording the title compound (1.62 g, 81%) as a purple foam. LCMS: R=1.05 min, m/z=816.5 (M+1) Method 2m_acidic.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][CH2:16][O:17][C:18]2[CH:27]=[C:26]3[C:21]([C:22]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]5[O:35][CH2:36][O:37][C:30]=45)=[N:23][CH:24]=[N:25]3)=[CH:20][C:19]=2[O:38][CH3:39])([OH:14])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[OH:14][C:11]1([CH2:15][CH2:16][O:17][C:18]2[CH:27]=[C:26]3[C:21]([C:22]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]5[O:35][CH2:36][O:37][C:30]=45)=[N:23][CH:24]=[N:25]3)=[CH:20][C:19]=2[O:38][CH3:39])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: COc1cc2c(Nc3cccc4c3OCO4)ncnc2cc1OCCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(Nc3cccc4c3OCO4)ncnc2cc1OCCC1(O)CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.5 %

Procedure:
A mixture of 7-[2-(N-tert-butoxycarbonyl-4-hydroxypiperidin-4-yl)ethoxy]-6-methoxy-4-(2,3-methylenedioxyanilino)quinazoline (0.067 g), trifluoro acetic acid (0.5 ml) and methylene chloride (3 ml) was stirred at ambient temperature for 1 hour. The solvent was evaporated and the residue was partitioned between methylene chloride and a saturated aqueous sodium bicarbonate solution. The organic phase was washed with brine, dried over magnesium sulphate and evaporated. There was thus obtained the title compound (0.015 g); NMR Spectrum: (DMSOd6 and CF3CO2D) 1.75 (m, 4H), 2.05 (t, 2H), 3.1 (m, 4H), 4.0 (s, 3H), 4.35 (t, 2H), 6.1 (s, 2H), 6.95 (m, 3H), 7.4 (s, 1H), 8.1 (s, 1H), 8.85 (s, 1H); Mass Spectrum: M+H+ 439.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[N:17]2[CH:21]=[CH:20][CH:19]=[N:18]2)[C:5]([Cl:22])=[CH:4][N:3]=1.[N:23]1([CH:29]2[CH2:35][CH2:34][C:33]3[CH:36]=[C:37]([NH2:40])[CH:38]=[CH:39][C:32]=3[CH2:31][CH2:30]2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[Cl:22][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[N:17]2[CH:21]=[CH:20][CH:19]=[N:18]2)=[N:7][C:2]([NH:40][C:37]2[CH:38]=[CH:39][C:32]3[CH2:31][CH2:30][CH:29]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[CH2:35][CH2:34][C:33]=3[CH:36]=2)=[N:3][CH:4]=1
Reactant: Nc1ccc2c(c1)CCC(N1CCOCC1)CC2
Reactant: COc1ccc(Nc2nc(Cl)ncc2Cl)c(-n2cccn2)c1
Product: COc1ccc(Nc2nc(Nc3ccc4c(c3)CCC(N3CCOCC3)CC4)ncc2Cl)c(-n2cccn2)c1

Procedure:
(2,5-Dichloro-pyrimidin-4-yl)-(4-methoxy-2-pyrazol-1-yl-phenyl)-amine, of Example 611c, was reacted with 7-Morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclo hepten-2-ylamine, in a similar manner as Example 601b, to yield desired product 5-Chloro-N*4*-(4-methoxy-2-pyrazol-1-yl-phenyl)-N*2*-(7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl)-pyrimidine-2,4-diamine as a lyophylate (25%); 1H NMR (400 MHz, DMSO-d6) δ 9.77 (s, 1H), 9.64 (bs, 1H), 9.33 (s, 1H), 8.75 (s, 1H), 8.11 (s, 1H), 8.00 (d, J=8.97 Hz, 1H), 7.83 (s, 1H), 7.41 (s, 1H), 7.25 (m, 2H), 7.1-6.95 (m, 2H), 6.54 (s, 1H), 4.00 (m, 2H), 3.88 (s, 3H), 3.8-3.7 (m, 2H), 3.6-3.5 (m, 1H), 3.4-3.1 (m, 4H), 2.8-2.6 (m, 4H), 2.29 (m, 2H), 1.42 (m, 2H); MS (m/e) 546.37 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:3]=1.[H-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:8])[CH2:15][S:12](=[O:14])(=[O:13])[C:4]=2[CH:3]=1
Reactant: COC(=O)c1ccc(Br)cc1S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CS(=O)(=O)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 102.2 %

Procedure:
A solution of methyl 4-bromo-2-(methylsulfonyl)benzoate (Intermediate 239; 4.00 g; 13.6 mmol) in anhydrous THF (60 ml) was treated with NaH (595 mg; 13.6 mmol) and stirred at RT for 1.5 h. The reaction was quenched with water. AcOEt and a 1N solution of HCl in water were added and the phases were separated. The organic phase was washed with brine, dried on MgSO4, filtered and concentrated to give the title compound as a yellow solid (3.63 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH2:9])=[CH:3][CH:2]=1.[C:10]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].[BH4-].[Na+].O>CO>[C:10]([C:14]1[CH:15]=[CH:16][C:17]([CH2:18][NH:9][CH2:8][CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:20][CH:21]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: NCCc1ccncc1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)c1ccc(CNCCc2ccncc2)cc1
Temperature: 25 °C
Yield: 91.3 %

Procedure:
1.22 g (10 mmol) of 2-(4-pyridyl)-ethyl amine and 1.62 g (10 mmol) of 4-tert-butyl benzaldehyde were dissolved in 20 ml methanol and stirred at rt over night. 555 mg (15 mmol) of sodium borohydride were added in portions under cooling. After complete addition the reaction mixture was stirred for 1 h at rt. Water was added and methanol was evaporated. The reaction mixture was extracted twice with diethyl ether. The combined organic layers were washed with water, dried over sodium sulfate, filtered and the solvent was evaporated to yield 2.45 g (91%) product as a light yellow oil. 1H NMR (DMSO-d6, 300 MHz): δ 8.49 (d, 2H), 7.34 (d, 2H) 7.21 (d, 2H), 7.13 (d, 2H), 3.77 (s, 2H), 2.93 (t, 2H), 2.81 (t, 2H), 1.31 (s, 9H).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=[O:2].[F:11][C:12]([Si](C)(C)C)([F:14])[F:13].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O1CCCC1>[F:11][C:12]([F:14])([F:13])[CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)[OH:2]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: N#Cc1ccc(C(O)C(F)(F)F)cc1
Reaction time: 1 h
Yield: 89.7 %

Procedure:
4-Formylbenzonitrile (200 mg, 1.53 mmol) was dissolved in tetrahydrofuran (4.0 mL). To this, (trifluoromethyl)trimethylsilane (271 μL, 1.83 mmol) and tetrabutylammonium fluoride (a 1.0 mol/L solution in tetrahydrofuran, 153 μL, 0.153 mmol) were added under a nitrogen atmosphere at room temperature and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, a 1 mol/L aqueous hydrogen chloride solution (3.0 mL) was added and the mixture was further stirred for 0.5 minute. Then, the reaction mixture was neutralized with a saturated sodium bicarbonate solution, and extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was subjected to slurry purification using hexane, to give 4-(2,2,2-trifluoro-1-hydroxyethyl)benzonitrile (Compound CL) (276 mg, yield: 90%).