Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[N:14]1[N:15]([C:19]2[N:24]=[C:23]([NH2:25])[CH:22]=[CH:21][CH:20]=2)[N:16]=[CH:17][CH:18]=1>C(#N)C>[N:14]1[N:15]([C:19]2[N:24]=[C:23]([NH:25][C:2]3[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=3[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:22]=[CH:21][CH:20]=2)[N:16]=[CH:17][CH:18]=1
Reactant: Nc1cccc(-n2nccn2)n1
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Solvent: CC#N
Product: CCOC(=O)c1nnc(Cl)cc1Nc1cccc(-n2nccn2)n1
Temperature: 140 °C
Yield: 35.4 %

Procedure:
To a solution of ethyl 4,6-dichloropyridazine-3-carboxylate (154 mg, 695 μmol) in acetonitrile was added 6-(2H-1,2,3-triazol-2-yl)pyridin-2-amine (112 mg, 695 μmol) and heated to 140° C. for 72 h. The mixture was cooled and precipitated by addition of acetone. The mixture was filtered and the solid collected was washed with methanol and ether then dried to give ethyl 4-(6-(2H-1,2,3-triazol-2-yl)pyridin-2-ylamino)-6-chloropyridazine-3-carboxylate (85 mg, 246 μmol, 35%) as an off white solid. 1H NMR (400 MHz, DMSO-d) δ ppm 10.60 (s, 1H), 9.50 (s, 1H), 8.26 (s, 2H), 8.08 (t, J=8.2 Hz, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.35 (d, J=8.2 Hz, 1H), 4.48 (q, J=7.3 Hz, 2H), 1.40 (t, J=7.3 Hz, 3H); MS (EI/CI) m/z: 346.0 [M+H].
Reaction SMILES: C(N(CC1C=CC=CC=1)C1([CH2:14][NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23](C)[CH:24]=3)[N:19]=[C:18]([N:27]3[CH2:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[S:30](=[O:39])(=[O:38])[CH2:29][CH2:28]3)[CH:17]=2)CCOC1)C1C=CC=CC=1.N[C@H]1[C@H:52]([OH:53])[CH2:51][N:50](C(OCC2C=CC=CC=2)=O)[CH2:49]1>>[O:38]=[S:30]1(=[O:39])[C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[CH2:33][N:27]([C:18]2[CH:17]=[C:16]([NH:15][C@@H:14]3[CH2:49][NH:50][CH2:51][C@H:52]3[OH:53])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH2:28][CH2:29]1
Reactant: N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(N(Cc4ccccc4)Cc4ccccc4)CCOC3)c2c1
Product: O=S1(=O)CCN(c2cc(N[C@@H]3CNC[C@H]3O)c3ccccc3n2)Cc2ccccc21

Procedure:
The title compound was prepared in analogy to Example 28-1 in Scheme 8 by using 4-(4-bromoquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1) and benzyl trans-3-amino-4-hydroxypyrrolidine-1-carboxylate. MS obsd. (ESI+) [(M+H)+] 439, 1H NMR (400 MHz, CD3OD) δ ppm 8.29-8.22 (d, J=7.6 Hz, 1 H), 8.12-8.08 (d, J=1.2 Hz, 1 H), 7.98-7.92 (d, J=7.6 Hz, 1 H), 7.88-7.82 (d, J=0.8 Hz, 1 H), 7.80-7.71 (m, 2 H), 7.62-7.58 (t, J=1.2 Hz, 1 H), 7.50-7.42 (t, J=6.8 Hz, 1 H), 6.20 (s, 1 H), 5.45-5.30 (q, J=7.2 Hz, 2 H), 4.62-4.52 (m, 2 H), 4.52-4.45 (m, 2 H), 4.05-3.95 (q, J=4.4 Hz, 1 H), 3.80-3.75 (t, J=2.8 Hz, 2 H), 3.75-3.68 (m, 1 H), 3.62-3.55 (dd, J=2.8, 12.8 Hz, 1 H), 3.48-3.40 (d, J=7.6 Hz, 1 H).
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:21])[C:7](=[O:20])[C:8]([CH3:19])([CH3:18])[CH2:9][N:10]2[CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[O:32][CH3:33].O.Cl>C(O)C>[CH:13]1([N:10]2[CH2:9][C:8]([CH3:19])([CH3:18])[C:7](=[O:20])[N:6]([CH3:21])[C:5]3[C:11]2=[N:12][C:2]([NH:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=2[O:32][CH3:33])=[N:3][CH:4]=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Yield: 47.8 %

Procedure:
To a solution of 10-chloro-2-cyclopentyl-4,4,6-trimethyl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 126; 616 mg, 2.0 mmol) and 4-amino-3-methoxybenzoic acid (378 mg, 2.2 mmol) in ethanol (5 mL) was added water (15 mL) and conc hydrochloric acid (0.335 mL). The mixture was heated under reflux for 36 hours. The reaction was cooled and a brown solid precipitated. This was filtered, dried and triturated under cold acetonitrile and then dried in vacuo to give the product as a pale brown solid (420 mg), 48%)
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].[C:6]1(=[O:11])[CH2:10][CH2:9][CH:8]=[CH:7]1.[NH4+].[Cl-]>O>[CH2:2]([C:6]1([OH:11])[CH2:10][CH2:9][CH2:8][CH2:7]1)[CH2:3][CH2:4][CH3:5]
Reactant: O=C1C=CCC1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: CCCCC1(O)CCCC1
Reaction time: 0.03 h
Yield: 97.7 %

Procedure:
nBuLi (1.00 mL; 1.50 mmol; 1.00 equiv) was added to a solution of cyclopentenone (84 mg; 1.0 mmol) in the presence of LaCl3.2LiCl (0.33 M; 3.03 mL, 1.00 mmol, 1.00 equiv) at 0° C. After 2 min, sat. aq. NH4Cl (2 mL) and water (2 mL) was added and the aqueous layer was extracted with ether (4×10 mL). The combined extracts were dried (Na2SO4). Careful evaporation under reduced pressure afforded analytically clean 1-butylcyclopentanol (8) as colorless oil (139 mg, 98%). The analytical data were found to be in accordance with the literature data.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=[CH:4][N:3]=1.O.[NH2:16][NH2:17]>>[CH3:14][N:11]1[CH2:12][CH2:13][N:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([NH:16][NH2:17])[CH:7]=2)[CH2:9][CH2:10]1
Reactant: NN
Reactant: CN1CCN(c2cc(Cl)ncn2)CC1
Solvent: O
Product: CN1CCN(c2cc(NN)ncn2)CC1

Procedure:
4-Chloro-6-(4-methyl-piperazin-1-yl)-pyrimidine, (200 mg, 0.94 mmol), and hydrazine hydrate, (200 μl, 4 mmol), were heated to 180° for 6 min in a Personal Chemistry Microwave. The solvent was evaporated affording [6-(4-Methyl-piperazin-1-yl)-pyrimidin-4-yl]-hydrazine as yellow brown crystals which were used without further purification.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[C:8]([O:16][CH2:17][CH2:18][O:19][C:20](ON1C(=O)CCC1=O)=[O:21])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[OH:4][CH2:3][C@@H:2]([NH:1][C:20]([O:19][CH2:18][CH2:17][O:16][C:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:15])=[O:21])[C:5]([OH:7])=[O:6]
Reactant: O=C(OCCOC(=O)c1ccccc1)ON1C(=O)CCC1=O
Reactant: N[C@H](CO)C(=O)O
Product: O=C(N[C@H](CO)C(=O)O)OCCOC(=O)c1ccccc1
Yield: 69 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, D-serine (252 mg, 2.4 mmol) and (2,5-dioxoazolidinyloxycarbonyloxy)ethyl benzoate (614 mg, 2.0 mmol) were reacted to provide 410 mg (69% yield) the title compound (28) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (CDCl3, 400 MHz): δ=8.00 (m, 2H), 7.55 (m, 1H), 7.40 (m, 2H), 7.01 (m, 1H), 6.59 (br s, 1H), 6.21 (m, 1H), 4.39 (m, 1H), 4.02 (m, 1H), 3.86 (m, 1H), 1.60 (2d, 3H). MS (ESI) m/z 298.10 (M+H)+; 315.11 (M+NH4)+, 320.07 (M+Na)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[OH:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1)[CH:22]=O.OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[OH:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[C:21]([C:22]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: COc1cc(C=O)cc(OCCO)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1cc(OCCO)cc(-c2nc3cc(OC)cc(OC)c3c(=O)[nH]2)c1
Temperature: 117.5 °C

Procedure:
To a solution of 2-amino-4,6-dimethoxy-benzamide (7.50 g, 38.2 mmol) and 3-(2-hydroxy-ethoxy)-5-methoxy-benzaldehyde (7.50 g, 38.2 mmol) in N,N-dimethylacetamide (30 mL) were added NaHSO3 (58.5 wt %, 4.37 g, 42.0 mmol) and p-TSA (0.72 g, 3.8 mmol). The reaction mixture was heated to 115-120° C. for 16 hours, and then cooled to room temperature. N,N-dimethylacetamide was removed under reduced pressure, the residue was diluted with water (50 mL), and the solid was filtered, collected and mixed with ether (50 mL), filtered, and dried under vacuum, to give 2-[3-(2-hydroxy-ethoxy)-5-methoxy-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one as a white solid. Yield: 10 g (70%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](=[O:50])[CH2:33][NH:34][C:35]([CH2:37][NH:38][CH2:39][C:40]([NH:42][CH:43]([CH:47]([CH3:49])[CH3:48])[C:44](O)=[O:45])=[O:41])=[O:36])=[CH:28][CH:27]=1.CN1CCOCC1>CN(C=O)C>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](=[O:50])[CH2:33][NH:34][C:35](=[O:36])[CH2:37][N:38]2[CH2:39][C:40](=[O:41])[NH:42][CH:43]([CH:47]([CH3:49])[CH3:48])[C:44]2=[O:45])=[CH:28][CH:27]=1
Reactant: CC(C)C(NC(=O)CNCC(=O)NCC(=O)c1ccc(Br)cc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)C1NC(=O)CN(CC(=O)NCC(=O)c2ccc(Br)cc2)C1=O
Yield: 58.5 %

Procedure:
HATU (3.70 g, 9.7 mmol) was added to a solution of 2-[2-({[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-methyl}-amino)-acetylamino]-3-methyl-butyric acid (2.78 g, 6.5 mmol), and 4-methylmorpholine (3.57 mL, 32.5 mmol) in DMF (100 mL). After 30 min the solvent was removed under reduced pressure. The residue was taken up in dichloromethane (150 mL) and washed with water (50 mL), aqueous hydrogen chloride (0.5 N, 2×50 mL), saturated sodium bicarbonate (50 mL) and dried over sodium sulfate. The mixture was filtered and the solvent was removed under reduced pressure. The residue was subjected to flash chromatography with eluent of (10% methanol in ethyl acetate) and hexane. The product-containing fractions were combined and the solvent was removed under reduced pressure to yield N-[2-(4-bromo-phenyl)-2-oxo-ethyl]-2-(3-isopropyl-2,5-dioxo-piperazin-1-yl)-acetamide (1.56 g, 3.8 mmol, 60%). C17H20BrN3O4 calculated 409.1 observed [M+1]+ 410.1; rt=2.00 min.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:16][O:15][C@H:14]([CH2:17][O:18][C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@H:13]1[CH2:12][O:11][NH:10]2>C(O)(=O)C.[Zn]>[NH2:10][C@@:9]1([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[CH2:16][O:15][C@H:14]([CH2:17][O:18][C:19]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C@H:13]1[CH2:12][OH:11]
Reactant: Fc1cccc([C@]23CO[C@H](COC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@H]2CON3)c1F
Agent: [Zn]
Solvent: CC(=O)O
Product: N[C@@]1(c2cccc(F)c2F)CO[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H]1CO
Temperature: 25 °C
Reaction time: 11.5 h

Procedure:
Zinc powder (10.1 g) was added to a suspension of (3aR,4S,6aS)-6a-(2,3-Difluorophenyl)-4-((trityloxy)methyl)tetrahydrofuro[3,4-c]isoxazole, obtained in Preparation Example 4-(22), (7.76 g) in acetic acid (75 ml) at RT. The mixture was stirred for 11.5 h at RT then the solid was removed by filtration through celite. The filtrate was concentrated in vacuo, then the residue was dissolved with EtOAc. 28% ammonia aqueous solution was added slowly, and the organic layer was separated, washed with brine, and dried over MgSO4. The solid was removed by filtration and the filtrate was concentrated under reduced pressure. Zinc powder (10.1 g) was added to the suspension of the residue in acetic acid (75 ml) at RT. After the mixture was stirred for 11.5 h at same temperature, the solid was removed by filtration through celite. The filtrate was concentrated in vacuo, then the residue was dissolved with EtOAc. 28% ammonia aqueous solution was added slowly, and the organic layer was separated, washed with brine, and dried over MgSO4. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The crude mixture was purified by amino silica gel column chromatography (gradient from 50% to 100% EtOAc in heptane) to afford the titled compound (7.04 g) as a white solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 2.60-2.64 (m, 1H), 3.27 (d, J=4.8 Hz, 2H), 3.61-3.65 (m, 1H), 3.89-3.94 (m, 2H), 4.30 (d, J=9.2 Hz, 1H), 4.33-4.37 (m, 1H), 7.04-7.16 (m, 2H), 7.20-7.30 (m, 10H), 7.40-7.43 (m, 6H)
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=3[C:28](=[O:29])[C:20]=2[C:19]2[C:14](=[CH:15][C:16]([NH:30][C:31](=[O:36])[C:32]([O:34][CH3:35])=[O:33])=[CH:17][CH:18]=2)[C:13]1=[O:37])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=3[C:28](=[O:29])[C:20]=2[C:19]2[C:14](=[CH:15][C:16]([NH:30][C:31](=[O:36])[C:32]([O:34][CH3:35])=[O:33])=[CH:17][CH:18]=2)[C:13]1=[O:37]
Reactant: COC(=O)C(=O)Nc1ccc2c3c(n(CCCNC(=O)OC(C)(C)C)c(=O)c2c1)-c1ccccc1C3=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COC(=O)C(=O)Nc1ccc2c3c(n(CCCN)c(=O)c2c1)-c1ccccc1C3=O

Procedure:
Compound 17 (0.070 g, 0.130 mmol) was treated with trifluoroacetic acid (0.5 mL) in chloroform (5 mL) for 2 h at room temperature. The solvent was removed on a rotary evaporator and the residue was then basified with 2 N NH3 in methanol to get the free amine, which was purified by silica gel column chromatography, eluting with chloroform-methanol, 8.7:1.3, to yield the product 22 (0.035 g, 65%) as a brown solid: mp 185-186° C. IR (KBr) 3014, 1692, 1581, 1570, 1533, 1307, 1198, 722, 455 cm−1; 1H NMR (CD3OD, 300 MHz) δ 8.55 (s, 1H), 8.23 (d, J=3.2 Hz, 1H), 7.71 (d, J=3.5 Hz, 1H), 7.54 (m, 1H), 7.36 (m, 3H), 4.52 (m, 2H), 3.91 (s, 3H), 3.05 (m, 2H), 2.28 (m, 2H); 13C NMR (CD3OD, 125 MHz) δ 191.6, 169.9, 166.8, 164.9, 155.4, 138.8, 137.9, 135.7, 134.9, 132.2, 129.6, 127.2, 125.0, 124.8, 124.1, 123.9, 118.6, 109.6, 52.9, 42.5, 38.2, 28.6; ESIMS m/z (relative intensity) 420 (MH+, 100); HRESIMS calcd for C23H21N3O5 420.1559 (MH+). found 420.1554 (MH+); HPLC purity: 98.2% (1% TFA in MeOH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([Br:32])[C:22]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Br:31])[CH:26]=1)[C:5]([NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1)(=[O:10])=[O:9])=[O:6].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([S:8]([NH:7][C:5](=[O:6])[C:4]2[CH:3]=[C:2]([Br:1])[C:22]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Br:31])[CH:26]=3)=[C:21]([Br:32])[CH:20]=2)(=[O:9])=[O:10])=[CH:12][CH:13]=1
Reactant: O=C(NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1cc(Br)c(OCc2cccc(Br)c2)c(Br)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)NC(=O)c2cc(Br)c(OCc3cccc(Br)c3)c(Br)c2)cc1
Temperature: 70 °C
Yield: 19.4 %

Procedure:
To a solution of N-[3,5-dibromo-4-(3-bromobenzyloxy)benzoyl]-4-nitrobenzenesulphonamide (0.25 mmol), prepared as described in Example 33, in ethanol (95%, 25 mL), sodium dithionite (1.26 mmol) was added and the reaction mixture stirred over night at 70° C. The reaction mixture was allowed to reach room temperature and then evaporated in vacuo. The residue was diluted with ethyl acetate and washed with an aqueous solution of sodium hydrogencarbonate (saturated). The organic phase was dried over magnesium sulphate and concentrated in vacuo. The residue was purified on column (silica gel, chloroform/methanol 17:3) and further purified by semi-preparative HPLC (column and eluents as described for Examples 27, 28 and 30) to give 30 mg (20%) of 4-amino-N-[3,5-dibromo-4-(3-bromobenzyloxy)-benzoyl]benzenesulphonamide.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[CH:4][N:3]=1.[C:26]([NH:30][S:31]([C:34]1[S:38][C:37](B(O)O)=[CH:36][CH:35]=1)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[C:26]([NH:30][S:31]([C:34]1[S:38][C:37]([C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:13]=[C:12]([CH:14]4[CH2:16][CH2:15]4)[NH:11][N:10]=3)[C:5]([CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[CH:4][N:3]=2)=[CH:36][CH:35]=1)(=[O:32])=[O:33])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B(O)O)s1
Reactant: CC(C)(C)[Si](C)(C)OCc1cnc(Br)nc1Nc1cc(C2CC2)[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2ncc(CO[Si](C)(C)C(C)(C)C)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Temperature: 90 °C
Yield: 43.5 %

Procedure:
A mixture of 2-bromo-5-((tert-butyldimethylsilyloxy)methyl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (210 mg, 0.49 mmol, 1.0 equiv.), 5-(N-tert-butylsulfamoyl)thiophen-2-ylboronic acid (260.4 mg, 0.99 mmol, 2 equiv.), PdCl2(dppf)CH2Cl2 (120.0 mg, 0.15 mmol, 0.3 equiv.), K2CO3 (236.67 mg, 1.72 mmol, 3.5 equiv.) in dioxane (10 mL) and water (2 mL) was heated for 12 h at 90° C. under nitrogen atmosphere. The solvent was removed and the residue was purified by silica gel chromatography (PE/EtOAc=5:12:1 as eluant) to give N-tert-butyl-5-(5-((tert-butyldimethylsilyloxy)methyl)-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophene-2-sulfonamide (120.0 mg, 43.5%) as white solid. LC-MS (m/z)=563.1 [M+H]+;
Reaction SMILES: [BH4-].[Na+].CO.[CH3:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH:9]=[CH:8][C:7]=1[CH:21]=[CH:22][C:23](=[O:25])[CH3:24]>C1COCC1>[CH3:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH:9]=[CH:8][C:7]=1[CH:21]=[CH:22][CH:23]([OH:25])[CH3:24]
Reactant: CC(=O)C=Cc1ccc(OCc2ccccc2C)cc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccccc2C)ccc1C=CC(C)O
Yield: 94 %

Procedure:
NaBH4 (20 mg, 0.51 mmol) was added to a 0.4 M solution of CeCl3 in MeOH (0.65 mL, 0.26 mmol), 31.4 (74 mg, 0.26 mmol), and THF (1 mL). The reaction was stirred, uncapped, until gas evolution ceased. The reaction was quenched with water (1.5 mL) and partitioned between water and diethyl ether. The aqueous layer was extracted 2 times with diethyl ether and the combined organic layers were washed with brine and concentrated in vacuo to yield 69 mg (93%) of 4-[2-Methyl-4-(2-methyl-benzyloxy)-phenyl]-but-3-en-2-ol (31.5). LC/MSD m/e: 266.3 (M−OH); 1H NMR (400 MHz) (DMSO-d6) δ 7.44 (2H, m), 7.25 (3H, m0, 6.86 (2H, m), 6.75 (1H, m), 6.08 (1H, m), 5.11 (2H, s), 4.40, (1H, m), 2.38 (3H, s), 2.32 (3H, s), 1.29 (3H, m).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:15]=[N+]=[N-])[N:11]([CH2:18][C:19]([N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([Cl:30])[CH:28]=3)[C:23]([CH3:32])([CH3:31])[CH2:22]2)=[O:20])[CH2:10][C@H:9]1[CH3:33])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:34]([OH:37])(=S)[CH3:35]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][NH:15][C:34](=[O:37])[CH3:35])[N:11]([CH2:18][C:19]([N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([Cl:30])[CH:28]=3)[C:23]([CH3:32])([CH3:31])[CH2:22]2)=[O:20])[CH2:10][C@H:9]1[CH3:33])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3ccc(Cl)cc32)[C@@H](CN=[N+]=[N-])CN1C(=O)OC(C)(C)C
Reactant: CC(O)=S
Product: CC(=O)NC[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)N1CC(C)(C)c2ccc(Cl)cc21
Reaction time: 18.5 h
Yield: 56 %

Procedure:
(2R,5R)-5-Azidomethyl-4-[2-(6-chloro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (81 mg, 0.17 mmol) was dissolved in thioacetic acid (459 μL) and left to stir for 18.5 h, then concentrated. The crude oil was purified by column chromatography on silica gel (gradient elution, 0-100%, EtOAc/petrol) to give the title compound (47 mg, 56%) as a colourless solid. 1H NMR (Me-d3-OD): 8.15 (1H, d), 7.21 (1H, d), 7.09 (1H, dd), 4.24-4.14 (1H, m), 4.06-3.96 (2H, m), 3.84 (1H, d), 3.71 (1H, d), 3.56 (1H, d), 3.48-3.40 (1H, m), 3.25-3.13 (1H, m), 3.04-2.96 (1H, m), 2.92 (1H, dd), 2.65 (1H, dd), 1.97 (3H, s), 1.49 (9H, s), 1.38 (6H, s), 1.32-1.19 (3H, m).
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([CH3:15])[O:8][C:7]([O:19]CC)([O:16][CH2:17][CH3:18])[C@H:6]1[CH3:22])(=[O:3])[CH3:2].O.Cl.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:22][CH:6]([CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]([C:11]([O:13][CH3:14])=[O:12])[C:9](=[O:8])[CH3:15])[C:7]([O:16][CH2:17][CH3:18])=[O:19]
Reactant: CCOC1(OCC)OC(C)=C(C(=O)OC)[C@@H](NC(C)=O)[C@@H]1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C)C(NC(C)=O)C(C(C)=O)C(=O)OC
Reaction time: 16 h
Yield: 61.2 %

Procedure:
To a solution of methyl trans-4-acetylamino-2,2-diethoxy-3,6-dimethyl-3,4-dihydro-2H-pyran-5-carboxylate (12.2 g) (Example 6) in 200 ml tetrahydrofuran was added 3.0 ml water and 1.0 ml 1N HCl. The mixture was stirred at 20°-25° C. for 16 hours, then neutralised by adding 1.0 g anhydrous potassium carbonate. The mixture was filtered and the filtrate evaporated at reduced pressure to give 11.4 g of crude product which was crystallised from toluene/hexane (50:50) giving ethyl 2-methyl-3-acetylamino-4-methoxycarbonyl-5-oxohexanoate (6.8 g), m.p. 93°-6° C.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:39]=[CH:38][C:13]([CH2:14][C:15]3([CH3:37])[C:19](=[O:20])[O:18]C(C4C=CC=CC=4)[N:16]3[C:27]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:28])=[CH:12][CH:11]=2)=[N:8][CH:9]=1>CO.O>[CH2:30]([O:29][C:27]([NH:16][C:15]([CH3:37])([CH2:14][C:13]1[CH:38]=[CH:39][C:10]([C:7]2[CH:6]=[CH:5][C:4]([F:3])=[CH:9][N:8]=2)=[CH:11][CH:12]=1)[C:19]([OH:20])=[O:18])=[O:28])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC1(Cc2ccc(-c3ccc(F)cn3)cc2)C(=O)OC(c2ccccc2)N1C(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(Cc1ccc(-c2ccc(F)cn2)cc1)(NC(=O)OCc1ccccc1)C(=O)O
Temperature: 80 °C
Reaction time: 2 h

Procedure:
5N Aqueous sodium hydroxide (1.45 mL) was added to an ambient temperature solution of benzyl 4-[4-(5-fluoropyridin-2-yl)benzyl]-4-methyl-5-oxo-2-phenyl-1,3-oxazolidine-3-carboxylate (180 mg, 0.36 mmol) in methanol (2 mL) and water (2 mL). After stirring at 80° C. for 2 h, the reaction mixture was concentrated. The residue was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried and concentrated in vacuo to afford 2-{[(benzyloxy)carbonyl]amino}-3-[4-(5-fluoropyridin-2-yl)phenyl]-2-methylpropanoic acid which was used in the subsequent step without further purification.
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].OCC[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=2)[C:14]([CH3:23])=[CH:13][C:12]1([CH3:25])[CH3:24]>S(=O)(=O)(O)O>[CH3:24][C:12]1([CH3:25])[CH:13]=[C:14]([CH3:23])[C:15]2[C:20](=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:11]1[CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2c(c1)N(CCO)C(C)(C)C=C2C
Agent: O=S(=O)(O)O
Product: COc1ccc2c(c1)N(CCOC(C)=O)C(C)(C)C=C2C
Temperature: 105 °C

Procedure:
18 g (0.17 mol) acetic anhydride was added to 10 g (0.04 mol) N-(2-hydroxyethyl)-2,2,4-trimethyl-7-methoxy-1,2-dihydroquinoline. 10 drops of concentrated sulphuric acid were added to this and it was heated for 1 h to 100 to 110° C. The reaction mixture was poured onto ice and extracted with chloroform. The combined organic phases were dried over sodium sulfate and distilled. The light-yellow oil that formed had a boiling point of 140° C./10−3 mbar.