Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14])([CH3:3])[CH3:2]>CO.[BH4-].[K+]>[OH:9][CH:8]1[C:7]2[C:6](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](=[O:14])[N:4]1[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)N1C(=O)c2ccccc2C1=O
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Product: CC(C)N1C(=O)c2ccccc2C1O
Temperature: 20 °C
Reaction time: 20 h
Yield: 150.9 %

Procedure:
3-Hydroxy-2-isopropyl-2,3-dihydroisoindol-1-one is prepared as described in Example 1, starting with 4.0 g of N-isopropylphthalimide in 20 cm3 of methanol and 1.1 g of potassium borohydride. The reaction mixture is stirred at a temperature in the region of 20° C. for 20 hours and is then cooled to a temperature in the region of 0° C. and distilled water is added dropwise. The solvent is then evaporated to dryness under reduced pressure (2 kPa) at a temperature in the region of 35° C. 6.1 g of 3-hydroxy-2-isopropyl-2,3-dihydroisoindol-1-one are thus obtained in the form of a white wax. (Rf=0.65, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (30/70 by volume)).
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:12][O:13][CH2:14][CH2:15][NH2:16].C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:16][CH2:15][CH2:14][O:13][CH3:12])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: COCCN
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: COCCNc1ccc2ncc(Br)n2n1

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and 2-methoxyethylamine according to general procedure 1 providing the amino compound (432 mg, 74%) as a yellow solid; Rf=0.71 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CD3OD) δ 7.57 (d, J=9.7 Hz, 1H), 7.42 (s, 1H), 6.75 (d, J=9.7 Hz, 1H), 3.68 (t, J=5.4 Hz, 2H), 3.59 (t, J=5.6 Hz, 2H), 3.43 (s, 3H); ES-MS: (M+H)=271, 273 m/z.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[NH:8][C:7]=2[CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:20][CH2:21][CH2:22][CH2:23]I>CCCCCCC.CCOC(C)=O>[Cl:20][CH2:21][CH2:22][CH2:23][N:8]1[C:7]2[CH:13]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[O:11][CH2:10][C:9]1=[O:12]
Reactant: COc1ccc2c(c1)NC(=O)CO2
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)N(CCCCl)C(=O)CO2
Yield: 42.1 %

Procedure:
6-Methoxy-4H-benzo[1,4]oxazin-3-one (81MF2249a) (0.212 g, 1.18 mmol), Cs2CO3 (0.578 g, 1.77 mmol) and 3-chloro-1-iodopropane (0.265 g, 1.3 mmol) were mixed according to GP5. CC (SiO2; Heptane/EtOAc 10:1-2) gave the title compound (81MF2249b) (0.127 g, 42%). 1H NMR (CDCl3) δ 6.88 (d, J=8.8 Hz, 1H), 6.62 (d, J=2.8 Hz, 1H), 6.50 (dd, J=2.8 Hz, J=8.8 Hz, 1H), 4.50 (s, 2H), 4.05-4.01 (m, 2H), 3.76 (s, 3H), 3.59 (t, J=6.2 Hz, 2H), 2.16-2.09 (m, 2H); 13C NMR (CDCl3) δ 164.8, 155.5, 139.3, 129.2, 117.4, 107.8, 101.9, 67.8, 55.8, 42.4, 38.9, 30.0.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][CH2:28][O:29][C:22]=3[CH:21]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][CH2:28][O:29][C:22]=4[CH:21]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccc4c(c3)OCCO4)c2c1C
Product: Cc1sc2nc(-n3ccnc3)nc(NCc3ccc4c(c3)OCCO4)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-5,6-dimethyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5,6-dimethyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.C([Li])CCC.CN([CH:18]=[O:19])C.[Na+].[Cl-]>C(OCC)C>[CH:18]([C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1)=[O:19]
Reactant: CN(C)C=O
Reactant: COc1cncc(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Product: COc1cncc(C=O)c1
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-Bromo-5-methoxypyridine (2.5 g, 13.3 mmol) in anhydrous diethyl ether cooled to −100° C. was added n-butyllithium (2.5M soln in hexanes: 5.85 mL, 14.6 mmol) dropwise whilst maintaining an internal temperature <−94° C. After subsequent stirring for 30 minutes, anhydrous DMF (1.34 mL, 17.3 mmol) was added and the reaction mixture allowed to warm to −60° C.. The solution was then poured into sat'd. aq. NaCl soln. and extracted with diethyl ether (3×100 mL), the ethereal phase dried (K2CO3), filtered and evaporated in vacuo. The residue was purified on silica gel eluting with a gradient of 0 to 30% EtOAc in hexanes to afford the title material as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH:35]([OH:39])[CH2:34]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:39][CH:35]1[CH2:36][CH2:37][CH2:38][CH:33]([NH:32][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=5)[N:8]([CH3:11])[N:7]=4)[N:13]=3)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[CH:19]=2)=[O:23])[CH2:34]1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Reactant: NC1CCCC(O)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)NC2CCCC(O)C2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
A 25 mL round-bottomed flask was charged with 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.10 g, 0.22 mmol), 3-aminocyclohexanol (mixture of cis and trans) (45 mg, 0.39 mmol), HBTU (0.10 g, 0.26 mmol), and HOBT (0.03 g, 0.26 mmol). Then added DMF (1.0 mL) followed by N,N-diisopropylethylamine (0.07 ml, 0.26 mmol). The yellow reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (30 mL). The organic layer was washed once with saturated NaHCO3 and water. The combined aqueous layers were back extracted with EtOAc (25 mL). The combined organic layers was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over SiO2 with EtOAc/hexanes (gradient: 0-100% EtOAc) to afford 106 mg of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-hydroxy-cyclohexyl)amide as an off-white foam. MS: [M+H]+=556.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[CH3:11][Si:12]([CH2:15][CH2:16][O:17][CH2:18]Cl)([CH3:14])[CH3:13].CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:18][O:17][CH2:16][CH2:15][Si:12]([CH3:14])([CH3:13])[CH3:11])[CH:9]=[CH:10][C:3]=12
Reactant: C[Si](C)(C)CCOCCl
Reactant: Brc1ccnc2[nH]ccc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1ccc2c(Br)ccnc21
Temperature: 25 °C
Yield: 99.2 %

Procedure:
A mixture of 4-bromo-1H-pyrrolo[2,3-b]pyridine (1.00 g, 5.08 mmol), SEMCl (0.898 mL, 5.08 mmol) and DIPEA (1.768 mL, 10.15 mmol) in DCM (20.0 mL) was stirred at RT. After 3 nights the mixture was evaporated to dryness. The residues were purified on silica eluting with isohexane and ethyl acetate (0-100%). The appropriate fractions were combined and evaporated to dryness producing the title compound (1.65 g). LCMS (A): m/z (M+H)+ 327/329, C13H19BrN2OSi requires 326/328 (basic).
Reaction SMILES: C(O[CH:9]1[O:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:10]1)C1C=CC=CC=1.[CH2:28]([OH:30])C>[Pd]>[OH:30][CH2:28][CH:9]1[O:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([CH:21]3[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]3)=[CH:19][CH:20]=2)[CH2:10]1
Reactant: CCO
Reactant: O=C1CCC(c2ccc(N3CC(OCc4ccccc4)OC3=O)cc2)CC1
Agent: [Pd]
Product: O=C1CCC(c2ccc(N3CC(CO)OC3=O)cc2)CC1

Procedure:
4.9 g (12.9 mmol) of (RS)-5-benzyloxy-3-[4-(4-oxo-cyclohexyl)-phenyl]-oxazolidin-2-one were dissolved in 500 ml of ethanol while heating and, after adding 5% Pd/C, hydrogenated at room temperature. After separating the catalyst the solvent was distilled off and the oil obtained was chromatographed on a 30-fold amount of silica gel. The methylene chloride-ethyl acetate (1:4) eluates were pooled and the solvent was distilled off. 3.2 g of product were obtained from ethyl acetate/hexane. M.p.: 151.5°-152.5°.
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[CH:8]=[CH:9][C:10]([N+:16]([O-])=O)=[C:11]([C:14]#[N:15])[C:12]=2[CH:13]=1)([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.[Ni]>[NH2:16][C:10]1[CH:9]=[CH:8][C:7]2[NH:6][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:13][C:12]=2[C:11]=1[C:14]#[N:15]
Reactant: CC(C)(C)c1cc2c(C#N)c([N+](=O)[O-])ccc2[nH]1
Agent: [Ni]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc2c(C#N)c(N)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a solution of 2-tert-butyl-5-nitro-1H-indole-4-carbonitrile (550 mg, 2.3 mmol) in EtOAc (10 mL) was added Raney Ni (0.1 g) under a nitrogen atmosphere. The mixture was stirred under hydrogen atmosphere (1 atm) at room temperature for 1 h. The catalyst was filtered over Celite and the filtrate was evaporated in vacuo to afford 5-amino-2-tert-butyl-1H-indole-4-carbonitrile (250 mg, 51%). 1H NMR (DMSO, 300 MHz) δ 10.93 (br s, 1 H), 7.25 (d, J=8.7 Hz, 1 H), 6.49 (d, J=8.7 Hz, 1 H), 5.94 (d, J=2.1 Hz, 1 H), 5.40 (br s, 2 H), 1.30 (s, 9 H). MS (ESI) m/z: 214.0 [M+H+].
Reaction SMILES: [CH2:1]([C:5]1([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[O:10][C:9](=[O:11])[CH:8]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7](=[O:19])[CH2:6]1)[CH2:2][C:3]#[CH:4].Br[C:26]1[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=1.CC(O)=O>CC#N>[CH:20]1([C:5]2([CH2:1][CH2:2][C:3]#[C:4][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=3)[O:10][C:9](=[O:11])[CH:8]([S:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:7](=[O:19])[CH2:6]2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C#CCCC1(C2CCCC2)CC(=O)C(Sc2ccccc2)C(=O)O1
Reactant: Oc1cccc(Br)c1
Solvent: CC(=O)O
Solvent: CC#N
Product: O=C1CC(CCC#Cc2cccc(O)c2)(C2CCCC2)OC(=O)C1Sc1ccccc1

Procedure:
The title compound was prepared analogously to Example 6 using 6-but-3-ynyl-6-cyclopentyl-3-phenylsulfanyl-dihydro-pyran-2,4-dione (described in Example 16) in place of 6-but-3-ynyl-6-dihydro-pyran-2,4-dione and 3-bromophenol in place of iodobenzene. 1H NMR (CDCl3): δ1.40-1.82 (m, 8H); δ2.14 (t, 1H, J=7.58 Hz); δ2.21-2.33 (m, 2H); δ0.40-2.56 (m, 2H); δ0.92 (dd, J1=17.94 Hz, J2=22.99 Hz, 2H); δ0.06-7.56 (m, 9H). Anal. Calcd. for C26H26O4S.0.2 AcOH. 1 MeCN: C, 69.95; H, 6.16; S, 6.85. Found C, 70.23; H, 6.58; S, 6.09. ESIMS (M+Na+): 457.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH:5]([N:15]=C(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[CH3:14])C>Cl>[NH2:15][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[CH3:14])[C:4]([OH:29])=[O:3]
Reactant: CCOC(=O)C(Cc1ccc(Cl)cc1C)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Product: Cc1cc(Cl)ccc1CC(N)C(=O)O
Temperature: 25 °C
Yield: 71.3 %

Procedure:
A mixture containing 2-(Benzhydrylidene-amino)-3-(4-chloro-2-methyl-phenyl)-propionic acid ethyl ester (1.7 g, 4.2 mmol) and 90 mL of 3N HCl was heated at 75 C overnight. The reaction was cooled to room temperature and washed with ethyl acetate. The aqueous phase was concentrated under reduced pressure to afford 2-Amino-3-(4-chloro-2-methyl-phenyl)-propionic acid (640 mg, 72%) as white solid. LCMS (APCI+) m/z 214 [M+H]+; Rt: 1.83 min. 1H NMR (D2O, 400 MHz) δ 7.18 (1H, s), 7.11 (1H, d, J 8.7 Hz), 7.05 (1H, d, J 8.3 Hz), 4.05-4.00 (1H, m), 3.23 (1H, dd, J 14.3 and 6.1 Hz), 2.98 (1H, dd, J 14.4 and 8.5 Hz), 2.19 (3H, s.)
Reaction SMILES: O=[CH:2][CH2:3][O:4][CH2:5][CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([N:23]([CH3:36])[CH2:24][CH2:25][CH2:26][N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:22])=[CH:17][CH:16]=1>>[C:30]([O:29][C:28]([N:27]([CH3:35])[CH2:26][CH2:25][CH2:24][N:23]([CH3:36])[C:21]([C:18]1[CH:19]=[CH:20][C:15]([NH:14][CH2:2][CH2:3][O:4][CH2:5][CH2:6][C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])=[CH:16][CH:17]=1)=[O:22])=[O:34])([CH3:32])([CH3:31])[CH3:33]
Reactant: CN(CCCN(C)C(=O)c1ccc(N)cc1)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)CCOCC=O
Product: CN(CCCN(C)C(=O)c1ccc(NCCOCCC(=O)OC(C)(C)C)cc1)C(=O)OC(C)(C)C
Yield: 82.6 %

Procedure:
The compound (87 mg, 0.461 mmol) obtained in Example 28b and the compound (150 mg, 0.461 mmol) obtained in Example 28d were used to give the title compound (188 mg; yield, 83%) as a colorless oily substance according to the method described in Example 18b.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[C:4]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[F:25])(=[O:17])=[O:16])[CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:34])C=1>C(Cl)Cl.CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:34])=[C:4]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[F:25])(=[O:17])=[O:16])[CH:3]=1
Reactant: O=C(O)CCSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)cc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CC(C)=O
Product: O=C(O)CCS(=O)c1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a solution of 3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)sulfanyl]propanoic acid (91 mg, 0.21 mmol) in CH2Cl2 (2 ml) and acetone (2 ml) was added mCPBA (50 mg, ˜0.21 mmol). The reaction was stirred at room temperature for 1 hour and was concentrated. The solid residue was rinsed with Et2O to yield the title compound (88 mg, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[CH:14]([CH3:28])[C:15]([C:21]1[CH:26]=[CH:25][N:24]=[C:23]([Cl:27])[CH:22]=1)([OH:20])[C:16]([F:19])([F:18])[F:17])[CH2:5]OS(C)(=O)=O.[C-:29]#[N:30].[Na+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][C:29]#[N:30])[CH:11]=[CH:12][C:13]=1[CH:14]([CH3:28])[C:15]([C:21]1[CH:26]=[CH:25][N:24]=[C:23]([Cl:27])[CH:22]=1)([OH:20])[C:16]([F:19])([F:18])[F:17]
Reactant: CC(c1ccc(COS(C)(=O)=O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(c1ccc(CC#N)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Temperature: 85 °C
Reaction time: 1.5 h

Procedure:
Methanesulfonic acid 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-benzyl ester (66 mg) was dissolved in DMF at RT under argon. Sodium cyanide (18 mg) was added and the mixture was warmed to 85° C. and allowed to stir for 1.5 hours. The mixture was diluted with ethyl acetate and washed with water and brine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:27][N:28]1[C:36]2[C:31](=[CH:32][C:33](B(O)O)=[CH:34][CH:35]=2)[CH:30]=[CH:29]1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:33]5[CH:32]=[C:31]6[C:36](=[CH:35][CH:34]=5)[N:28]([CH3:27])[CH:29]=[CH:30]6)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: Cn1ccc2cc(B(O)O)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccc6c(ccn6C)c5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and N-methyl-indole-5-boronic acid following a procedure analogous to that described for Intermediate 6. LC (method 4): tR=0.87 min; Mass spectrum (ESI+): m/z=488 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[S:12]([O-:15])([O-:14])=[O:13].[Na+:16].[Na+]>C(O)C.O>[CH2:10]([O:9][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][S:12]([O-:15])(=[O:14])=[O:13])[CH3:11].[Na+:16]
Reactant: O=S([O-])[O-]
Reactant: CCOC(=O)CCCCCBr
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCCCCS(=O)(=O)[O-]
Yield: 100 %

Procedure:
To a solution of ethyl 6-bromohexanoate (61b) (2.48 g, 11.0 mmol) in ethanol (6 ml) a solution of sodium sulfite (2.16 g, 20.6 mmol) in water (9 ml) was added and the resulting mixture was refluxed for 1 hour. The reaction mixture was evaporated under reduced pressure and the obtained solid was extracted with boiling ethanol in Soxhlet extraction apparatus for 15-20 hours. The extract was evaporated and the residue was crystallised from ethanol-diethyl ether (1:10) giving the title compound (2.71 g, 99%) in a form of a white solid material. 1H NMR (DMSO-d6, HMDSO),δ:1.05-1.78 (6H, m); 1.17 (3H, t, J=7.2 Hz); 2.26 (4H, t J=7.5 Hz); 4.05 (2H, q, J=7.2 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[Cl:9].C([Li])CCC.[C:15]([N:22]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>O1CCCC1>[Cl:9][C:3]1[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=1[C:24]1([OH:27])[CH2:25][CH2:26][N:22]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: Clc1cccc(Br)c1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(Cl)c2Cl)C1

Procedure:
Preparation according to Example 23: 1-bromo-2,3-dichlorobenzene (2.1 g, 9.23 mmol) in dry tetrahydrofuran (40 mL), n-butyllithium (2.5 M in tetrahydrofuran, 3.7 mL, 9.23 mmol), 1-N-boc-3-pyrrolidinone (1.13 g, 6.15 mmol) in dry tetrahydrofuran (10 mL). Purified by flash column chromatography on silica gel (isooctane/ethyl acetate, 4:1 to 1:1). Yield: 1.23 g. MS m/z (rel. intensity, 70 eV) 230 (25), 196 (46), 172 (19), 57 (bp), 56 (29).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[CH:5]=[C:4]([Cl:12])[N:3]=1.[CH3:13][Al](C)C>CN(C=O)C.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>[Cl:12][C:4]1[N:3]=[C:2]([CH3:13])[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[CH:5]=1
Reactant: C[Al](C)C
Reactant: Nc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1nc(Cl)cc(N)c1[N+](=O)[O-]
Temperature: 70 °C
Yield: 44.4 %

Procedure:
To a pressure vessel, a degassed solution of 2,6-dichloro-3-nitro-pyridin-4-ylamine (3.0 g, 14.4 mmol) (R. J. Rousseau and R. K. Robins J. Heterocyclic Chem. 2, 1965, 196) and tetrakis(triphenylphosphine)palladium(0) (1.67 g, 1.44 mmol) in DMF (45 mL) was stirred at room temperature. To this mixture was added dropwise a solution of trimethylaluminium (7.93 mL, 15.8 mmol, 2M in toluene). The resulting mixture was sealed and heated at 70° C. for 3 hours. The reaction mixture was poured into ice/water (800 mL). The organic material was extracted with EtOAc (5×200 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The crude material was purified on silica gel dry column using EtOAc:Hexane gradient (1:9) to (3:7) to afford the desired compound as a yellow solid (1.20 g, 45%), HPLC: 99% (220 nm), LCMS (+ESI, M+H+) m/z 188, IR (KBr, cm−1) 3431, 3310, 3172, 1653, 1506, 1264; 1H NMR (400 MHz, CDCl3) δ 7.19 (s, 1H), 6.57 (br s, 2H), 2.63 (s, 3H);.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[F:29][C:30]1[CH:31]=[C:32]([NH:36][NH2:37])[CH:33]=[CH:34][CH:35]=1>>[F:29][C:30]1[CH:31]=[C:32]([N:36]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]5[CH2:27][CH2:26][CH2:25][CH2:24]5)(=[O:21])=[O:22])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:37]2)[CH:33]=[CH:34][CH:35]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)N3CCCC3)c2)ccc1=O
Reactant: NNc1cccc(F)c1
Product: O=c1ccn(-c2cccc(S(=O)(=O)N3CCCC3)c2)nc1-c1ccnn1-c1cccc(F)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-[3-(pyrrolidine-1-sulfonyl)-phenyl]-1H-pyridazin-4-one (A-29) and 3-fluoro-phenylhydrazine according to the method described for example 91. MS: M=466.2 (M+H)+
Reaction SMILES: COP([CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[O:8]1)(=O)OC.[CH:17]([C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][N:26]=1)[C:22]#[N:23])=O.C(N(CC)CC)C>C1COCC1>[O:16]=[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7](=[CH:17][C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][N:26]=2)[C:22]#[N:23])[O:8]1
Reactant: COP(=O)(OC)C1OC(=O)c2ccccc21
Reactant: N#Cc1ccnc(C=O)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1ccnc(C=C2OC(=O)c3ccccc32)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cooled suspension (ca 0° C.) of [(3-Oxo-1,3-dihydro-isobenzofuran-1-yl)-phosphonic acid dimethyl ester]phosphonate (i)(8.0 g, 33.0 mmol) in THF (400 mL) was added crude 2-formyl-isonicotinonitrile (iid)(30.0 mmol) followed by triethylamine (6.2 mL, 33.0 mmol). The mixture was stirred for 30 minutes at 0° C. and then allowed to warm overnight.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:4]([F:13])[C:3]=1[OH:14].[F:15][C:16]1[CH:17]=[CH:18][C:19]([CH3:25])=[C:20]([N:22]=[C:23]=S)[CH:21]=1>CO>[F:15][C:16]1[CH:17]=[CH:18][C:19]([CH3:25])=[C:20]([NH:22][C:23]2[O:14][C:3]3[C:4]([F:13])=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:7][C:2]=3[N:1]=2)[CH:21]=1
Reactant: Cc1ccc(F)cc1N=C=S
Reactant: COC(=O)Cc1ccc(N)c(O)c1F
Solvent: CO
Product: COC(=O)Cc1ccc2nc(Nc3cc(F)ccc3C)oc2c1F
Temperature: 25 °C
Reaction time: 120 h
Yield: 48.6 %

Procedure:
In methanol (30 ml) was dissolved methyl (4-amino-2-fluoro-3-hydroxyphenyl)acetate (1.0 g, 5.02 mmol). To the resulting solution was added 5-fluoro-2-methylphenyl isothiocyanate (1.0 g, 5.98 mmol). After the resulting mixture was stirred at room temperature for 5 days, mercuric oxide (yellow) (1.14 g, 4.36 mmol) was added thereto. The mixture was stirred at 70° C. for 6 hours. After cooling to room temperature, the reaction mixture was filtered through Celite and washed with methanol. The filtrate was distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from chloroform/ethyl acetate (30/1, v/v) eluate fractions, methyl (2-(5-fluoro-2-methylphenylamino)-7-fluoro-6-benzoxazolyl)acetate (810 mg, 56% (2 steps)) was obtained as a pink solid.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1.[C:23]([C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[C:28](O)=[O:29])#[N:24]>>[C:23]([C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([C:34]([F:35])([F:37])[F:36])[CH:33]=1)[C:28]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)[CH:4]=1)=[O:29])#[N:24]
Reactant: N#Cc1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Product: Cc1ccc(NC(=O)c2cc(C#N)cc(C(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12

Procedure:
Analogously to the process described in Example 26, 80 mg (0.276 mmol) of the compound of Example 6A and 60 mg (0.276 mmol) of the compound of Example 42A gave 72 mg (54% of theory) of the title compound. In this case, the reaction time was 18 h, and subsequent trituration of the product with diisopropyl ether could be dispensed with.