Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:8]([CH2:9][CH2:10][C@@H:11]([OH:19])[CH2:12][C@@H:13]([OH:18])[CH2:14][C:15](O)=[O:16])[C:7]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)=[C:6]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:5]=1[C:33]([NH:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:34])[CH3:3].[Mg+2].[Br-].[Br-].Cl.[NH2:46][OH:47].C(=O)(O)[O-].[Na+]>C1COCC1.CO.C(Cl)Cl.CO.CCOC(C)=O.CC#N>[F:26][C:23]1[CH:22]=[CH:21][C:20]([C:7]2[N:8]([CH2:9][CH2:10][C@@H:11]([OH:19])[CH2:12][C@@H:13]([OH:18])[CH2:14][C:15]([NH:46][OH:47])=[O:16])[C:4]([CH:2]([CH3:3])[CH3:1])=[C:5]([C:33](=[O:34])[NH:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:6]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:25][CH:24]=1
Reactant: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H](O)C[C@@H](O)CC(=O)O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Br-]
Solvent: CC#N
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H](O)C[C@@H](O)CC(=O)NO

Procedure:
By a procedure similar to Lova-HA, atorvastatin (168 mg, 0.31 mmol, in the lactone form) was treated with MgBr2 (115 mg, 0.62 mmol), hydroxylamine hydrochloride (184 mg, 2.6 mmol), and sodium bicarbonate (209 mg, 2.5 mmol) in anhydrous THF/MeOH (7:3, 1 mL) at ambient temperature for 20 h to give Atorva-HA (91 mg, 51%). The purity was 95% as shown by HPLC analysis on an HC—C18 column (Agilent, 4.6×250 mm, 5 Gm), tR=14.8 min (gradients of 30-100% aqueous CH3CN in 30 min). C33H36FN3O5; colorless oil; [α]26D=−1.3 (EtOAc, c=1.0); TLC (CH2Cl2/MeOH (9:1)) Rf=0.33; IR νmax (neat) 3405, 3301, 3059, 2960, 2926, 1738, 1657, 1595, 1527, 1508, 1436, 1314, 1241, 1223, 1157, 1108, 1078, 1046, 843, 753, 692 cm−1; 1H NMR (DMSO-d6, 400 MHz) δ 10.31 (1H, br s), 9.77 (1H, br s), 8.68 (1H, br s), 7.50 (2H, d, J=7.6 Hz), 7.18-7.24 (6H, m), 7.07 (4H, br s), 6.98-7.00 (2H, m), 4.69 (1H, br s), 4.60 (1H, d, J=4.0 Hz), 3.92-3.95 (1H, m), 3.72-3.83 (2H, m), 3.53 (1H, br s), 3.21-3.25 (1H, m), 2.01 (2H, d, J=6.0 Hz), 1.63 (1H, br s), 1.53 (1H, br s), 1.28-1.38 (8H, m) ppm; 13C NMR (DMSO-d6, 100 MHz) δ 167.4, 166.1, 162.8, 160.3, 139.4, 135.9, 134.9, 133.4, 129.1 (2×), 128.7, 128.4 (2×), 127.6 (2×), 127.3, 125.3, 122.9, 120.6, 119.4 (2×), 117.5, 115.4, 115.2, 66.0, 65.6, 43.8, 40.9, 40.7, 25.6, 22.3 (2×) ppm; ESI-HRMS (negative mode) calcd. for C33H35FN3O5: 572.2561. found: m/z 572.2562 [M−H]−.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[N:15]=[N:16][N:17]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:18]=3)=[CH:10][N:9]=2)[CH2:4][CH2:3]1.[Br:25][C:26]1[CH:27]=[CH:28][C:29]([F:33])=[C:30](O)[CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([F:33])=[C:28]([CH:27]=1)[O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[N:9]=[CH:10][C:11]([C:14]3[N:15]=[N:16][N:17]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:18]=3)=[CH:12][N:13]=2)[CH2:6][CH2:7]1
Reactant: Oc1cc(Br)ccc1F
Reactant: CCOC(=O)Cn1nnc(-c2cnc(N3CCC(O)CC3)nc2)n1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)Cn1nnc(-c2cnc(N3CCC(Oc4cc(Br)ccc4F)CC3)nc2)n1

Procedure:
The title compound was prepared in a similar manner as that described for Example 3 (step 4) from ethyl {5-[2-(4-hydroxypiperidin-1-yl)pyrimidin-5-yl]-2H-tetrazol-2-yl}acetate, 5-bromo-2-fluorophenol, triphenylphosphine and di-tert-butyl azodicarboxylate.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[CH3:9][C:10]1[N:11]=[C:12]([NH:22][C:23](=[NH:27])SCC)[S:13][C:14]=1[C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=1>CC(O)C.C(OCC)(=O)C>[CH3:9][C:10]1[N:11]=[C:12]([NH:22][C:23]([NH:2][OH:3])=[NH:27])[S:13][C:14]=1[C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=1
Reactant: CCSC(=N)Nc1nc(C)c(-c2cc(C)ccn2)s1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: Cc1ccnc(-c2sc(NC(=N)NO)nc2C)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 43.9 %

Procedure:
To a suspension of hydroxylamine hydrochloride (146 mg) and sodium acetate (172 mg) in 2-propanol (4 ml) was added N-(4-methyl-5-(4-methylpyridin-2-yl)thiazol-2-yl)-S-ethylisothiourea (205 mg), and the mixture was stirred at 90° C. for 1 hour. The mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel, 3 to 4% methanol in dichloromethane) to give N-(4-methyl-5-(4-methylpyridin-2-yl)thiazol-2-yl)-N′-hydroxyguanidine (81 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2C)=[CH:5][N:4]=1.IC1C=CC=CC=1[F:27]>>[F:27][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]#[C:11][C:6]1[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[N:4][CH:5]=1
Reactant: COc1cc(C#Cc2ccccc2C)cnc1OC
Reactant: Fc1ccccc1I
Product: COc1cc(C#Cc2ccccc2F)cnc1OC

Procedure:
Prepared as described for 2,3-dimethoxy-5-[(2-methylphenyl)ethynyl]pyridine (Intermediate 33) but using 1-iodo-2-fluorobenzene instead of 1-iodo-2-methylbenzene.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:16][N:6]2[C:7](=[O:15])[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]2=[N:4]1.[C:17]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C>[C:17]1([N:23]2[CH2:28][CH2:27][N:26]([CH2:2][CH:3]3[CH2:16][N:6]4[C:7](=[O:15])[NH:8][C:9]5[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=5[C:5]4=[N:4]3)[CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C1Nc2ccccc2C2=NC(CBr)CN12
Solvent: CC#N
Product: O=C1Nc2ccccc2C2=NC(CN3CCN(c4ccccc4)CC3)CN12
Yield: 76.2 %

Procedure:
A mixture of 2-bromomethyl-2,3-dihydroimidazo[1,2-c]-quinazolin-5(6H)-one (0.5 g, 1.78 mmol), N-phenylpiperazine (0.28 mL, 3.56 mmol) in acetonitrile (25 mL) was refluxed for 13 hours. The hot mixture was filtered and washed with acetonitrile (10 mL) to give 2-(4-phenyl-1-piperazinyl)methyl-2,3-dihydroimidazo[1,2-c]-quinazolin-5(6H)-one (490 mg, 76%). An analytical sample was prepared from a mixture of acetonitrile and methanol (1:1), mp 257°-258° C. ms: m/z 361 (M+). 1H NMR (300 MHz, DMSO-d6): δ2.43-2.73 (m, 7H, CH2), 3.11 (t, 3H, CH2), 3.65 (q, 1H, CH), 3.91 (t, 1H, CH), 4.41 (m, 1H, CH), 6.75 (t, 1H, Ar--H), 6.91 (d, 2H, Ar--H), 7.06 (q, 2 H, Ar--H), 7.17 (q, 2H, Ar--H), 7.48 (p, 1H, Ar--H), 7.78 (d, 1H, Ar--H), 10.53 (s, 1H, NH). Anal. Calcd for C21H23N5O: C, 69.78; H, 6.41; N, 19.38. Found: C, 69.79; H, 6.45; N, 19.37.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C@H:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([N:18]([CH3:25])[CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:17])[CH:14]=2)[CH2:9][CH2:8]1)=[O:5].Cl[C:31]1[CH:36]=[CH:35][N:34]=[C:33]([NH2:37])[N:32]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[NH2:37][C:33]1[N:34]=[C:35]([N:22]2[CH2:21][CH2:20][CH:19]([N:18]([CH3:25])[C:16]([C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[CH2:9][CH2:8][C@H:7]4[NH:6][C:4](=[O:5])[C:3]3[CH:26]=[CH:27][CH:28]=[CH:29][C:2]=3[Cl:1])=[O:17])[CH2:24][CH2:23]2)[CH:36]=[CH:31][N:32]=1
Reactant: Nc1nccc(Cl)n1
Reactant: CN(C(=O)c1ccc2c(c1)[C@H](NC(=O)c1ccccc1Cl)CC2)C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CN(C(=O)c1ccc2c(c1)[C@H](NC(=O)c1ccccc1Cl)CC2)C1CCN(c2ccnc(N)n2)CC1
Reaction time: 0.15 h
Yield: 45 %

Procedure:
A mixture of (R)-3-(2-chlorobenzamido)-N-methyl-N-(piperidin-4-yl)-2,3-dihydro-1H-indene-5-carboxamide (stage 2H-214) (200 mg, 0.486 mmol, 1.0 eq), 4-chloro-pyrimidin-2-ylamine (94 mg, 0.728 mmol, 1.5 eq) and DIPEA (0.125 ml, 0.728 mmol, 1.5 eq) in dioxane (10 ml) was refluxed for 16 h. When the reaction was complete according to TLC monitoring, concentration under reduced pressure was carried out, and the reside was taken up in dichloromethane (50 ml) and washed with water (30 ml) and saturated sodium chloride solution (30 ml). The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 6% methanol in dichloromethane). Yield: 45% (110 mg, 0.267 mmol) Analytical Data—Single Substances Method 1: Equipment and methods for HPLC-MS analysis: HPLC: Waters Alliance 2795 with PDA Waters 2998; MS: Micromass Quattro Micro™ API; column: Waters Atlantis® T3, 3 μm, 100 Å, 2.1×30 mm; column temperature: 40° C., eluent A: purified water+0.1% formic acid; eluent B: acetonitrile (gradient grade)+0.1% formic acid; gradient: 0% B to 100% B in 8.8 min, 100% B for 0.4 min, 100% B to 0% B in 0.01 min, 0% B for 0.8 min; flow: 1.0 ml/min; ionization: ES+, 25 V; batch: 100 μl/min 70% methanol+0.2% formic acid; UV: 200-400 nm.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([CH:11]([CH3:13])[CH3:12])=[C:9]([S:14]S(C3C=CC(C)=CC=3)(=O)=O)[CH:8]=[C:7]([CH3:25])[C:5]=2[N:6]=1.[OH:26][C:27]1[CH2:32][C@@:31]([CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=2)([CH:33]([CH3:35])[CH3:34])[O:30][C:29](=[O:45])[CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[S:3][C:4]2[C:10]([CH:11]([CH3:12])[CH3:13])=[C:9]([S:14][C:28]3[C:29](=[O:45])[O:30][C@:31]([CH2:36][CH2:37][C:38]4[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=4)([CH:33]([CH3:35])[CH3:34])[CH2:32][C:27]=3[OH:26])[CH:8]=[C:7]([CH3:25])[C:5]=2[N:6]=1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c3nc(N)sc3c2C(C)C)cc1
Reactant: CC(C)[C@]1(CCc2ccc(O)cc2)CC(O)=CC(=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)C[C@@](CCc3ccc(O)cc3)(C(C)C)OC2=O)c(C(C)C)c2sc(N)nc12

Procedure:
The title compound was prepared according to General Method 16a using toluene-4-thiosulfonic acid S-(2-amino-7-isopropyl-4-methyl-benzothiazol-6-yl)ester (Example BB-5; 0.35 g, 1.27 mmol), (S)-4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-isopropyl-5,6-dihydro-pyran-2-one (Example J-10; 0.35 g. 1.27 mmol), potassium carbonate (0.7 g), and DMF (5 mL). The crude reaction mixture was purified by flash chromatography (20% EtOAc in hexanes to 50% EtOAc in hexanes to 5% MeOH in EtOAc as eluents), mp 232-234° C. MS (APCI): 513 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([O-:13])=[O:12].[Na+].[CH2:15]1[O:18][CH:16]1[CH3:17].S(=O)(=O)(O)O>O>[OH:18][CH:16]([CH3:17])[CH2:15][S:11]([C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)[O-])c1
Reactant: CC1CO1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(O)CS(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl

Procedure:
150 g (0.5 mol) of 81% pure sodium 2-chloro-5-nitrobenzenesulphinate are presented in 300 ml of water at pH 8-8.5 and 60° C. To this are added dropwise in the couse of about 8 hours 200 ml of propylene oxide while the pH of the reaction mixture is constantly maintained between 7.5 and 9.5 with 20% strength sulphuric acid. After cooling down, the solids are filtered off with suction and washed twice with 200 ml of water. Drying at 70° C. in vacuo gives 118 g of colourless 2-chloro-5-nitrophenyl 2-hydroxypropyl sulphone.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:15]([C:22]1[CH:27]=[CH:26][C:25]([Mg]Br)=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1C=CC(OC2C=CC(Br)=CC=2)=CC=1.[Cl-].[NH4+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([C:25]2[CH:26]=[CH:27][C:22]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:23][CH:24]=2)([OH:14])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Br[Mg]c1ccc(Oc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Brc1ccc(Oc2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Oc3ccccc3)cc2)CC1
Yield: 45 %

Procedure:
To an 100 ml tetrahydrofuran solution of 3.5 g of N-tert-butoxycarbonyl-4-piperidone, a 35 ml of 4-phenoxyphenyl magnesium bromide prepared from 4-bromodiphenyl ether (0.6 mol/l tetrahydrofuran solution) was dropwise added under ice cooling and the resultant mixture was stirred for 1 hour. To the reaction mixture was added a 30 ml of saturated aqueous ammonium chloride solution. The product was extracted with ether. The extract was washed with saturated saline, dried, filtered, then concentrated under reduced pressure to give a residue, which was then purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give N-tert-butoxycarbonyl-4-(4-phenoxyphenyl)-4-piperidinol in an amount of 2.92 g (yield 45%).
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[CH3:7][N:8]1[C:12]2[C:13]([CH2:17][OH:18])=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[N:9]1>ClCCl>[CH3:7][N:8]1[C:12]2[C:13]([CH:17]=[O:18])=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[N:9]1
Reactant: Cn1nnc2cccc(CO)c21
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cn1nnc2cccc(C=O)c21
Reaction time: 2 h
Yield: 46.6 %

Procedure:
To a stirred mixture of 7.4 parts of potassium permanganate, 0.6 parts of 2-(2-methoxyethoxy)-N,N-bis[2-(2-methoxyethoxy)ethyl] ethamamine and 130 parts of dichloromethane was added dropwise a solution of 7.6 parts of 1-methyl-1H-benzotriazole-7-methanol in dichloromethane. Upon complete addition, stirring was continued for 2 hours. The reaction mixture was filtered over diatomaceous earth and washed with dichloromethane. The organic layer was washed with 30 parts of a hydrochloric acid solution 2N and then with a sodium carbonate solution, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 3.5 parts (46.6%) of 1-methyl-1-H-benzotriazole-7-carboxaldehyde; mp. 126° C. (int. 18).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH:9]=O)[CH:6]=[CH:5][CH:4]=1.[CH:11]1([NH2:14])[CH2:13][CH2:12]1>>[CH:11]1([NH:14][CH2:9][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=2)[CH2:13][CH2:12]1
Reactant: COc1cccc(C=O)n1
Reactant: NC1CC1
Product: COc1cccc(CNC2CC2)n1

Procedure:
prepared by reaction of 6-methoxypyridine-2-carbaldehyde with cyclopropylamine
Reaction SMILES: FC1C=CC=CC=1C(Cl)=O.[F:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](Cl)=[O:16].[NH2:21][C:22]1[CH:23]=[C:24]([CH:35]=[CH:36][N:37]=1)[C:25]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>>[CH2:28]([NH:27][C:25](=[O:26])[C:24]1[CH:35]=[CH:36][N:37]=[C:22]([NH:21][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][CH:20]=[C:12]([F:11])[CH:13]=2)[CH:23]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: Nc1cc(C(=O)NCc2ccccc2)ccn1
Agent: O=C(Cl)c1ccccc1F
Product: O=C(NCc1ccccc1)c1ccnc(NC(=O)c2cccc(F)c2)c1
Yield: 44 %

Procedure:
Following the procedure as describe in Example 6, making variations as required to replace 2-fluorobenzoyl chloride with 3-fluorobenzoyl chloride to react with 2-amino-N-benzylisonicotinamide, N-benzyl-2-(3-fluorobenzamido)isonicotinamide was obtained as a colorless solid in 44% yield: mp 140-143° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.71 (s, 1H), 8.60 (s, 1H), 8.41-8.39 (m, 1H), 7.70-7.55 (m, 3H), 7.51-7.44 (m, 1H), 7.37-7.25 (m, 6H), 6.76-6.66 (m, 1H), 4.65 (d, J=5.8 Hz, 2H); MS (ES+) m/z 350.5 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]([C:13]3[N:18]=[CH:17][C:16]([C:19]4[CH:20]=[N:21][NH:22][CH:23]=4)=[CH:15][N:14]=3)[CH:10]=[CH:11][CH:12]=2)[CH:4]=[N:3]1.[H-].[Na+].C(=O)([O-])[O-].[Cs+].[Cs+].Br.Br[CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=1>CC(N(C)C)=O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]([C:13]3[N:14]=[CH:15][C:16]([C:19]4[CH:20]=[N:21][N:22]([CH2:34][CH2:35][C:36]5[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=5)[CH:23]=4)=[CH:17][N:18]=3)[CH:10]=[CH:11][CH:12]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cccc(-c3ncc(-c4cn[nH]c4)cn3)c2)cn1
Reactant: BrCCc1ccncc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cn1cc(-c2cccc(-c3ncc(-c4cnn(CCc5ccncc5)c4)cn3)c2)cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 2-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]-5-(1H-pyrazol-4-yl)pyrimidine (example 3, 120 mg; 0.40 mmol; 1.0 eq.) in dry DMA (1 mL) was added over a suspension of NaH (60% in oil, 28 mg; 1.19 mmol; 3.0 eq.) in dry DMA (2 mL) maintained at 0° C. under nitrogen atmosphere. The resulting mixture was stirred for one hour at 0° C. then heated at 100° C. O/N after the addition of a solution of 14-(2-Bromo-ethyl)-pyridine hydrobromide (159 mg; 0.60 mmol; 1.5 eq.) in DMA (2 mL). Cesium carbonate (388 mg; 1.19 mmol; 3.00 eq.) and 4-(2-Bromo-ethyl)-pyridine hydrobromide (159 mg; 0.60 mmol; 1.5 eq.) were added and the reaction mixture was heated again at 100° C. O/N. Reaction mixture was then cooled down to RT and quenched with water and extracted with DCM (three times). Combined organic phases were washed with water, brine, dried over magnesium sulfate, filtered and concentrated. The resulting oil was purified by autopreparative LC/MS to give the title compound a white foam (80 mg, 49%). 1H NMR (300 MHz, DMSO-d6) δ 9.12 (s, 2H), 8.56-8.50 (m, 1H), 8.50-8.41 (m, 2H), 8.38 (s, 1H), 8.26 (s, 1H), 8.24-8.17 (m, 1H), 8.15 (s, 1H), 7.92 (s, 1H), 7.77-7.66 (m, 1H), 7.51 (t, J=7.7 Hz, 1H), 7.29-7.19 (m, 2H), 4.48 (t, J=7.1 Hz, 2H), 3.89 (s, 3H), 3.21 (t, J=7.0 Hz, 2H). HPLC (Condition A): Rt 2.47 min (purity 99.6%). MS (ESI+): 408.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[N:6][C:7]=1[I:8].[C:11](Cl)(Cl)=[S:12]>CN(C1C=CN=CC=1)C.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:10][C:11](=[S:12])[NH:9][C:5]2=[N:6][C:7]=1[I:8]
Reactant: S=C(Cl)Cl
Reactant: Nc1cc(Cl)c(I)nc1N
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: S=c1[nH]c2cc(Cl)c(I)nc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DMAP (15.4 g, 126 mmol) was added to a THF (200 mL) solution of 5-chloro-6-iodopyridine-2,3-diamine (17 g, 63.1 mmol). Thiophosgene (4.9 mL, 63.1 mmol) was then added drop-wise via addition funnel under nitrogen and allowed to stir at rt for 1 h. The mixture was then partitioned between ethyl acetate (500 mL) and 2N HCl (100 mL). The ethyl acetate layer was washed with brine, dried over magnesium sulfate and concentrated to give the desired product as a white powder, which was used in the next step without further purification. LC-MS: calculated for C6H3ClIN3S 311.5, observed m/e: 311.91 (M+H)+ (Rt 1.69/5 min).
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[N:22]=[C:23]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([C:36]([F:39])([F:38])[F:37])=[O:35])=[CH:30][CH:29]=2)[O:24][CH:25]=1.O>CN(C=O)C>[F:39][C:36]([F:37])([F:38])[S:34]([C:31]1[CH:32]=[CH:33][C:28]([CH:27]=[CH:26][C:23]2[O:24][CH:25]=[C:21]([CH2:20][O:18][C:15]3[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)=[CH:17][CH:16]=3)[N:22]=2)=[CH:29][CH:30]=1)=[O:35]
Reactant: O=S(c1ccc(C=Cc2nc(CCl)co2)cc1)C(F)(F)F
Reactant: Oc1ccc(OCCCn2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(c1ccc(C=Cc2nc(COc3ccc(OCCCn4ccnn4)cc3)co2)cc1)C(F)(F)F
Reaction time: 0.25 h
Yield: 27 %

Procedure:
14 mg (0.55 mmol) 95% sodium hydride were given to a solution of 110 mg (0.50 mmol) 4-(3-[1,2,3]triazol-1-yl-propoxy)-phenol in 4.0 ml DMF and stirred for 15 min. 168 mg (0.50 mmol) 4-chloromethyl-2-[2-(4-trifluoromethanesulfinyl-phenyl)-vinyl]-oxazole were added and stirring continued at r.t. overnight. After addition of 8 ml water the resulting precipitate was collected and purified by chromatography on silica gel (eluent: ethyl acetate/n-heptane 4:1) to yield 70 mg (27%) colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[CH:6]=[C:7]([CH3:12])[C:8]=1[C:9](O)=[O:10].[N:23]1([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=2)[CH:6]=[C:7]([CH3:12])[C:8]=1[C:9]([N:31]1[CH2:32][CH2:33][CH:28]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:29][CH2:30]1)=[O:10]
Reactant: C1CCN(C2CCNCC2)C1
Reactant: COc1cc(-c2cccc(C(F)(F)F)c2)cc(C)c1C(=O)O
Product: COc1cc(-c2cccc(C(F)(F)F)c2)cc(C)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for intermediate 1,3-methoxy-5-methyl-3′-trifluoromethyl-biphenyl-4-carboxylic acid (intermediate 10) was converted into its acid chloride and reacted with 4-pyrrolidin-1-yl-piperidine to give the title compound as colorless amorphous solid. MS: 447.1 (MH+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]([C:10]1[C:19]2[C@H:20]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)[O:21][C:22]3([CH2:26][CH2:25][CH2:24][CH2:23]3)[C:18]=2[C:17]2[C:16](=[O:37])[CH2:15][C:14]([CH3:39])([CH3:38])[CH2:13][C:12]=2[N:11]=1)([CH3:9])[CH3:8].[OH-].[Na+]>O1CCCC1.O.C(OC(=O)C)C>[CH:7]([C:10]1[C:19]2[C@H:20]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:35])([F:34])[F:36])=[CH:31][CH:32]=3)[O:21][C:22]3([CH2:23][CH2:24][CH2:25][CH2:26]3)[C:18]=2[C:17]2[C@@H:16]([OH:37])[CH2:15][C:14]([CH3:39])([CH3:38])[CH2:13][C:12]=2[N:11]=1)([CH3:9])[CH3:8]
Reactant: CC(C)c1nc2c(c3c1[C@H](c1ccc(C(F)(F)F)cc1)OC31CCCC1)C(=O)CC(C)(C)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1nc2c(c3c1[C@H](c1ccc(C(F)(F)F)cc1)OC31CCCC1)[C@@H](O)CC(C)(C)C2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
120 μl of a 1 M solution of lithium aluminiumhydride in tetrahydrofurane are added dropwise to 55 mg (S)-4′-isopropyl-7′,7′-dimethyl-3′-(4-(trifluoromethyl)phenyl)-7′,8′-dihydro-3′H-spiro[cyclopentane-1,1′-furo[3,4-c]quinolin]-9′(6′H)-one in 2 ml tetrahydrofurane at room temperature. The mixture is stirred for 2 hours and then cooled to 0° C. 10 μl water and 10 μl 4 N solution of sodium hydroxide in water are added successively and the mixture is stirred for further 30 minutes. Then the mixture is diluted with ethylacetate and dried with magnesium sulphate. The solvents are evaporated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethylacetate 90:10 to 50:50).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][OH:12])=[O:4].[N:39]1([C:45](Cl)=[O:46])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>>[NH2:27][C:24]1[CH:23]=[CH:22][C:21]([S:18]([N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C@H:10]([CH2:11][OH:12])[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3]([C@@H:2]([NH:1][C:45]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[O:46])[CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)=[O:4])(=[O:20])=[O:19])=[CH:26][CH:25]=1
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](N)Cc1ccc2ccccc2c1)S(=O)(=O)c1ccc(N)cc1
Reactant: O=C(Cl)N1CCOCC1
Product: CC(C)CN([C@H](CO)CCCCNC(=O)[C@H](Cc1ccc2ccccc2c1)NC(=O)N1CCOCC1)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (2S,5S)-2-amino-N-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexyl}-3-naphthalen-2-yl-propionamide (product of example 49) as described in general procedure D using 4-morpholinecarbonyl chloride. The final product was obtained in 21% yield.