Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](S(C1C=CC=CC=1)(=O)=O)[N:6]=[C:5]2[N:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[N:20]1[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]1
Reactant: CN1CCN(c2nn(S(=O)(=O)c3ccccc3)c3ccc(Br)cc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(c2n[nH]c3ccc(Br)cc23)CC1
Reaction time: 6 h

Procedure:
To a stirred solution, under N2, 5-bromo-3-(4-methyl-1-piperazinyl)-1-phenylsulfonyl-1H-indazole (4.4 g, 0.01 mol) of Example 4c in THF (70 ml), was added, dropwise, lithium aluminum hydride [20 ml of a 1M solution in tetrahydrofuran (THF)]. The reaction was then stirred for 6 hours at reflux. The reaction was cooled in an ice bath, water was added cautiously and then the reaction was filtered. The filter cake was washed with THF and then methanol, and the filtrate was concentrated to yield 5-bromo-3-(4-methyl-1-piperazinyl)-1H-indazole.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[C:4]1=[O:17].[Cl:18][C:19]1[C:20]([O:25][C:26]2[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[N:21][CH:22]=[CH:23][CH:24]=1>>[C:12]([C:11]1[CH:10]=[C:9]([CH:16]=[CH:15][CH:14]=1)[CH2:8][N:5]1[CH2:6][CH2:7][C@H:3]([NH:2][S:32]([C:29]2[CH:30]=[CH:31][C:26]([O:25][C:20]3[C:19]([Cl:18])=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH:27][CH:28]=2)(=[O:34])=[O:33])[C:4]1=[O:17])#[N:13]
Reactant: N#Cc1cccc(CN2CC[C@H](N)C2=O)c1
Reactant: O=S(=O)(Cl)c1ccc(Oc2ncccc2Cl)cc1
Agent: Cl
Product: N#Cc1cccc(CN2CC[C@H](NS(=O)(=O)c3ccc(Oc4ncccc4Cl)cc3)C2=O)c1

Procedure:
The title compound is prepared from 3-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)benzonitrile hydrochloride as in EXAMPLE 24, Part B using 4-(3-chloropyridin-2-yloxy)benzene sulfonyl chloride in place of 6-methoxynaphthalene-2-sulfonyl chloride.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C(C)=CC=CC=1>[C:12]1([NH:11][C:8]([C:7]2[C:2]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)=[O:10])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1cccnc1Cl
Solvent: Cc1ccccc1C
Product: O=C(Nc1ccccc1)c1cccnc1Nc1ccccc1
Temperature: 190 °C
Yield: 26.3 %

Procedure:
To a suspension of 31.5 g (0.2 mole) of 2-chloro-3-pyridinecarboxylic acid in 75 mL of xylene was added 18.6 g (0.2 mole) of aniline, and the reaction mixture was heated at 190° C. (oil bath) for 45 min; then cooled. The xylene was filtered, and the reaction melt that had formed was crushed and partitioned between 100 mL of aqueous NaHCO3 (pH 8) and CH2Cl2 (150 mL). The solid that remained suspended in the two-phase system was filtered and discarded. The filtrate was concentrated to 200 mL, and the solid that precipitated from the two-phase system was filtered to give 7.6 g (13%) of N-phenyl-2-(phenylamino)-3-pyridinecarboxamide. Acetic acid was added to the filtrate to acidify the aqueous layer to pH 6 and the CH2Cl2 layer was separated. The aqueous solution was extracted with CH2Cl2 and the combined extracts were concentrated to 100 mL; the solid that precipitated was filtered and washed sequentially with water and CH2Cl2 to give 15.6 g of the product. An additional 5.3 g of the product was to obtained from the filtrate for a total yield of 20.9 g (49%). The combined product was triturated with CH2Cl2 and then filtered to give 19.6 (46%) of the product as a yellow solid; mp 152°-155° C.; TLC (C6H12 -EtAc; 4:1 and EtAc-MeOH-NH4OH, 16:3:1) showed a single component. MS (EI) m/e (relative intensity): 214 (M+, 100), 213 (94), 195 (70), 169 (45), 168 (70), 167 (22), 77 (37), 51 (26).
Reaction SMILES: ClC1C=CC2N(C(CNC3N=C(N4CCC(C)(O)CC4)C=CN=3)=C(C3C=CC=CC=3)N=2)C=1.[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[N:41]=[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][N:43]3[C:48]=2[CH2:49][C:50]2[CH:55]=[N:54][CH:53]=[C:52](Cl)[N:51]=2)=[CH:36][CH:35]=1.[CH3:57][NH:58][CH2:59][CH2:60][OH:61]>>[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[N:41]=[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][N:43]3[C:48]=2[CH2:49][C:50]2[N:51]=[C:52]([N:58]([CH3:57])[CH2:59][CH2:60][OH:61])[CH:53]=[N:54][CH:55]=2)=[CH:36][CH:35]=1
Reactant: Clc1ccc(-c2nc3ccccn3c2Cc2cncc(Cl)n2)cc1
Reactant: CNCCO
Agent: CC1(O)CCN(c2ccnc(NCc3c(-c4ccccc4)nc4ccc(Cl)cn34)n2)CC1
Product: CN(CCO)c1cncc(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)n1

Procedure:
The title compound was prepared according to the experimental for compound 187 from 2-(4-chlorophenyl)-3-((6-chloropyrazin-2-yl)methyl)imidazo[1,2-a]pyridine and 2-(methylamino)ethanol. M/e+ 394 for C21H21ClN5O (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.06 (d, J=6.6 Hz, 1H), 7.89 (s, 1H), 7.78 (d, J=8.4 Hz, 2H), 7.70 (s, 1H), 7.60 (dd, J=8.4, 0.7 Hz, 1H), 7.40 (d, J=8.4 Hz, 2H), 7.17 (m, 1H), 6.77 (t, J=6.9 Hz, 1H), 4.34 (s, 2H), 3.64 (t, J=5.1 Hz, 2H), 3.54 (t, J=5.1 Hz, 2H), 3.05 (s, 3H) ppm.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[NH:13]1[C:21]2[C:16](=[CH:17][C:18]([C:22]([OH:24])=O)=[CH:19][CH:20]=2)[CH:15]=[CH:14]1.Cl.[C:26]1(/[CH:32]=[CH:33]/[C:34]2[CH2:35][CH2:36][NH:37][CH2:38][CH:39]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O>[NH:13]1[C:21]2[C:16](=[CH:17][C:18]([C:22]([N:37]3[CH2:36][CH:35]=[C:34]([CH:33]=[CH:32][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:39][CH2:38]3)=[O:24])=[CH:19][CH:20]=2)[CH:15]=[CH:14]1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: C1=C(/C=C/c2ccccc2)CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc2[nH]ccc2c1)N1CC=C(C=Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.77 g, 4.02 mmol) was added to a mixture of indole-5-carboxylic acid (0.45 g, 2.79 mmol), (E)-4-(2-phenylethenyl)-1,2,3,6-tetrahydropyridine hydrochloride (0.59 g, 2.66 mmol), 1-hydroxybenzotriazole hydrate (0.56 g, 3.3 mmol) and triethylamine (1.1 ml, 7.9 mmol) in dimethylformamide (20 ml). The reaction mixture was stirred at room temperature, under nitrogen, overnight then poured into water (200 ml) and extracted with ethyl acetate (2×100 ml). The extracts were washed with 1M hydrochloric acid (2×100 ml), saturated brine (100 ml), combined and dried (MgSO4). The residue after evaporation of the solvent was purified by flash chromatography, eluting with 2:1, 3:1 then 4:1 ethyl acetate/petrol (60°-80°), to afford the title compound as an off-white solid (0.55 g, 63%); δH (CDCl3) 2.50 (2H, br s, tetrahydropyridinyl CH2), 3.76 (2H, v br s, tetrahydropyridinyl CH2), 4.31 (2H, v br s, tetrahydropyridinyl CH2), 5.84 (1H, v br s, tetrahydropyridinyl CH), 6.51 (1H, d, J 16.2 Hz, CH=CHPh), 6.60 (1H, br s, 3'-H), 6.81 (1H, d, J 16.2 Hz, CH=CHPh), 7.20-7.42 (9H, m, ArH), 7.42 (1H, s, ArH), and 8.46 (1H, br s, NH).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:17]O>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Reactant: CO
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(F)c(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.8 %

Procedure:
To a solution of 2,6-dichloro-5-fluoronicotinic acid (16) (5 g, 23.8 mmol) in methanol (50 ml) was added thionyl chloride in dropwise (5.66 g, 47.62 mmol) at 0° C. and 2 drops of DMF [vigourous bubbling was observed]. The mixture was stirred at room temperature for 3 h. To this methanol was added and stirred the reaction mixture for 2 h at RT. The reaction mixture is concentrated under reduced pressure to and the mixture was poured in to ice cold water (20 mL) and extracted with dichloromethane (2×50 mL). The combined organic layer was washed with water, brine and solvent was evaporated under reduced pressure to yield methyl 2,6-dichloro-5-fluoronicotinate (17) (5 g, 93.8%).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[O:7][C:6]2[CH:8]=[CH:9][C:10]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:22]4[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH3:30])=[CH:24][CH:23]=4)=[CH:16][CH:15]=3)=[CH:11][C:5]=2[C:4](=[O:31])[O:3]1.[CH:33](=O)[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>>[CH2:33]([N:12]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][CH3:30])=[CH:26][CH:27]=2)=[CH:16][CH:15]=1)[C:10]1[CH:9]=[CH:8][C:6]2[O:7][C:2]([CH3:1])([CH3:32])[O:3][C:4](=[O:31])[C:5]=2[CH:11]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Reactant: CCCCCC=O
Product: CCCCCCN(Cc1ccc(C#Cc2ccc(CCC)cc2)cc1)c1ccc2c(c1)C(=O)OC(C)(C)O2
Yield: 74.7 %

Procedure:
The title compound was prepared following procedure described in Example 23, step b) from 2,2-dimethyl-6-({4-[(4-propylphenyl)ethynyl]benzyl}amino)-4H-1,3-benzodioxin-4-one (660 mg; 1.55 mmol) and hexanal (Aldrich, 279.41 μl, 2.33 mmol). Purification of the crude (880 mg) by flash chromatography using silica gel (EtOAc/c-Hex, 5:95 then 10:90) gave 590 mg (75%) of the title compound as a beige powder. HPLC, Rt.: 6.37 min (purity: 61.9%), 1H NMR (CDCl3) δ: 7.42 (m, 4H), 7.12-7.19 (m, 5H), 6.78 (m, 2H), 4.48 (s, 2H), 3.34 (t, J=7.6 Hz, 2H), 2.57 (t, J=7.8 Hz, 2H), 1.68 (s, 6H), 1.61 (m, 4H), 1.24 (m, 6H), (0.91 (t, J=7.3 Hz, 3H), 0.86 (t, J=6.7 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([OH:17])=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH:34]1([NH:40]O)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.O>CN(C)C=O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([O:17][NH:40][CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1
Reactant: O=C(O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Reactant: ONC1CCCCC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(ONC1CCCCC1)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
A solution of 7-chloro-3-(carboxy)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione (300 mg, 1.03 mmol) (compound of Example 9) and 1,1'-carbonyldiimidazole (251 mg, 1.55 mmol) in N,N-dimethylformamide (12 mL) was stirred for 1 hour. In one portion N-cyclohexylhydroxylamine hydrochloride (469 mg, 3.09 mmol) was added and the solution was stirred for 2 hours at room temperature. To the resulting solution was added water (15 mL). The insoluble material was filtered and dried to give the title compound (286 mg, 72% yield, m.p. 220° C.).
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([CH3:9])([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].C(=O)(O)[O-].[Na+].[CH3:15][O:16][CH2:17][C:18](Cl)=[O:19].Cl>C(OCC)C.O>[CH3:15][O:16][CH2:17][C:18]([NH:1][C@@H:2]([C:6]([CH3:9])([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4])=[O:19]
Reactant: CC(C)(C)[C@H](N)C(=O)O
Reactant: COCC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: COCC(=O)N[C@H](C(=O)O)C(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 20.7 %

Procedure:
(S)-2-amino-3,3-dimethylbutanoic acid (0.50 g, 3.8 mmol) and sodium bicarbonate (0.80 g, 9.5 mmol) were dissolved into water (20 mL) then cooled in an ice bath. Methoxyacetyl chloride (0.38 mL, 4.2 mmol) was dissolved in diethyl ether (5 mL) and added dropwise with vigorous stirring. The solution was stirred at ambient temperature for 5 hours then adjusted to pH 3 with concentrated hydrochloric acid and extracted into ethyl acetate. The organic solution was dried over sodium sulfate, filtered, and concentrated to give 0.16 g (21%) of the title compound as a waxy solid.
Reaction SMILES: C(OC1C=C(O)C=CC=1)C1C=CC=CC=1.Cl[CH:17]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].S1C=CC(COC2C=C(O)C=CC=2)=C1.S1C=CC(COC2C=C(C=CC=2)OC(C2C=CC=CC=2)CCC(OCC)=O)=C1.C1(CCCC([O-])=O)C=CC=CC=1.[OH:85][C:86]1[CH:96]=[C:95]([O:97][CH2:98][C:99]2[CH:104]=[CH:103][CH:102]=[CH:101][CH:100]=2)[CH:94]=[CH:93][C:87]=1[C:88]([NH:90][CH2:91][CH3:92])=[O:89]>>[CH2:91]([NH:90][C:88]([C:87]1[CH:93]=[CH:94][C:95]([O:97][CH2:98][C:99]2[CH:104]=[CH:103][CH:102]=[CH:101][CH:100]=2)=[CH:96][C:86]=1[O:85][CH:17]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:89])[CH3:92]
Reactant: CCNC(=O)c1ccc(OCc2ccccc2)cc1O
Reactant: CCOC(=O)CCC(Cl)c1ccccc1
Agent: CCOC(=O)CCC(Oc1cccc(OCc2ccsc2)c1)c1ccccc1
Agent: O=C([O-])CCCc1ccccc1
Agent: Oc1cccc(OCc2ccccc2)c1
Product: CCNC(=O)c1ccc(OCc2ccccc2)cc1OC(CCC(=O)OCC)c1ccccc1

Procedure:
By proceeding in a similar manner, but replacing methyl 4-benzyloxy-2-hydroxybenzoate with 3-benzyloxyphenol and ethyl (RS)-4-chloro-4-phenylbutanoate with ethyl (RS)-4-chloro-4-(2-methyl)phenylbutanoate, there is prepared ethyl (RS)-4-[(3-benzyloxy)phenoxy]-4-(2-methylphenyl)butanoate. By proceeding in a similar manner, but replacing methyl 4-benzyloxy-2-hydroxybenzoate with 3-(3-thienylmethoxy)phenol, there is prepared ethyl (RS)-4-[3-(3-thienylmethoxy)phenoxy]-4-phenylbutanoate. By proceeding in a similar manner, but replacing methyl 4-benzyloxy-2-hydroxybenzoate with 2-hydroxy-4-(3-thienylmethoxy)acetophenone, there is prepared ethyl (RS)-4-[2-acetyl-5-(3-thienylmethoxy)phenoxy)]-4-phenylbutanoate. By proceeding in a similar manner but replacing methyl 4-benzyloxy-2-hydroxybenzoate with 2-hydroxy-4-benzyloxy-N-ethylbenzamide there is obtained ethyl (RS)-4-[2-(N-ethylcarbamoyl)-5-benzyloxyphenoxy]-4-phenyl-butanoate. By proceeding in a similar manner but replacing methyl 4-benzyloxy-2-hydroxybenzoate with 2-hydroxy-4-(3-thienylmethoxy)acetophenone and ethyl (RS)-4-chloro-4-phenylbutanoate with ethyl (RS)-4-chloro-4-(2-methylphenyl)butanoate, there is prepared ethyl (RS)-4-[2-acetyl-5-(3-thienylmethoxy)phenoxy]-4-(2-methylphenyl)-butanoate. By proceeding in a similar manner, but replacing methyl 4-benzyloxy-2-hydroxybenzoate with 2-hydroxy-4-(3-pyridylmethoxy)acetophenone, there is prepared ethyl (RS)-4-[2-acetyl-5-(3-pyridylmethoxy)phenoxy]-4-phenylbutanoate. By proceeding in a similar manner, but replacing methyl 4-benzyloxy-2-hydroxybenzoate with 4-benzyloxy-2-hydroxybenzamide, there is prepared ethyl (RS)-4-[2-carbamoyl-5-benzyloxyphenoxy]-4-phenylbutanoate. By proceeding in a similar manner, but replacing methyl 4-benzyloxy-2-hydroxybenzoate with 4-benzyloxy-2-hydroxy-N,N-dimethylbenzamide, there is prepared ethyl (RS)-4-[2-N,N-dimethylcarbamoyl-5-benzyloxyphenoxy]-4-phenylbutanoate. By proceeding in a similar manner. but replacing methyl 4-benzyloxy-2-hydroxybenzoate with 4-(3-thienylmethoxy)-2-hydroxybenzamide and ethyl (RS)-4-chloro-4-phenylbutanoate with ethyl (RS)-4-chloro-4-(2-methylphenyl)butanoate, there is prepared ethyl (RS)-4-[2-carbamoyl-5-(3-thienylmethoxy)phenoxy]-4-(2-methylphenyl)butanoate.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[O:12]1[CH2:17][CH2:16][O:15][C:14]2[CH:18]=[C:19]([NH:22][C:23]3[N:32]=[CH:31][CH:30]=[CH:29][C:24]=3[C:25](OC)=[O:26])[CH:20]=[CH:21][C:13]1=2.[OH-].[Na+]>C(OCC)(=O)C>[O:12]1[CH2:17][CH2:16][O:15][C:14]2[CH:18]=[C:19]([NH:22][C:23]3[C:24]([CH2:25][OH:26])=[CH:29][CH:30]=[CH:31][N:32]=3)[CH:20]=[CH:21][C:13]1=2
Reactant: COC(=O)c1cccnc1Nc1ccc2c(c1)OCCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1cccnc1Nc1ccc2c(c1)OCCO2
Yield: 101.4 %

Procedure:
Under a nitrogen gas stream, 1.70 g (41 mmol) of lithium aluminum hydride was added to tetrahydrofuran (100 mL) under ice cooling, and a tetrahydrofuran (30 mL) solution of 9.86 g (34 mmol) of methyl 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)aminonicotinate was added dropwise to the mixture. Ethyl acetate was added to the reaction mixture, and subsequently, 17 mL of a 10% aqueous solution of sodium hydroxide was added thereto. Insoluble materials were filtered off. The filtrate was concentrated, and the residue was dissolved in ethyl acetate, dried, filtered, and concentrated. Thus, 8.9 g of the title compound was obtained as an orange-colored viscous product (yield: quantitative).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[N:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[NH2:21][CH:22]([CH:25]1[CH2:27][CH2:26]1)[CH2:23][OH:24]>>[CH:25]1([CH:22]([NH:21][C:12]([C:10]2[CH:9]=[N:8][C:7]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[CH2:23][OH:24])[CH2:27][CH2:26]1
Reactant: NC(CO)C1CC1
Reactant: O=C(O)c1cnc(N2CC(F)(F)C2)c(OCC2CC2)n1
Product: O=C(NC(CO)C1CC1)c1cnc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 15, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyrazine-2-carboxylic acid (Example 8d, 100 mg, 0.35 mmol) and β-amino-cyclopropaneethanol (CAN 776315-67-4, 78.94 mg, 0.53 mmol) as starting materials, and isolated (20 mg, 14.91%) as light brown solid; LC-MS (UV peak area, ESI) 97.84%, 368.9 (M+H).
Reaction SMILES: [C:1]([S-:3])#[N:2].[K+].C(Cl)(C)=O.[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:18])=[C:15]([CH:17]=1)[NH2:16].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CO.O>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:18])=[C:15]([NH:16][C:1]([NH2:2])=[S:3])[CH:17]=1
Reactant: COc1ccc(C)c(N)c1
Reactant: N#C[S-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CO
Product: COc1ccc(C)c(NC(N)=S)c1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 78 %

Procedure:
To a solution of KSCN (780 mg, 8.02 mmol) in acetone (10 mL) was added dropwise at room temperature as solution of AcCl (900 μL, 8.02 mmol) in acetone (10 mL). The reaction mixture was stirred for 15 min at 50° C. Then, a solution of 5-methoxy-2-methylaniline (1.0 g, 7.29 mmol) in acetone (10 mL) was added and the reaction mixture was stirred at 50° C. for 15 min. Water was added and the solid was filtered, washed with more water and ether to give a white solid. A solution of the latter with K2CO3 (2.0 g, 14.58 mmol) in MeOH (20 mL) was stirred at room temperature for 3 h. MeOH was removed under reduced pressure and the solid was washed with water and ether to give III-b as a white solid in 78% yield. 1H NMR (300 MHz, DMSO-d6) δ 9.20 (s, 1H), 7.13 (d, J=8.4 Hz, 1H), 6.81 (d, J=2.4 Hz, 1H), 6.75 (dd, J=8.3, 2.6 Hz, 1H), 3.71 (s, 3H), 2.10 (s, 3H).
Reaction SMILES: [P:1]([O-:13])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[K+].C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=O.C([NH3+])CCC.C([NH3+])CCC.[Cl:35][CH2:36]OS(Cl)(=O)=O>C(Cl)Cl.O>[P:1]([O:13][CH2:36][Cl:35])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:2]
Reactant: CC(C)(C)OP(=O)([O-])OC(C)(C)C
Reactant: O=S(=O)(Cl)OCCl
Agent: CCCC[NH3+]
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OP(=O)(OCCl)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 100 mL round bottomed flask was charged with potassium ditert-butyl phosphate (1.0 g, 4.03 mmol), sodium bicarbonate (677.4 mg, 8.06 mmol), n-butylammonium sulfate (68.2 mg, 0.403 mmol), water (10 ml) and methylene chloride (5 ml). To the mixture was added a solution of chloromethylchlorosulfonate (797.9 mg, 4.84 mmol) in methylene chloride (5 ml), and the mixture stirred at room temperature for 2 hours. To the reaction product was added water (30 ml), and the whole was extracted with methylene chloride (30 ml×3). The combined organic layers were washed with brine (30 ml), dried with Na2SO4, and solvent removed under reduced pressure. The residue was purified by column-chromatography (silica gel=80 g, hexane/ethyl acetate=1:1) to give di-t-butyl chloromethyl phosphate, as a colorless oil.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[O:12][CH3:13].[CH3:15][C:16]1([CH3:29])[C@@H:18]2[CH2:19][C:20]3[C:24]([C@H:17]12)=[C:23]([CH3:25])[S:22][C:21]=3[C:26](O)=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:13][O:12][C:5]1[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:4]=1[C:3]1[N:14]=[C:26]([C:21]2[S:22][C:23]([CH3:25])=[C:24]3[C:20]=2[CH2:19][C@H:18]2[C:16]([CH3:29])([CH3:15])[C@H:17]23)[O:1][N:2]=1
Reactant: COc1ccc(C(=N)NO)c(OC)c1
Reactant: Cc1sc(C(=O)O)c2c1[C@H]1[C@@H](C2)C1(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2noc(-c3sc(C)c4c3C[C@@H]3[C@H]4C3(C)C)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 9.9 %

Procedure:
A mixture of N-hydroxy-2,4-dimethoxy-benzamidine (98 mg, 0.50 mmol), (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid (111 mg, 0.50 mmol), TBTU (178 mg, 0.55 mmol) and DIPEA (646 mg, 5 mmol) in DMF (4 mL) is stirred at rt for 45 min, then at 110° C. for 1 h. The reaction mixture is directly subjected to prep. HPLC purification (Phenomenex Aqua 75×30 mm, gradient with acetonitrile/water containing 0.5% formic acid) to give 3-(2,4-dimethoxy-phenyl)-5-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-[1,2,4]oxadiazole (19 mg) as a colourless lyophilisate; LC-MS: tR=1.17 min, [M+1]+=383.13; 1H NMR (CDCl3): δ 7.89 (d, J=8.8 Hz, 1H), 6.46 (dd, J=2.3, 8.8 Hz, 1H), 6.43 (d, J=2.3 Hz, 1H), 3.83 (s, 3H), 3.74 (s, 3H), 2.96 (dd, J=5.9, 18.8 Hz, 1H), 2.80 (d, J=18.8 Hz, 1H), 2.29 (s, 3H), 1.88-1.78 (m, 2H), 1.02 (s, 3H), 0.63 (s, 3H).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]3[C:15]4[NH:16][C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=5[C:23](=[O:24])[C:14]=4[CH2:13][NH:12]3)=[CH:10][C:5]=2[CH2:4][CH2:3]1.Br[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]3[C:15]4[NH:16][C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=5[C:23](=[O:24])[C:14]=4[CH2:13][N:12]3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[CH:10][C:5]=2[CH2:4][CH2:3]1
Reactant: O=c1c2c([nH]c3ccccc13)C(c1ccc3c(c1)CCO3)NC2
Reactant: Brc1ccccn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: O=c1c2c([nH]c3ccccc13)C(c1ccc3c(c1)CCO3)N(c1ccccn1)C2

Procedure:
3-(2,3-dihydro-5-benzofuranyl)-1,2,3,4-tetrahydro-9H-pyrrolo[3,4-b]quinolin-9-one HCl (0.30 g, 0.88 mmol) and 2-bromo-pyridine (2 mL), Pd2dba3 (0.23 g, 0.25 mmol), BINAP (0.47 g, 0.75 mmol) and NaOtBu (0.66 g, 6.87 mmol) were stirred in 1,4-dioxane (4 mL) at 90° C. for 1 hour. The resulting mixture was concentrated and then filtered on a plug of Celite with CH2Cl2. Purification by preparative TLC (5% CH3OH/CH2Cl2) yielded the title product as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH2:18])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH:18][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)=[O:28])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C(C)C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(F)cc2)cc1-c1c(Br)cnn1C(C)C
Reaction time: 8 h
Yield: 32.1 %

Procedure:
To a solution of 3-(4-bromo-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.08 g, 0.258 mmol) in CH2Cl2, was added 4-fluoro phenyl isocyanate (0.036 g, 0.263 mmol) and stirred overnight. The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo to yield Compound 50 as a colorless solid (0.037 g, 32%). LCMS m/z (%)=449 M+H+ (81Br, 58), 447 M+H+ (79 Br, 63), 1H NMR (400 MHz, CDCl3) δ: 7.5 (s, 1H), 7.346 (d, 1.95 Hz, 2H), 7.326 9 bs, 1H), 7.151 (d, J=4.77 Hz, 1H), 7.124 (t, 1H), 6.995 (d, J=1.87 Hz, 2H), 6.869 (d, J=5.42 Hz, 1H), 6.847 (d, J=4.71 Hz, 1H), 4.045 (m, 1H), 3.651 (s, 3H), 1.333 (d, J=6.61 Hz, 3H), 1.160 (d, J=6.61 Hz, 3H).