Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].Cl[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>COCCOC>[C:8]1([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C1COCCN1
Reactant: Clc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Product: c1ccc(N2CCOCC2)cc1
Temperature: 50 °C

Procedure:
In air, potassium tert-butoxide (127 mg, 1.10 mmol) and complex Ih (6.8 mg, 0.01 mmol, 1.0 mol %) as defined in Example 1 were weighed into a vial with a stir bar and the vial was capped with a septum. The atmosphere was replaced with inert gas (Ar) and 1 mL of dry DME added and stirred until all the solids had dissolved. Chlorobenzene (102 μL, 112.56 mg, 1.0 mmol) and morpholine (96 μL, 96 mg, 1.10 mmol) were then added in quick succession with rapid stirring. The septum was then replaced with a Teflon® lined cap under inert gas (Ar) and the vial heated at 50° C. for 1 hour. After this time the reaction mixture was cooled and partitioned between water and ether, the organic phase was dried (anhydrous MgSO4), filtered, and the solvent removed. The resultant residue was purified by flash chromatography eluting with 9:1 pentane:ether. N-Phenylmorpholine was obtained as a white solid 155 mg, 95% yield.
Reaction SMILES: [C:1]1([CH:14]=O)[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH:4]=[CH:3][N:2]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[N:16]1[C:25]2[CH:24]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:23][CH2:22][CH2:21][C:20]=2[CH:19]=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(O)(=O)C>[C:1]1([CH2:14][N:26]([CH:24]2[C:25]3[N:16]=[CH:17][CH:18]=[CH:19][C:20]=3[CH2:21][CH2:22][CH2:23]2)[CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH:4]=[CH:3][N:2]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: O=Cc1nccc2c1[nH]c1ccccc12
Reactant: CC(C)(C)OC(=O)NCCCCNC1CCCc2cccnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCCCN(Cc1nccc2c1[nH]c1ccccc12)C1CCCc2cccnc21
Yield: 24 %

Procedure:
A heavy-walled Pyrex tube was charged with a solution of 9H-pyrido[3,4-b]indole-1-carbaldehyde, 2, (0.20 g, 1.02 mmol) in 1,2-dichloroethane (5 mL). This solution was treated with tert-butyl 4-(5,6,7,8-tetrahydroquinolin-8-ylamino)butylcarbamate, 3, (0.36 g, 1.12 mmol), sodium triacetoxyborohydride (0.43 g, 2.04 mmol), 4 A molecular sieves and a catalytic amount of acetic acid (2 drops). The reaction mixture was exposed to microwave irradiation for 10 min at a temperature of 100° C. After the irradiation, the reaction mixture was cooled with high-pressure air until the temperature had fallen below 40° C. The crude reaction mixture was poured onto a saturated aqueous solution of sodium bicarbonate. The product was extracted with dichloromethane. The combined organic layers were washed with brine, dried over potassium carbonate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-5% methanol/CH2Cl2) to afford 0.12 g (24% yield) of desired product 4: 1H NMR (400 MHz, CDCl3) δ 13.43 (bs, 1H), 8.67 (d, J=3.6 Hz, 1H), 8.24 (d, J=5.6 Hz, 1H), 8.10 (d, J=7.6 Hz, 1H), 7.82 (d, J=5.2 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.54 (dt, J=1.2, 7.4 Hz, 1H), 7.41 (d, J=7.2 Hz, 1H), 7.21 (dt, J=0.8, 7.2 Hz, 1H), 7.14 (dd, J=4.8, 7.6 Hz, 1H), 4.28-4.02 (m, 4H), 2.90-2.60 (m, 5H), 2.44-2.26 (m, 2H), 2.12-2.04 (m, 1H), 1.96-1.84 (m, 1H), 1.80-1.65 (m, 1H), 1.44-1.25 (m, 1H), 1.33 (s, 9H), 1.22-1.12 (m, 1H); ESI+ MS: m/z (rel intensity) 500.2 (100, [M+H]+).
Reaction SMILES: [Na].Cl[C:3]1[N:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]>C(O)CCC>[CH2:5]([O:6][C:3]1[C:4]([C:5]([OH:7])=[O:6])=[CH:8][CH:9]=[CH:10][N:11]=1)[CH2:4][CH2:8][CH3:9]
Reactant: O=C(O)c1cccnc1Cl
Agent: [Na]
Solvent: CCCCO
Product: CCCCOc1ncccc1C(=O)O
Temperature: 80 °C
Yield: 192.3 %

Procedure:
Sodium (3.0 g, 130 mmol) was added to n-butanol (100 mL), and the mixture warmed to 80° C. until a solution was obtained, and then 2-chloro-nicotinic acid (10.0 g, 63.4 mmol) added, and the reaction heated under reflux for 4 hours. The cooled mixture (which solidified on cooling) was crushed and then partitioned between ethyl acetate and aqueous hydrochloric acid (sufficient to achieve pH 4), and the layers separated. The organic phase was washed with brine, and evaporated under reduced pressure. The residue was redissolved in ethyl acetate, dried (MgSO4) and re-evaporated to give the title compound as a solid (11.9 g, 96%).
Reaction SMILES: C(S[C:9]1[C:10]([O:23][CH3:24])=[C:11]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=[O:22])[CH:12]=[C:13]([F:15])[CH:14]=1)C1C=CC=CC=1.[S:25]([Cl:29])(Cl)(=[O:27])=[O:26]>>[F:15][C:13]1[CH:12]=[C:11]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=[O:22])[C:10]([O:23][CH3:24])=[C:9]([S:25]([Cl:29])(=[O:27])=[O:26])[CH:14]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1c(SCc2ccccc2)cc(F)cc1N1CCCCC1=O
Product: COc1c(N2CCCCC2=O)cc(F)cc1S(=O)(=O)Cl

Procedure:
Intermediate 14 (1.6 g, 4.63 mmol) was converted to the title compound sulfonyl chloride using the procedure described in example 1; 1.6). The crude material was used without further purification in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([Cl:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[Cl:14][C:15]1[CH:16]=[C:17](/[CH:22]=[CH:23]/[S:24](Cl)(=[O:26])=[O:25])[CH:18]=[CH:19][C:20]=1[Cl:21]>>[Cl:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([NH:1][S:24](/[CH:23]=[CH:22]/[C:17]2[CH:18]=[CH:19][C:20]([Cl:21])=[C:15]([Cl:14])[CH:16]=2)(=[O:26])=[O:25])=[C:3]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:4]=1
Reactant: O=S(=O)(Cl)/C=C/c1ccc(Cl)c(Cl)c1
Reactant: Nc1cc(F)c(Cl)cc1S(N)(=O)=O
Product: NS(=O)(=O)c1cc(Cl)c(F)cc1NS(=O)(=O)/C=C/c1ccc(Cl)c(Cl)c1
Yield: 40 %

Procedure:
The title compound was synthesized as described for Example 226 a) in 40% yield, starting from 2-amino-5-chloro-4-fluorobenzenesulfonamide and (E)-2-(3,4-dichlorophenyl)ethenesulfonyl chloride.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[C:12]([OH:18])=[CH:13][C:14](=[O:17])[NH:15][CH:16]=1>N1C=CC=CC=1>[Cl:10][C:11]1[C:12]([O:18][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][C:14]([O:17][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:15][CH:16]=1
Reactant: O=c1cc(O)c(Cl)c[nH]1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(Oc1cc(OC(=O)c2ccccc2)c(Cl)cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
A 1.76 ml quantity of benzoyl chloride was added to a suspension of 1.00 g of 5-chloro-4-hydroxy-2-pyridone in 30 ml of pyridine, and the mixture was stirred at room temperature for two hours. The solvent was distilled off and the residue was dissolved in a mixture solution of 60 ml of ethyl acetate and 30 ml of water. The ethyl acetate layer was separated, washed twice with 30 ml of water, dried on anhydrous sodium sulfate and concentrated. The concentrate was further washed with a small amount of ethanol, giving 2.11 g of the title compound in a yield of 86.8%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([NH:19][OH:20])[CH:17]=[CH:18][C:13]=2[N:12]2[C:21]([CH3:24])=[N:22][N:23]=[C:11]2[CH2:10][N:9]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N:19]=[O:20])[CH:17]=[CH:18][C:13]=2[N:12]2[C:21]([CH3:24])=[N:22][N:23]=[C:11]2[CH2:10][N:9]=1
Reactant: Cc1nnc2n1-c1ccc(NO)cc1C(c1ccccc1Cl)=NC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1nnc2n1-c1ccc(N=O)cc1C(c1ccccc1Cl)=NC2

Procedure:
Manganese dioxide, 20 g, was added to a suspension of 2 g of 6-(2-chlorophenyl)-8-hydroxyamino-1-methyl-4H-s-triazolo-[4,3-a][1,4]benzodiazepine in 1 l of methylene chloride. After stirring for 3 hr at room temperature the manganese dioxide was separated by filtration over celite. The filtrate was evaporated and the residue was crystallized from methylene chloride/ether to yield the above-named product, with mp. 190°-195° dec. For analysis it was recrystallized from ethanol/ether.
Reaction SMILES: [CH:1]([C:3]1[C:12]2[O:13][C:14]3([C:24]([CH3:26])([CH3:25])[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([O:27][CH3:28])[CH:22]=4)[N:17]3[CH3:29])[CH:15]=[N:16][C:11]=2[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)=O.[Cl-].[C:31]([CH2:33][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:32]>>[C:31]([CH:33]=[CH:1][C:3]1[C:12]2[O:13][C:14]3([C:24]([CH3:25])([CH3:26])[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([O:27][CH3:28])[CH:22]=4)[N:17]3[CH3:29])[CH:15]=[N:16][C:11]=2[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)#[N:32]
Reactant: N#CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc2c(c1)C(C)(C)C1(C=Nc3c(c(C=O)cc4ccccc34)O1)N2C
Agent: [Cl-]
Product: COc1ccc2c(c1)C(C)(C)C1(C=Nc3c(c(C=CC#N)cc4ccccc34)O1)N2C

Procedure:
This compound is prepared according to the method employed for Example 4, from 0.39 g (1 mmol) of the compound of Example 2 and 0.34 g (1 mmol) of cyanomethyltriphenylphosphonium chloride.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[CH3:18][N:19]([CH3:29])[C:20]1[N:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[CH3:18][N:19]([CH3:29])[C:20]1[N:25]=[CH:24][C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([F:17])[CH:3]=2)=[CH:22][CH:21]=1
Reactant: CN(C)c1ccc(B(O)O)cn1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(N(C)C)nc4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, grey solid (76 mg, 90%), MS (ISP) m/z=339.5 [(M+H)+], mp 259° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 6-dimethylamino-pyridin-3-ylboronic acid (53.9 mg, 0.325 mmol).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[C-:18]#[N:19].[K+]>C(O)C>[C:18]([CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)#[N:19]
Reactant: COc1ccc(-c2ccc(CCCl)cc2)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Product: COc1ccc(-c2ccc(CCC#N)cc2)cc1
Yield: 52 %

Procedure:
4-[2-Cyanoethyl]-4'-methoxy-biphenyl was prepared from 4-[2-chloroethyl]-4'-methoxy-biphenyl (see Example A) by boiling with potassium cyanide in aqueous ethanol for 78 hours. Yield: 52% of theory; m.p. 105°-107° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([NH:9][C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:18])[CH:12]=2)=[C:4]([OH:20])[CH:3]=1.Cl.N1C=CC=CC=1>>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]2[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:18])[CH:12]=3)[O:20][C:4]=2[CH:3]=1
Reactant: O=C(Nc1cc(O)c(Cl)cc1O)c1ccc(O)c(F)c1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1ccc(-c2nc3cc(O)c(Cl)cc3o2)cc1F

Procedure:
The title compound was prepared in substantially the same manner as described in Example 1, step b, from N-(4-chloro-2,5-dihydroxyphenyl)-3-fluoro-4-hydroxybenzamide and pyridine hydrochloride and was obtained as a white solid, m.p. 258-260° C.; MS m/e 278 (M−H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[C:21]1([CH2:27][O:28][C:29]2[C:30]([O:39][CH2:40][CH2:41]O)=[CH:31][C:32]3[C:37]([CH:38]=2)=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:41][CH2:40][O:39][C:30]2[C:29]([O:28][CH2:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)=[CH:7][CH:6]=1
Reactant: OCCOc1cc2ccccc2cc1OCc1ccccc1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)C(=O)c1ccc(OCCOc2cc3ccccc3cc2OCc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (2.29 g) in dimethylformamide (30 mL) under argon was treated with 55% sodium hydride (0.552 g), stirred for 15 minutes and treated with the mesylate (4.3 g) prepared from 2-[3-(phenylmethoxy)-2-naphthalenyloxy]ethanol. The mixture was heated under argon at 60° C. overnight. The cooled mixture was treated with glacial acetic acid (2 drops) and the volatiles were removed under vacuum. The residue was mixed with water and extracted with dichloromethane. The organic layer was washed with water, dried (Na2SO4), filtered, and evaporated to give crude product. The material was purified by HPLC (dichloromethane-hexane; 3:1 plus 2% ethyl acetate) to provide, after crystallization from dichloromethane-methanol, 3.0 g of alpha-oxo-4-[[2-[3-(phenylmethoxy)-2-naphthalenyloxy]ethyl]oxy]benzeneacetic acid methyl ester as a colorless solid, mp 115°-117° C.
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH3:12])[C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.C1C(=O)N([Br:28])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:28][CH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)([CH3:12])[C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(Oc1ccc(C)cc1)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(C)(Oc1ccc(CBr)cc1)c1ccccc1
Yield: 66.9 %

Procedure:
A solution of the product of Step B (26 mg, 0.096 mmol) NBS (16 mg, 0.95 eq) and AIBN (2 mg, catalytic amount) in CCl4 (2 mL) was heated to reflux for 1 hour and then concentrated in vacuo. The residue was purified on a silica gel flash chromatography column (125×20 mm) eluted with 5% ethyl acetate/hexane to yield 21 mg (62%) of the title compound.
Reaction SMILES: ClC1C(Cl)=CC=CC=1[CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][NH:25]3)=[CH:21][CH:20]=2)[CH2:11][CH2:10]1.[Na+].[I-].[Cl:30][C:31]1[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:32]=1[N:38]1CCCN(CCCCOC2C=C3C(CCC(=O)N3)=CC=2)CC1.CCN(C(C)C)C(C)C>CC#N>[Cl:30][C:31]1[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:32]=1[N:38]1[CH2:9][CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][NH:25]3)=[CH:21][CH:20]=2)[CH2:11][CH2:10]1
Reactant: Clc1cccc(C2CCN(CCCOc3ccc4cn[nH]c4c3)CC2)c1Cl
Reactant: O=C1CCc2ccc(OCCCCN3CCCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Clc1cccc(N2CCCN(CCCOc3ccc4cn[nH]c4c3)CC2)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.2 %

Procedure:
A mixture of intermediate 44 (43.7 mg, 0.17 mmol) and NaI (51.3 mg, 0.34 mmol) in CH3CN (3 mL) was heated to reflux for 30 min and then cooled to rt. To this mixture was added intermediate 2 (57.9 mg, 0.21 mmol), followed then by DIEA (0.066 mL, 0.38 mmol). The resulting mixture was heated to reflux and stirred for 4 h. Precipitated crystals were filtered off and the filtrate was evaporated under reduced pressure. The residue was extracted with EtOAc. The combined EtOAc layers were washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by ISCO to give 6-(3-(4-(2,3-dichlorophenyl)-1,4-diazepan-1-yl)propoxy)-1H-indazole (compound 46) (43.6 mg, 61%). 1H NMR (400 MHz, CDCl3): δ 7.96 (d, J=0.8 Hz, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.15-7.07 (m, 2H), 7.00 (dd, J=7.4, 2.3 Hz, 1H), 6.88 (s, 1H), 6.80 (dd, J=8.8, 2.1 Hz, 1H), 4.09 (t, J=6.1 Hz, 2H), 3.43-3.37 (m, 2H), 3.29 (t, J=6.1 Hz, 2H), 3.14-3.05 (m, 4H), 3.00-2.92 (m, 2H), 2.22-2.10 (m, 4H). HPLC: 99%, RT 4.201 min. MS (ESI) m/z 419.10 [M+H]+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@:8]3([OH:27])[CH2:9][CH2:10][C@@H:11]2/[CH:12]=[CH:13]/[C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:28]([O:1][C@H:2]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@:8]3([OH:27])[CH2:9][CH2:10][C@@H:11]2/[CH:12]=[CH:13]/[C:14]([O:16][CH3:17])=[O:15])[CH2:3]1)(=[O:30])[CH3:29]
Reactant: COC(=O)/C=C/[C@H]1CC[C@]2(O)[C@@H]3CC[C@@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COC(=O)/C=C/[C@H]1CC[C@]2(O)[C@@H]3CC[C@@H]4C[C@@H](OC(C)=O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
To a solution of 9.00 g of methyl (E)-3β,14β-dihydroxy-5β-pregn-20-ene-21-carboxylate (Boutagy J. and Thomas R., Aust. J. Pharm. Sci., 1972, NS1, 67) in 40 ml of pyridine, 0.04 g of 4-dimethylaminopyridine and 11.5 ml of acetic anhydride were added at room temperature, under nitrogen atmosphere. After 4 hrs the reaction was concentrated under reduced pressure, neutralized with aqueous sodium dihydrogenphosphate and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness to give 9.05 g of methyl (E)-3β-acetoxy-14β-hydroxy-5β-pregn-20-ene-21-carboxylate.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([O:23][CH3:24])=[C:7]([O:21][CH3:22])[CH:8]=2)[N:3]=1.Cl.[CH2:26]([NH2:28])[CH3:27]>>[CH3:22][O:21][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[O:23][CH3:24])[N:3]=[C:2]([NH:28][CH2:26][CH3:27])[N:11]=[C:10]2[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1
Reactant: COc1cc2nc(Cl)nc(-c3cccc([N+](=O)[O-])c3)c2cc1OC
Reactant: CCN
Agent: Cl
Product: CCNc1nc(-c2cccc([N+](=O)[O-])c2)c2cc(OC)c(OC)cc2n1
Yield: 35.7 %

Procedure:
Starting from 500 mg 2-chloro-6,7-dimethoxy-4-(3-nitrophenyl)quinazoline and 1.18 g ethylamine hydrochloride, 183 mg of the title compound was obtained as yellow crystals in the same manner as in Production Example 4.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[O:8][C:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[CH2:10][C:3]=12.C(=O)([O-])[O-].[Na+].[Na+].[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>O>[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[O:8][C:9]4([CH:15]5[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]5)[CH2:11]4)[CH2:10][C:3]=23)[CH2:27][CH2:26]1
Reactant: Clc1ccnc2c1CC1(CN3CCC1CC3)O2
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CN1CCN(c2ccnc3c2CC2(CN4CCC2CC4)O3)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48 %

Procedure:
A solution of 97 mg (0.387 mmol) of 4'-chlorospiro[1-azabicyclo[2.2.2]octane-3,2'(3'H)-furo[2,3-b]pyridine] in 1 mL of 1-methylpiperazine was heated to reflux under a nitrogen atmosphere and stirred for 18 hours. Upon cooling to ambient temperature, the diluted with 40 mL of water, basicified with 2 mL of saturated aqueous sodium carbonate and extracted with chloroform (3×25 mL). The combined organic extract was dried over anhydrous magnesium sulfate, concentrated in vacuo, and flash chromatographed on neutral silica gel using a 4:1 mixture of ammoniated chloroform/methanol to provide 59 mg (48%) of the title compound as an amber oil: electrospray MS (m/z, relative intensity) 315 ([MH]+).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:22])[NH:7][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH3:21])=[CH:13][CH:12]=2)=[N:9][N:10]=1)[CH2:3][CH3:4].[CH:23]1([C:28](Cl)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH3:21][C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]([C:8]2[NH:7][C:6](=[O:22])[C:5]([CH:2]([NH:1][C:28]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:29])[CH2:3][CH3:4])=[N:10][N:9]=2)=[CH:12][CH:13]=1
Reactant: CCC(N)c1nnc(-c2ccc(C)c3ccccc23)[nH]c1=O
Reactant: O=C(Cl)C1CCCC1
Product: CCC(NC(=O)C1CCCC1)c1nnc(-c2ccc(C)c3ccccc23)[nH]c1=O

Procedure:
In analogy to the procedure for Example 36A, 600 mg (2.04 mmol) 6-(1-aminopropyl)-3-(4-methyl-1-naphthyl)-1,2,4-triazin-5(4H)-one, 270 mg (2.04 mmol) cyclopentanecarbonyl chloride and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification.
Reaction SMILES: [N+](C1C=CC([O:10][P:11]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)(=[O:31])[O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][N:17]=[C:16]3[C:22]2[NH:23][C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)=CC=1)([O-])=O.CC=C(C)C.[CH2:43](O)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.N12CCCN=C1CCCCC2>ClCCl>[CH2:43]([O:10][P:11]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)(=[O:31])[O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[C:16]2[C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=[N+]([O-])c1ccc(OP(=O)(Oc2ccc3[nH]nc(-c4cc5ccccc5[nH]4)c3c2)c2ccccc2)cc1
Reactant: OCc1ccccc1
Agent: CC=C(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: O=P(OCc1ccccc1)(Oc1ccc2[nH]nc(-c3cc4ccccc4[nH]3)c2c1)c1ccccc1

Procedure:
Phenylphosphonic acid 3-(1H-indol-2-yl)-1H-indazol-5-yl ester benzyl ester is prepared according to procedure F using 150 mg of phenyl-phosphonic acid 3-(1H-indol-2-yl)-1H-indazol-5-yl ester 4-nitrophenyl ester (prepared according to procedure F) in solution in 2 ml of dichloromethane stabilized with amylene, 310 μl of benzyl alcohol and 44 μl of 1,8-diazabicyclo[5.4.0]undec-7-ene. The reaction crude is purified by preparative LC/MS to obtain 16.9 mg of phenylphosphonic acid 3-(1H-indol-2-yl)-1-indazol-5-yl ester benzyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:14])=O>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1c(Cl)cncc1Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1c(Cl)cncc1Cl

Procedure:
A mixture of 3,5-dichloroisonicotinic acid (2.88 g, 15 mmol) and thionyl chloride (30 ml) was heated to reflux. A few drops of DMF were added and the suspension refluxed for 2 h to give a slightly yellow solution. Excess reagent was removed under reduced pressure and the residue azeotroped with toluene (2×50 ml) to give 3,5-dichloroisonicotinoyl chloride. This was dissolved in CH2Cl2 (50 ml) and added to a solution of 4-aminobenzyl alcohol (1.60 g, 13 mmol) and NMM (1.65 ml, 15 mmol) in CH2Cl2 (50 ml). The mixture was stirred at room temperature overnight. Manganese IV oxide (activated, <5 micron, ˜85%, 22 g) was added to the resulting suspension. The mixture was stirred at room temperature for 6 h then filtered through Celite®. The filtrate was washed with dilute hydrochloric acid (1M, 50 ml) and saturated aqueous sodium hydrogen carbonate (50 ml), dried (Na2SO4) and evaporated under reduced pressure to give the title compound (2.40 g, 63%) as a pale yellow solid. δH (DMSO-d6) 11.35 (1H, s, CHO), 9.95 (1H, s, CONH), 8.83 (2H, s, pyH), 7.96 (2H, d, J 8.7 Hz, ArH) and 7.88 (2H, d, J 8.7 Hz, ArH); m/z (ESI, 60V) 295 (M++1).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[CH3:20][S:21]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>>[CH3:20][S:21]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][S:16]([C:14]2[S:15][C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])=[CH:26][CH:25]=1)(=[O:22])=[O:23]
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)NCc3ccc(S(C)(=O)=O)cc3)s2)c(C)[nH]c1=O

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 4-methanesulfonyl-benzyl amine as described in Step 5, Example 24 to give the title compound. MS: m/e 467 (M+H).