Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([N:10]2[CH2:13][CH:12]([O:14][C:15]3[CH:20]=[CH:19][C:18](I)=[CH:17][N:16]=3)[CH2:11]2)=[O:9])[N:2]=1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1[B-](F)(F)F.[K+].CCO.C(N(CC)CC)C>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([N:10]2[CH2:13][CH:12]([O:14][C:15]3[CH:20]=[CH:19][C:18]([C:24]4[C:23]([F:22])=[CH:28][CH:27]=[CH:26][C:25]=4[F:29])=[CH:17][N:16]=3)[CH2:11]2)=[O:9])[N:2]=1
Reactant: O=C(Nc1cccnn1)N1CC(Oc2ccc(I)cn2)C1
Reactant: Fc1cccc(F)c1[B-](F)(F)F
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccnn1)N1CC(Oc2ccc(-c3c(F)cccc3F)cn2)C1
Temperature: 80 °C
Yield: 16.6 %

Procedure:
3-(5-iodo-pyridin-2-yloxy)-azetidine-1-carboxylic acid pyridazin-3-ylamide (50 mg, 0.126 mmol), potassium 2,6-difluorophenyltrifluoroborate (29 mg, 0.132 mmol), triethylamine (0.05 ml, 0.38 mmol) 1,1′-bis[(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with CH2Cl2 (5 mg, 5 mole %) and EtOH (108 mg, 0.786 mmol) were combined and heated at 80° C. for 16 h. The reaction had not gone to completion so further potassium 2,6-difluorophenyltrifluoroborate (29 mg, 0.132 mmol), 1,1′-bis[(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with CH2Cl2 (5 mg, 5 mole %) and triethylamine (0.05 ml, 0.38 mmol) were added and the mixture heated for a further 5 h. The reaction mixture was allowed to cool before being passed through a pad of celite and washed through with EtOAc and MeOH. These organics were evaporated in vacuo, to afford a crude oil, which was purified by flash chromatography, eluting with a gradient of 0 to 4% MeOH in CH2Cl2 to a afford still impure product as a brown oil. This was purified by HPLC (pH 4, HCO2NH4/HCO2H/H2O/MeCN) to afford the desired product as a white solid (8 mg, 17%)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13](=[O:22])[C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[F:21])[CH2:9][CH2:10]Cl.[H-].[Na+].O>CN(C)C=O>[F:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([F:20])[C:14]=1[C:13]1[O:22][CH2:10][CH2:9][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])[N:12]=1
Reactant: O=C(NC(CCCl)c1ccccc1Br)c1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cccc(F)c1C1=NC(c2ccccc2Br)CCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
To a solution of 10.0 g of N-[1-(2-bromophenyl)-3-chloropropyl]-2,6-difluorobenzamide in 60 ml of N,N-dimethylformamide at a temperature of from 5° C. to 10° C., was added portionwise 1.1 g of 60% dispersion in mineral oil of sodium hydride. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into iced water and extracted with ethyl acetate. The ethyl acetate solution was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to afford 7.4 g of 2-(2,6-difluorophenyl)-4-(2-bromophenyl)-5,6-dihydro-4H-1,3-oxazine. ND23.0 1.5750
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][OH:12])=[CH:5][N:4]=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>>[CH3:13][S:14]([O:12][CH2:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[N:4][CH:5]=1)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CCCO)cn1
Product: COc1ccc(CCCOS(C)(=O)=O)cn1

Procedure:
In substantially the same manner as in Reference Example 85, 3-(2-methoxy-5-pyridyl)propanol was reacted with methanesulfonyl chloride to give 3-(2-methoxy-5-pyridyl)propyl methanesulfonate. The yield was quantative. Oily substance.
Reaction SMILES: Br.[Br-].[CH3:3][N:4]([CH3:27])[CH2:5][CH2:6][CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[Br:33][C:34]1[CH:35]=[CH:36][C:37]2[CH2:43][O:42][C:41]3[CH:44]=[CH:45][CH:46]=[CH:47][C:40]=3[C:39](=O)[C:38]=2[CH:49]=1>CCCCCC.O1CCCC1>[Br:33][C:34]1[CH:35]=[CH:36][C:37]2[CH2:43][O:42][C:41]3[CH:44]=[CH:45][CH:46]=[CH:47][C:40]=3/[C:39](=[CH:7]\[CH2:6][CH2:5][N:4]([CH3:27])[CH3:3])/[C:38]=2[CH:49]=1
Reactant: CN(C)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1c2cc(Br)ccc2COc2ccccc21
Agent: Br
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN(C)CC/C=C1/c2cc(Br)ccc2COc2ccccc21

Procedure:
Anhydrous 3-(dimethylamino)propyltriphenylphosphonium bromide hydrobromide (31 g., 60.9 mmole), 122 mmole of n-butyl lithium in hexane, and 9-bromo-6,11-dihydrodibenz[b,e]oxepin-11-one (12.7 g., 43.8 mmole) were reacted in 750 mL dry tetrahydrofuran by the procedure of Example I, Step b. This provided an E/Z (1:6) isomeric mixture of bromoamines. Recrystallization of the mixture from ethyl acetate/methanol gave 1.2 g. of pure Z-isomer as its hydrochloride salt, melting range 91°-100° C. and 2.16 g. of an E/Z (1:4) isomeric mixture which was used in the next step without further purification. pmr (Z-isomer) (CDCl3) δ: 6.94-7.46 (m, 7H, aromatic), 5.64 (t, J=8.0 Hz, 1H, CH=), 5.15 (br s, 2H, CH2O), 3.07 (m, 4H, NCH2CH2), 2.75 (s, 6H, NMe2).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][N:5]1[C:13]2[CH2:12][CH2:11][N:10]([C:14](=[O:16])[CH3:15])[CH2:9][C:8]=2[C:7]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)=[N:6]1.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[C:52]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[N:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)#[N:53].CO.C(Cl)Cl>C(Cl)Cl.O>[C:14]([N:10]1[CH2:11][CH2:12][C:13]2[N:5]([CH2:4][CH:2]([OH:1])[CH2:3][N:63]3[CH2:62][CH2:61][N:60]([C:55]4[CH:56]=[CH:57][CH:58]=[CH:59][C:54]=4[C:52]#[N:53])[CH2:65][CH2:64]3)[N:6]=[C:7]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[C:8]=2[CH2:9]1)(=[O:16])[CH3:15]
Reactant: N#Cc1ccccc1N1CCNCC1
Reactant: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC2CO2)C1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC(O)CN2CCN(c3ccccc3C#N)CC2)C1
Reaction time: 48 h

Procedure:
A solution of 1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (0.84 g, 2.30 mmol) in CH2Cl2 (10 mL) was treated with ytterbium(III) triflate (0.29 g, 0.46 mmol) and 1-(2-cyanophenyl)-piperazine (0.75 g, 3.5 mmol) at 25° C. and stirred for 48 h before it was diluted with CH2Cl2 (100 mL) and H2O (50 mL). The organic layer was separated, washed with H2O (2×50 mL), dried over Na2SO4, and concentrated. Column chromatography (silica, 5% MeOH/CH2Cl2) afforded 1.15 g (90%) of light yellow crystals. TLC (silica, 10% MeOH/CH2Cl2): Rf=0.30. MS (electrospray): m/z 553.3 ([M+H]+, C29H31F3N6O2 requires 552.3). 1H NMR (CDCl3, 400 MHz, a mixture of two rotamers): 7.82 and 7.68 (AB pattern, Jab=8.2 Hz, 2H), 7.76 and 7.72 (AB pattern, Jab=8.4 Hz, 2H), 7.60-7.48 (m, 2H), 7.05-7.00 (m, 2H), 4.90 and 4.78 (AB pattern, Jab=16 Hz, 1H), 4.69 (s, 1H), 4.30-3.71 (m, 6H), 3.25 (m, 4H), 3.02-2.75 (m, 4H), 2.70-2.65 (m, 2H), 2.60-2.53 (m, 2H), 2.23 (s, 1.5H), 2.18 (s, 1.5H).
Reaction SMILES: C([N:4]1[CH2:19][CH2:18][C:7]2[N:8]3[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[N:10]=[C:9]3[S:17][C:6]=2[CH2:5]1)(=O)C.[OH-].[Na+]>C(O)C>[CH2:5]1[C:6]2[S:17][C:9]3[N:8]([C:7]=2[CH2:18][CH2:19][NH:4]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:10]=3
Reactant: CC(=O)N1CCc2c(sc3nc4ccccc4n23)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: c1ccc2c(c1)nc1sc3c(n12)CCNC3
Reaction time: 1 h

Procedure:
2-Acetyl-1,2,3,4-tetrahydropyrido[4',3':4,5]thiazolo[3,2-a]benzimidazole (13.5 g., 0.05 mole) is dissolved in 100 ml. of absolute ethanol. Sodium hydroxide (3 ml. of 50% aqueous sodium hydroxide) is added and the reaction mixture is digested on the steam cone for one hour. It is then concentrated in vacuo and the residue is washed with water. The white crystalline material is filtered and dried to yield 7.3 g. of 1,2,3,4-tetrahydropyrido[4',3':4,5]thiazolo[3,2-a]benzimidazole, which is recrystallized from methanol-chloroform to yield 4.3 g. of analytical sample, m.p. 238°-243°.
Reaction SMILES: P([O-])([O-])([O-])=O.[F:6][C:7]1[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([F:17])[CH:10]=[CH:9][C:8]=1[C:18]1[N:19]=[C:20]([NH:23][C:24](=[O:39])[CH2:25][C:26]2[C:34]3[C:33](=[O:35])[N:32]([CH3:36])[C:31](=[O:37])[N:30]([CH3:38])[C:29]=3[S:28][CH:27]=2)[S:21][CH:22]=1.[P:40]([O:52][CH2:53]I)([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41].[H-].[Na+]>CN(C=O)C>[P:40]([O:52][CH2:53][N:19]1[C:18]([C:8]2[CH:9]=[CH:10][C:11]([F:17])=[C:12]([C:13]([F:15])([F:14])[F:16])[C:7]=2[F:6])=[CH:22][S:21][C:20]1=[N:23][C:24](=[O:39])[CH2:25][C:26]1[C:34]2[C:33](=[O:35])[N:32]([CH3:36])[C:31](=[O:37])[N:30]([CH3:38])[C:29]=2[S:28][CH:27]=1)([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:41]
Reactant: CC(C)(C)OP(=O)(OCI)OC(C)(C)C
Reactant: Cn1c(=O)c2c(CC(=O)Nc3nc(-c4ccc(F)c(C(F)(F)F)c4F)cs3)csc2n(C)c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(CC(=O)N=c3scc(-c4ccc(F)c(C(F)(F)F)c4F)n3COP(=O)(OC(C)(C)C)OC(C)(C)C)csc2n(C)c1=O

Procedure:
The title compound was prepared according to the general procedure as described in method A for the preparation of phosphate derivatives by coupling reaction of N-{4-[2,4-difluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-5-yl)acetamide (3.10 g, 3.01 mmol) with freshly prepared di-tert-butyl iodomethyl phosphate (intermediate 2) (4.20 g, 12.02 mmol in presence of sodium hydride (60% dispersion in mineral oil, 360 mg, 9.01 mmol) in dry DMF (31 ml) to yield 2.45 g of pure product as an off-white solid; 1H NMR (300 MHz, CDCl3): δ 1.46 (s, 18H), 3.34 (s, 3H), 3.57 (s, 3H), 4.43 (s, 2H), 6.43 (d, J=7.8 Hz, 2H), 6.79 (s, 1H), 7.08 (t, J=9.0 Hz, 1H), 7.47 (s, 1H), 8.48 (q, J=8.7 Hz, 1H); ESI (m/z): 738.05 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[C:12]([N:19]1[CH2:26][CH2:25][CH2:24][C@H:20]1[C:21](O)=[O:22])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>ClCCl>[C:15]([O:14][C:12]([N:19]1[CH2:26][CH2:25][CH2:24][C@H:20]1[C:21]([NH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])=[O:22])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: Cc1c(N)cccc1C(=O)O
Solvent: ClCCl
Product: Cc1c(NC(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cccc1C(=O)O
Reaction time: 18 h
Yield: 45 %

Procedure:
N-(3-Dimethylaminopropyl)-N-ethylcarbodimide HCl salt (3.1 g, 16.6 mmol) was added to a suspension of 3-amino-2-methylbenzoic acid (2.5 g, 16.6 mmol) and N-Boc-L-proline (3.5 g, 16.6 mmol) in dichloromethane (40 mL). The reaction mixture was stirred under nitrogen for 18 h, diluted with solvent (1 vol) and washed with 1N HCl, brine, and dried (MgSO4). Concentration gave a foam with was applied to a 40 M Biotage SiO2 column, and eluted by gradient 20%-60% B (1000 mL); A=1% acetic acid/hexanes; B=1% acetic acid/ethyl acetate to give J.36 (S)-3-(1-(tert-butoxycarbonyl)pyrrolidine-2-carboxamido)-2-methylbenzoic acid 2.6 g (45%). 1H NMR (300 MHz, DMSO-d6) δ: 12.5 (br. s, 1H), 9.52/9.46 (s, 1H), 7.57 (d, J=7.3 Hz, 1H), 7.44-7.40 (m, 1H), 7.29-7.24 (m, 1H), 4.32-4.28 (m, 1H), 3.47-3.48 (m, 1H), 3.34-3.29 (m, 1H), 2.33 (s, 3H), 1.93-1.80 (m, 4H), 1.41/1.36 (s, 9H). LC (Cond.-J1): 1.55 min; LCMS: Anal. Calcd. for [M+H]+ C18H25N2O5: 349.18; found 349.33.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](C=O)=[C:13]([CH3:15])[N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:6]=2[CH:25]=1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[C:13]([CH3:15])[N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:6]=2[CH:25]=1
Reactant: Cc1nc2n(c1C=O)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: Cc1cn2c(n1)CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2

Procedure:
A mixture of 1.0 g. of 8-chloro-6-(2-chlorophenyl)-2-methyl-4H-imidazo[1,2-a][1,4]benzodiazepine-1-carboxaldehyde (II) and 0.1 g. of tris(triphenylphosphine)rhodium chloride in 50 ml. of benzene is refluxed for about 6 hours. The mixture is then allowed to cool and filtered to remove the catalyst. The filtrate thus obtained is concentrated in vacuo to give 8-chloro-6-(2-chlorophenyl)-2-methyl-4H-imidazo[1,2-a][1,4]benzodiazepine, which is further purified by chromatography on silica gel and/or crystallization.
Reaction SMILES: CO[C:3](=[O:19])[C@H:4]([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH2:5].[CH3:20][N:21]=[C:22]=[S:23].N>C(O)C>[C:11]([NH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:4]1[NH:5][C:22](=[S:23])[N:21]([CH3:20])[C:3]1=[O:19])(=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)c1ccccc1
Reactant: CN=C=S
Agent: N
Solvent: CCO
Product: CN1C(=O)C(CCCCNC(=O)c2ccccc2)NC1=S
Temperature: 40 °C

Procedure:
A solution of Nε-benzoyl-L-lysine methyl ester (26 g) and methyl isothiocyanate (6.75 g) in ethanol (250) was heated under reflux for 12 hours. The solution was saturated with ammonia at 0°C and heated in a bomb at 40°C for 3 days. Evaporation of the solvent gave a gum which was crystallised from isopropyl alcohol. Recrystallisation from iso-propyl alcohol gave the title compound as the quarter isopropyl alcohol solvate 10 g (m.p. 137-8°C). Found: C, 59.4; H, 6.25; N, 13.1. C15H19N3O2S.1/4C3H8O requires C, 59.0; H, 6.6; N, 13.1%.
Reaction SMILES: [CH2:1]1[C@H:5]2[CH2:6][NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10](=O)[N:4]2[CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:25])=CC=1>C1(C)C=CC=CC=1>[CH2:1]1[C@H:5]2[CH2:6][NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10](=[S:25])[N:4]2[CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2NC[C@@H]2CCCN12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: S=C1c2ccccc2NC[C@@H]2CCCN12
Yield: 73.4 %

Procedure:
To 50 ml of toluene, there were added 2.02 g of (11aS)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one prepared in Reference Example 24 and 4.04 g of the Lawesson's reagent and the mixture was heated under reflux for one hour. After cooling the reaction solution, it was concentrated. The resulting residue was subjected to silica gel column chromatography and then eluted with chloroform/acetone (99/1). The elute was concentrated and recrystallized from ethyl acetate to give 1.6 g (yield 73.3%) of the title compound.
Reaction SMILES: [OH:1][CH:2]([CH3:10])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.Cl[C:12]1[N:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]>O1CCOCC1>[OH:1][CH:2]([CH3:10])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:12]2[N:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=[O:15])[CH2:6][CH2:5]1
Reactant: O=C(O)c1cccnc1Cl
Reactant: CC(O)CN1CCNCC1
Solvent: C1COCCO1
Product: CC(O)CN1CCN(c2ncccc2C(=O)O)CC1
Reaction time: 48 h

Procedure:
Grams 3 of 1-(2-hydroxypropyl)piperazine and 1.6 g of 2-chloronicotinic acid in 50 ml dioxane were refluxed for 2 days. The react ion mixture was cooled, then allowed to rest for 2 days, the solvent was removed and the residue was crystallized from absolute ethanol to give 1.2 g of 2-[4-(2-hydroxypropyl)piperazin-1-yl]nicotinic acid, melting at 222°-223° C. (with decomposition).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][O:13][CH3:14].[C:15]1([CH3:24])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.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>[CH3:14][O:13][CH2:12][C:3]1[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH3:24]
Reactant: COCc1cc(C(=O)OC)ccc1Br
Reactant: Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COCc1cc(C(=O)OC)ccc1-c1ccccc1C

Procedure:
A mixture of methyl 4-bromo-3-(methoxymethyl)benzoate (40.0 g, 154 mmol), o-tolylboronic acid (23.1 g, 170 mmol), K2CO3 (106.7 g; 772 mmol) and tetrakis(triphenylphosphine)palladium (0) (1.8 g; 1.54 mmol) was prepared in toluene (200 mL) and water (200 mL) and degassed with N2. The reaction mixture was heated at reflux for 1 hour, and then filtered through a pad of Celite and extracted with EtOAc (1 L). The organic layer was washed with a saturated aqueous solution of NaHCO3 (250 mL), water (250 mL) and brine (250 mL), dried (MgSO4) and concentrated affording the title compound as a yellow oil used without further purification (41.9 g, quantitative). HPLC (Method A), Rt 5.3 min (purity: 89.4%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=O)[CH3:2].[CH2:11]1[CH2:16]CC[CH2:13][CH2:12]1.C(OOC(C)(C)C)(C)(C)C>>[C:1]1([O:4][CH:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH:13]=[CH:12][CH:11]=[CH:16][CH:2]=1
Reactant: C1CCCCC1
Reactant: CC(=O)Oc1ccccc1
Agent: CC(C)(C)OOC(C)(C)C
Product: c1ccc(OC2CCCCC2)cc1
Temperature: 90 °C

Procedure:
Into a pressure vessel phenyl acetate (126 μL, 1 mmol, 1 eq) was added and diluted with cyclohexane (1.080 mL, 10 mmol, 10 eq). To this stirring solution was added 1 mol % of a stock solution of {[Cl2NN]Cu}2(benzene) from the catalyst stock solution described in Example 4 (200 μL=0.01 mmol). After adding of tert-butyl peroxide (220 μL, 1.2 mmol), the pressure vessel was sealed and heated to 90° C. for 24 hr. The catalyst was separated by exposing the mixture to air and filtering through Celite®. After removing cyclohexane under vacuum, the residue was analyzed by 1H NMR and GC/MS to determine the yield and consumption of starting materials.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.FC(F)(F)C(O)=O.[NH:22]1[CH2:27][CH2:26][CH:25]([O:28][N:29]2[C:37](=[O:38])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]2=[O:39])[CH2:24][CH2:23]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([S:9]([N:22]2[CH2:27][CH2:26][CH:25]([O:28][N:29]3[C:30](=[O:39])[C:31]4[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:37]3=[O:38])[CH2:24][CH2:23]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1c2ccccc2C(=O)N1OC1CCNCC1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2ccccc2C(=O)N1OC1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 92.5 %

Procedure:
3-(Trifluoromethyl)benzenesulfonyl chloride (3.23 g, 13.2 mmol) was added to a solution of 2-(piperidin-4-yloxy)isoindoline-1,3-dione trifluoroacetic acid (3.56 g, 9.80 mmol) and N,N-diisopropylethylamine (7.10 g, 55.0 mmol) in CH2Cl2 (85 ml), and stirred at room temperature for 17 hours. The reaction mixture was washed with aqueous 1 N HCl solution (20 ml×3), aqueous NaHCO3 solution (20 ml×3), brine (20 ml×2), dried over Na2SO4, filtered and concentrated in vacuo to give 2-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-4-yloxy)isoindoline-1,3-dione (4.12 g, 93%) as a white solid: LCMS: 454 [M+1]+.
Reaction SMILES: [S:1]([C:5]1[O:13][C:12]2[CH:11]=[C:10]([CH3:14])[N:9]=[CH:8][C:7]=2[CH:6]=1)(=[O:4])(=[O:3])[NH2:2].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>C(#N)C.C(Cl)(Cl)Cl>[CH3:17][N:18]([CH3:20])[CH:19]=[N:2][S:1]([C:5]1[O:13][C:12]2[CH:11]=[C:10]([CH3:14])[N:9]=[CH:8][C:7]=2[CH:6]=1)(=[O:3])=[O:4]
Reactant: Cc1cc2oc(S(N)(=O)=O)cc2cn1
Reactant: COC(OC)N(C)C
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: Cc1cc2oc(S(=O)(=O)N=CN(C)C)cc2cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93 %

Procedure:
To a suspension of 2-sulfamoyl-6-methylfuro[3,2-c]pyridine (3.65 g, 17.2 mmol) in acetonitrile (80 ml), under a nitrogen atmosphere, was added N,N-dimethylformamide dimethyl acetal (2.6 ml, 19.6 mmol). This reaction was stirred for 1.5 hours at room temperature and then diluted with chloroform and washed with water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered through a charcoal pad and the solvent evaporated. The residue was triturated with diethyl ether and the product collected (4.31 g, 93% yield) and used as is. A small portion was crystallized from ethyl acetate for microanalysis, mp. 175°-177° C.
Reaction SMILES: Cl.C1(C(=[N:15][C:16]2[N:21]=[N:20][CH:19]=[C:18]([C:22]3[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=3)[C:25]([O:27][CH3:28])=[O:26])[CH:17]=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[NH2:15][C:16]1[N:21]=[N:20][CH:19]=[C:18]([C:22]2[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=2)[C:25]([O:27][CH3:28])=[O:26])[CH:17]=1
Reactant: COC(=O)c1cccc(-c2cnnc(N=C(c3ccccc3)c3ccccc3)c2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cccc(-c2cnnc(N)c2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 218.1 %

Procedure:
1.0 M HCl (2.0 mL) was added to a solution of methyl 3-{6-[(diphenylmethylene)amino]pyridazin-4-yl}benzoate (0.16 g, 0.40 mmol) in THF (4.0 mL) and then the reaction was stirred at r.t. for 1.5 h. The mixture was carefully neutralized with Na2CO3 (2.0 eq) and then concentrated under reduced pressure to give the crude product (0.20 g) which was directly used in the next reaction without further purification. LCMS (M+H)+: m/z=230.1
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([F:14])[CH:13]=2)=[CH:6][C:5]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([Cl:28])([F:27])[F:26])=[CH:20][CH:19]=2)=[O:16])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.Cl.Cl.[NH2:40][CH2:41][CH:42]1[CH2:46][NH:45][CH2:44][CH:43]1[OH:47].C([O-])([O-])=O.[Na+].[Na+]>CC(O)C>[NH2:40][CH2:41][CH:42]1[CH:43]([OH:47])[CH2:44][N:45]([C:2]2[C:7]([C:8]3[CH:9]=[N:10][CH:11]=[C:12]([F:14])[CH:13]=3)=[CH:6][C:5]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][C:25]([Cl:28])([F:26])[F:27])=[CH:22][CH:23]=3)=[O:16])=[CH:4][N:3]=2)[CH2:46]1
Reactant: NCC1CNCC1O
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2cncc(F)c2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: NCC1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2-c2cncc(F)c2)CC1O
Temperature: 80 °C
Reaction time: 72 h

Procedure:
2-Chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5′-fluoro-[3,3′-bipyridine]-5-carboxamide (Stage 266.1, 80 mg, 0.183 mmol) and DIPEA (0.224 mL, 1.282 mmol) were added to a vial containing iPrOH (2 mL) and 4-(aminomethyl)pyrrolidin-3-ol dihydrochloride (Stage 267.1, 37.1 mg, 0.192 mmol) was added under an argon atmosphere. The RM was stirred at 80° C. for 3 days. The RM was treated with sat. aq. Na2CO3 (20 mL) and extracted with EtOAc. The combined extracts were washed with brine (10 mL), dried over Na2SO4, filtered and evaporated to dryness under reduced pressure to give the crude product was purified by preparative HPLC (Condition 14). Fractions containing product were treated with sat. aq. Na2CO3 and the MeCN was evaporated off under reduced pressure. The resulting aq. residue was extracted with EtOAc and the combined extracts were dried over Na2SO4, filtered and evaporated. The residue was suspended in DCM/Et2O/n-hexane. The obtained solid was filtered off, washed with Et2O, n-hexane and dried to afford the title product as a white solid. HPLC (Condition 10) tR=5.74 min, UPLC-MS (Condition 3) tR=0.83 min, m/z=508 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.41-3.33 (m, 7H) 3.92-4.21 (m, 1H) 7.34 (d, J=8.99 Hz, 2H) 7.85 (d, J=9.38 Hz, 3H) 8.03-8.11 (m, 1H) 8.47-8.54 (m, 1H) 8.59 (m, J=2.70 Hz, 1H) 8.77 (m, J=2.30 Hz, 1H) 10.19 (s, 1H).