Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([C@:8]1([O:29][C:30](=[O:32])[CH3:31])[C@:24]2([CH3:25])[C@H:11]([C@H:12]3[C@H:21]([C:22](=[O:26])[CH2:23]2)[C@:20]2([CH3:27])[C:15](=[CH:16][C:17](=[O:28])[CH:18]=[CH:19]2)[CH2:14][CH2:13]3)[CH2:10][CH2:9]1)=[O:7])(=[O:3])[CH3:2].[BH4-].[Na+]>O1CCCC1.CO.Cl>[C:1]([O:4][CH2:5][C:6]([C@:8]1([O:29][C:30](=[O:32])[CH3:31])[C@:24]2([CH3:25])[C@H:11]([C@H:12]3[C@H:21]([C@@H:22]([OH:26])[CH2:23]2)[C@:20]2([CH3:27])[C:15](=[CH:16][C:17](=[O:28])[CH:18]=[CH:19]2)[CH2:14][CH2:13]3)[CH2:10][CH2:9]1)=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)[C@@]1(OC(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3C(=O)C[C@@]21C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)OCC(=O)[C@@]1(OC(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Temperature: 0 °C

Procedure:
To an ice cooled solution of intermediate 2 (2.22 g, 5.0 mmol) in tetrahydrofuran (15 ml) and MeOH (15 ml), sodium borohydride (221 mg, 5.84 mmol) is added in portions over a period of 2.5 hours. The reaction mixture is poured in 1 N HCl and ice (150 ml). The formed precipitate is extracted with AcOEt (3×100 ml), and the combined organic layers are dried over anhydrous Na2SO4 and concentrated. The crude material is crystallized from Ethyl acetate/petroleum ether. The residue from mother liquor is purified by flash chromatography on silica gel, in gradient elution from DCM to DCM/AcOEt 40:60 affording a second crop. The combined crops give the title the compound (1.85 g, 83% total yield).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([S:12](Cl)(=[O:14])=[O:13])=[CH:9][CH:8]=[CH:7][C:6]=2[CH:5]=[N:4][CH:3]=1.[C:16]([O:20][C:21]([NH:23][C@H:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C>C(Cl)Cl>[C:16]([O:20][C:21]([NH:23][C@H:24]1[CH2:28][CH2:27][N:26]([S:12]([C:10]2[C:11]3[C:2]([Br:1])=[CH:3][N:4]=[CH:5][C:6]=3[CH:7]=[CH:8][CH:9]=2)(=[O:14])=[O:13])[CH2:25]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: O=S(=O)(Cl)c1cccc2cncc(Br)c12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
A solution of 4-bromo-5-isoquinolinesulfonyl chloride (0.50 g) prepared according to a known method (described in Japanese Patent No. 2763791), and (S)-3-(tert-butoxycarbonylamino)pyrrolidine (0.33 g, Tokyo Kasei Kogyo) in methylene chloride (5 ml) was added with triethylamine (0.68 ml, Wako Pure Chemical Industries) at 0° C., and the mixture was stirred at the same temperature for 30 minutes, and then further stirred at room temperature for 5 hours. The reaction mixture was washed with saturated brine (10 ml), and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:1) to obtain the title compound (0.62 g).
Reaction SMILES: [CH2:1]1[O:3][C@@H:2]1[CH2:4][OH:5].[NH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1>C(O)C>[N:6]1([CH2:1][C@H:2]([OH:3])[CH2:4][OH:5])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: OC[C@@H]1CO1
Reactant: C1COCCN1
Solvent: CCO
Product: OC[C@@H](O)CN1CCOCC1
Temperature: 25 °C
Yield: 112.9 %

Procedure:
A solution of (R)-glycidol (0.33 mL, 5.0 mmol) and morpholine (0.65 mL, 7.5 mmol, 1.5 equiv.) in abs. ethanol was heated in a microwave for 4 min. at 140 0° C., cooled to room temperature and concentrated at 70° C. under a 12 mBar vacuum to afford (2S)-3-(4-morpholinyl)-1,2-propanediol (0.91 g, 113%): 1H NMR (CDCl3) δ 2.37 (dd, J=3.9, 12.5 Hz, 1H), 2.41-2.48 (m, 2H), 2.57 (dd, J=9.7, 12.5 Hz, 1H), 3.51 (dd, J=4.3, 11.4 Hz, 1H), 3.66-3.79 (m, 5H), 3.81-3.87 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[CH:23](SC)[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C(Cl)Cl.C(O)(=O)C.[Zn]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][CH:13]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:19]=3)[CH2:14]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=S(=O)(NCC1Cc2ccccc2C1)c1ccc(Cl)cc1
Reactant: CCOC(=O)C(Cl)SC
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc2c(c1)CC(CNS(=O)(=O)c1ccc(Cl)cc1)C2
Temperature: 110 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
16.1 g (50.0 mmol) of [2-[(4-chlorophenyl)sulfonylaminomethyl)indan and 9.27 g (55.0 mmol) of ethyl alpha-chloro-alpha-(methylthio)acetate were dissolved in 50 ml of methylene chloride, to which 6.44 ml (55.0 mmol) of stannic chloride was slowly added dropwise. After stirring for 3 hours, the reaction mixture was poured into ice-water, and the organic phase was collected, washed, dried and condensed. The residue was dissolved in 180 ml of acetic acid, added with 40 g of zinc powder and heated at 110° C. for 1 hour. After cooling, the precipitates were filtrated and washed thoroughly with chloroform and the solvent was removed. The residue was dissolved in 300 ml of ethyl acetate, and washed with water, saturated aqueous sodium bicarbonate solution and water in this order, and dried. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a solvent mixture of ethyl acetate and hexane to obtain 16.7 g of colorless needles. Yield: 82%.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>O1CCCC1.CCOCC>[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCCCO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 8.5 g 5-hexen-1-ol in 100 mL tetrahydrofuran is added 14 mL dihydropyran followed by 0.5 g p-toluenesulfonyl chloride. The mixture is stirred at room temperature for 18 hours and then diluted with ether. The mixture is then washed with saturated aqueous sodium bicarbonate, dried, filtered and evaporated. The resulting oil is chromatographed over silica gel using hexane/ether (18:1) as eluent to give 6-(2-tetrahydropyranyloxy)-hex-1-ene; NMR (CDCl3): delta 5.85 (m,1H), 4.6 (brs,1H).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[C:6]1([CH:12]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]([N:15]=[C:16]=[O:17])=[O:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>ClCCl>[CH2:1]([O:5][C:16](=[O:17])[NH:15][C:13](=[O:14])[CH:12]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C=NC(=O)C(c1ccccc1)c1ccccc1
Reactant: CCCCO
Solvent: ClCCl
Product: CCCCOC(=O)NC(=O)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
To a stirred solution of 1-butanol (0.32 ml, 3.49 mmol) in dichloromethane (4 ml) was added a solution of diphenylacetyl isocyanate (2.33 ml, 0.5M in CH2Cl2, 1.16 mmol) and the mixture was stirred at RT for 1 h. Removal of the solvent in vacuum left a yellow oil, which was purified by column chromatography on silica gel (ethyl acetate/hexane 1:2) to give the title compound (0.3 g, 83%) as a light yellow solid, m.p. 82-84° C. and MS: m/e=334 (M+Na+).
Reaction SMILES: C([O:4][C:5]1[C:6]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:7]=2[S:8][C:9]=1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)C.[OH-].[Na+].Cl>C(O)C>[CH2:10]([C:9]1[S:8][C:7]2[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:6]=2[C:5]=1[OH:4])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(=O)Oc1c(Cc2ccccc2)sc2ccc(Cl)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Oc1c(Cc2ccccc2)sc2ccc(Cl)cc12
Yield: 46.1 %

Procedure:
A mixture of 3-acetoxy-2-benzyl-5-chlorobenzo[b]thiophene (100 mg) and 2N aqueous sodium hydroxide (2 ml) in ethanol (1 ml) was heated at reflux temperature for 1 hour. The reaction mixture was cooled in an ice bath and acidifed with concentrated hydrochloric acid. The solid that separated out was collected by filtration, washed with water, and dried in vacuo over calcium sulfate to afford 2-benzyl-5-chloro-3-hydroxybenzo[b]thiophene as a white solid (40 mg); m/z 274 (M+.).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.C1(S([N:38]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40](B(O)O)=[CH:39]2)(=O)=O)C=CC=CC=1.[OH-].[K+]>>[NH:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40]([C:2]2[N:3]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:5]3[N:11]=[C:10]([CH2:12][N:13]4[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)=[CH:39]1
Reactant: O=S(=O)(c1ccccc1)n1cc(B(O)O)c2ccccc21
Reactant: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Agent: [K+]
Agent: [OH-]
Product: CC(C)(O)C1CCN(Cc2ccc3nc(-c4c[nH]c5ccccc45)nc(N4CCOCC4)c3n2)CC1

Procedure:
2-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol from Example 8 (0.1 g) was reacted with 1-(phenylsulfonyl)-3-indoleboronic acid via General Procedure A to yield 56.9 mg 133 following phenylsulfonyl group deprotection with aqueous potassium hydroxide at 50° C. for 2 hours then reverse phase HPLC purification. MS (Q1) 487.3 (M)+
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=2)[C:3]1=[O:19].[CH3:20][O:21][C:22]1[CH:31]=[C:30]2[C:25]([CH:26]=[CH:27][C:28]([S:32](Cl)(=[O:34])=[O:33])=[CH:29]2)=[CH:24][CH:23]=1>C(Cl)Cl>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][S:32]([C:28]3[CH:27]=[CH:26][C:25]4[C:30](=[CH:31][C:22]([O:21][CH3:20])=[CH:23][CH:24]=4)[CH:29]=3)(=[O:34])=[O:33])[C:3]2=[O:19])=[CH:10][C:11]=1[N+:16]([O-:18])=[O:17]
Reactant: COc1ccc2ccc(S(=O)(=O)Cl)cc2c1
Reactant: Nc1ccc(CCN2CC[C@H](N)C2=O)cc1[N+](=O)[O-]
Solvent: ClCCl
Product: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(CCc4ccc(N)c([N+](=O)[O-])c4)C3=O)cc2c1

Procedure:
The title compound is prepared in CH2Cl2 instead of CH3CN as described in EXAMPLE 1, Part K using 3-(S)-amino-1-[2-(4-amino-3-nitrophenyl)-ethyl]-pyrrolidin-2-one in place of 7-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-1-chloro-isoquinoline hydrochloride and 7-methoxynaphthalene-2-sulfonyl chloride as prepared in EXAMPLE 1, Part J. After similar workup, the organic phase is concentrated in vacuo to afford the title compound as a pale yellow solid which is used as is in the subsequent step.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH:15]([C:19]([NH2:21])=[O:20])[CH2:14]1.C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[O:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4][CH:3]1[CH2:2][N:13]1[CH2:18][CH2:17][CH2:16][CH:15]([C:19]([NH2:21])=[O:20])[CH2:14]1
Reactant: BrCC1COc2ccccc2O1
Reactant: NC(=O)C1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: NC(=O)C1CCCN(CC2COc3ccccc3O2)C1

Procedure:
To a mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (0.2 g, 0.87 mmol) and piperidine-3-carboxylic acid amide (0.13 g, 1.05 mmol) in acetonitrile (20 ml) was added K2CO3 (0.60 g, 4.36 mmol) and KI (0.72 g, 4.36 mmol). The reaction mixture was refluxed for 2 h. Water (100 ml) was then added. The reaction mixture was extracted with EtOAc (3×5 ml). The combined organic phases were dried (Na2SO4), filtered and the filtrate was evaporated to give the title compound, which was purified by column chromatography (EtOAc/heptane, 50:50).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9].[Na+].[S:25]1[CH2:30][CH2:29][N:28]([C:31]2([C:34]([O-])=[O:35])[CH2:33][CH2:32]2)[CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:34]([C:31]2([N:28]3[CH2:27][CH2:26][S:25][CH2:30][CH2:29]3)[CH2:33][CH2:32]2)=[O:35])[C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9]
Reactant: O=C([O-])C1(N2CCSCC2)CC1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Agent: [Na+]
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C(=O)C2(N3CCSCC3)CC2)CC1
Yield: 46 %

Procedure:
The reaction of (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 7H with 1-thiomorpholinocyclopropanecarboxylic acid sodium salt 16C carried out according to the general procedure L yielded (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-thiomorpholinocyclopropanecarbonyl)pyrrolidine-2-carboxamide as a light brown solid (46%). MS ISP (m/e): 523.3 (100) [(M+H)]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[CH2:4][CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1)[CH3:2].O.O.[Sn](Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[CH2:16]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][S:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=1)[CH3:17]
Reactant: CCN(CC)CCSc1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCN(CC)CCSc1ccc(N)cc1
Temperature: 25 °C

Procedure:
To a solution of 7.4 g (29 mmol) of N,N-diethyl-2-[(4-nitrophenyl)thio]ethanamine in 150 mL of ethanol add 32.8 g (140 mmol) of tin(II) chloride dihydrate. Reflux the reaction mixture for about 5 h. After this time, cool the reaction mixture to room temperature and carefully add the mixture to a solution of 75 g (0.54 mol) of potassium carbonate in 500 mL of water. Extract the mixture with 3×500 mL of ethyl acetate. Combine the organic extracts and wash with 2×350 mL of saturated aqueous sodium chloride solution. Dry the organic extracts over anhydrous sodium sulfate. Remov the drying agent by filtration and evaporate the solvent in vacuo to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[O:38])=[CH:32][N:31]=1>C(Cl)Cl>[Cl:29][C:30]1[N:31]=[CH:32][C:33]([NH:36][C:37]([N:9]2[CH2:10][CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:28])=[O:38])=[CH:34][CH:35]=1
Reactant: O=C=Nc1ccc(Cl)nc1
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Product: CC(C)(C)CC1CN(C(=O)Nc2ccc(Cl)nc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 71 %

Procedure:
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (60.8 mg, 0.144 mmol) and 2-chloro-5-isocyanatopyridine (109.1 mg, 0.144 mmol, Maybridge) in CH2Cl2 (6 mL) was stirred at rt for 16 hrs. The reaction mixture was then purified by flash column to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carboxylic acid (6-chloro-pyridin-3-yl)-amide (59.1 mg, 71.1%). HRMS (ES+) m/z Calcd for C28H25Cl3F2N4O+H [(M+H)+]: 577.1135; Found: 577.1135.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][NH:6][C:5](=[O:9])[C:4]=1[C:10]1[NH:21][C:20]2[CH:19]=[C:18]3[C:14]([CH:15]=[N:16][NH:17]3)=[CH:13][C:12]=2[N:11]=1.Cl.[NH2:23][CH2:24][C@H:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=1)[OH:26].CN1CCOCC1>C(#N)C>[Cl:33][C:29]1[CH:28]=[C:27]([C@H:25]([OH:26])[CH2:24][NH:23][C:3]2[CH:8]=[CH:7][NH:6][C:5](=[O:9])[C:4]=2[C:10]2[NH:21][C:20]3[CH:19]=[C:18]4[C:14]([CH:15]=[N:16][NH:17]4)=[CH:13][C:12]=3[N:11]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: O=c1[nH]ccc(Cl)c1-c1nc2cc3cn[nH]c3cc2[nH]1
Reactant: NC[C@@H](O)c1cccc(Cl)c1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CC#N
Product: O=c1[nH]ccc(NC[C@@H](O)c2cccc(Cl)c2)c1-c1nc2cc3cn[nH]c3cc2[nH]1
Temperature: 80 °C
Yield: 60.8 %

Procedure:
The mixture of crude 4-chloro-3-(1,7-dihydro-1,2,5,7-tetraaza-s-indacen-6-yl)-1H-pyridin-2-one hydrochloric acid salt (80 mg, 0.25 mmol), (S)-2-amino-1-(3-chloro-phenyl)-ethanol hydrochloric acid salt (80 mg, 0.38 mmol), N-methyl morpholine (0.5 ml, excess), and acetonitrile (15 mL) was heated to 80° C. overnight and cooled to room temperature. After concentration in vacuo, the residue was purified by prep. HPLC to yield the titled compound (64 mg, 61%). 1H NMR (400 MHz, CD3OD) δ 8.16 (s, 1H), 7.90 (s, 1H), 7.62 (s, 1H), 7.59 (s, 1H), 7.54 (s, 1H), 7.27–7.41 (m, 4H), 6.21 (d, J=7.6 Hz, 1H), 4.99 (m, 1H), 3.60–3.71 (m, 2H). LCMS (t=1.44 min), [M+H]+421.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:13]=[C:12]([C@H:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:15]([CH3:18])([CH3:17])[CH3:16])[NH:11][N:10]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C>[CH2:33]([N:11]1[C:12]([C@H:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:15]([CH3:18])([CH3:17])[CH3:16])=[N:13][C:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])=[N:10]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](c1nc(-c2cc(F)ccc2F)n[nH]1)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](c1nc(-c2cc(F)ccc2F)nn1Cc1ccccc1)C(C)(C)C

Procedure:
To a stirred suspension of (R)-tert-butyl 1-(3-(2,5-difluorophenyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropylcarbamate (5.89 g, 16.1 mmol) and Cs2CO3 (10.5 g, 32.2 mmol) in DMF (46 mL, 0.35 M) was added benzyl bromide (2.11 mL, 17.7 mmol). Once the organic layer was separated and washed with H2O, brine, then dried over Na2SO4, filtered, and evaporated in vacuo to give (R)-tert-butyl 1-(1-benzyl-3-(2,5-difluorophenyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl-carbamate. The desired regioisomer was obtained on silica gel column (0% to 100% EtOAc in Hexanes, 3.25 g, 44.3%). The structure was verified by 1H NMR nOe experiments.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[NH:8][C:7]1=[O:17].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(N(CC)CC)C>[CH3:18][S:19]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[NH:8][C:7]1=[O:17])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: O=c1[nH]c(=O)n(CCCCO)c2ccccc12
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCCn1c(=O)[nH]c(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred suspension of 1-[4-hydroxybutyl)-2,4(1H,3H)-quinazolinedione (778 mg) in chloroformtetrahydrofuran (40 ml, 1:1 V/V) was added methanesulfonyl chloride (0.57 ml), and triethylamine (1.85 ml) on an ice-bath. After stirring for 18 hours at room temperature, the reaction mixture was heated at 50° C. for 30 hours with stirring. After evaporation of the solvents the residue was diluted with ethyl acetate. The mixture was washed in turn with water and brine, dried over magnesium sulfate, and evaporated. 1-(4-Methanesulfonyloxybutyl)-2,4(1H,3H)-quinazolinedione (675 mg) as a crystal was obtained by recrystallization from methanol.
Reaction SMILES: CO[CH:3]=[C:4]([CH3:8])[C:5](Cl)=[O:6].C1C=CC=CC=1.[OH:15][CH2:16][CH2:17][CH:18]1[CH2:20][CH:19]1[N:21]1C=CC(=O)[NH:24][C:22]1=[O:23].CN(C)C=O>[Ag]OC#N.C(OCC)C>[OH:15][CH2:16][CH2:17][CH:18]1[CH2:20][CH:19]1[N:21]1[CH:3]=[C:4]([CH3:8])[C:5](=[O:6])[NH:24][C:22]1=[O:23]
Reactant: COC=C(C)C(=O)Cl
Reactant: O=c1ccn(C2CC2CCO)c(=O)[nH]1
Agent: N#CO[Ag]
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: Cc1cn(C2CC2CCO)c(=O)[nH]c1=O
Temperature: -15 °C

Procedure:
3-Methoxymethacrylic acid chloride (2.68 g) and 25 mL of benzene are combined in a round bottom flask. To this mixture is added 6.4 g of silver cyanate and the resultant mixture heated to reflux temperature. After 40 min at reflux temperature the mixture is cooled to -15° C. In a separate round bottom flask, 1.0 g of the product of Step A of Example 8, 30 mL of dimethyl formamide (DMF) and 10 mL of diethyl ether are combined and this second mixture cooled to -15° C. The acylisocyanate mixture is added to the amine and the resultant solution stirred at -15° C. for 2 h. and allowed to stand in the refrigerator overnight. The reaction mixture is concentrated and the crude material is purified by column chromatography. The material recovered from the column and 5 mL of 2N aqueous sulfuric acid solution are combined in a round bottom flask and this reaction mixture heated at reflux temperature for 2 h. The mixture is adjusted to pH 7 with aqueous barium hydroxide, filtered and the filtrate concentrated. The residue is purified by column chromatography to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH2:15])=[O:14])=[CH:8][CH:7]=1.C(COC)OC.[Cl:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C(O)C>[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:4]([CH2:5][C:6]3[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH2:15])=[O:14])=[CH:8][CH:7]=3)[CH:3]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: COc1ccc(Cc2ccc(NC(N)=O)cc2)cc1Br
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: COc1ccc(Cc2ccc(NC(N)=O)cc2)cc1-c1cccc(Cl)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 51 %

Procedure:
To a 20 mL vial equipped with a magnetic stir bar and a screw cap was added [4-(3-bromo-4-methoxy-benzyl)-phenyl]-urea (I-44) synthesized above compound (250 mg, 0.746 mmol), dimethoxyethane (5 mL), ethanol (1 mL) and water (1 mL). To this mixture were added 3-chlorophenylboronic acid (140 mg, 0.895 mmol), potassium phosphate (316 mg, 1.49 mmol) and tetrakis(triphenylphosphine) palladium (30 mg, 0.0254 mmol). The stirring reaction mixture was degassed by bubbling N2 gas through the solution for 10 min. The vial was capped and placed in an oil bath with stirring at 80° C. for 16 h. The cooled reaction mixture was concentrated to dryness, then diluted with water (5 mL) and ethyl acetate (15 mL). The aqueous layer was extracted with ethyl acetate (2×5 mL) and the combined organic extracts were dried (Na2SO4), filtered and concentrated under a stream of N2 gas. The residue was purified by flash chromatography on silica gel (35 g) utilizing 9:1 dichloromethane/acetone as eluent. Fractions pure by TLC were combined and concentrated to give 139 mg (51%) of [4-(3′-chloro-6-methoxy-biphenyl-3-ylmethyl)-phenyl]-urea (P-378) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 3.74 (s, 3H), 3.83 (s, 2H), 5.75 (br s, 2H), 7.03 (d, J=8.4 Hz, 1H), 7.08 (m, 2H), 7.15 (d, J=2.4 Hz, 1H), 7.18 (dd, J=8.4, 2.4 Hz, 1H), 7.28 (m, 2H), 7.36-7.41 (m, 3H), 7.48 (m, 1H), 8.40 (br s, 1H) ppm. MS (APCI+): 367.0 (M++1); LC-MS: 95.9% purity.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1.Cl[C:11]([O:13][CH3:14])=[O:12]>>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:11](=[O:12])[O:13][CH3:14])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1Cl
Reactant: COC(=O)Cl
Product: COC(=O)Nc1cc(Br)cnc1Cl

Procedure:
Prepared according to the methods described in reagent preparation 26 using 5-bromo-2-chloropyridin-3-amine and methyl chloroformate in step 1.