Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.CCN(C(C)C)C(C)C.[O:30]1[C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=[N:31]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CO>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:35]([C:34]2[O:30][N:31]=[CH:32][CH:33]=2)=[O:36])=[C:4]([F:20])[C:5]=1[O:10][C:11]1[CH:12]=[C:13]([C:14]#[N:15])[CH:16]=[C:17]([Cl:19])[CH:18]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: O=C(O)c1ccno1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3ccno3)c2F)c1
Reaction time: 8 h
Yield: 46.2 %

Procedure:
In a 1 dram vial, 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (25 mg, 0.080 mmol), DIPEA (0.014 mL, 0.080 mmol) and 5-isoxazolecarboxylic acid (9.09 mg, 0.080 mmol) were dissolved in DMF (1 mL). HATU was added (30.6 mg, 0.080 mmol) and the solution stirred overnight. The reaction mixture was diluted to 2 mL with MeOH. Purification was accomplished by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.015 g, 46%) as a white solid. 1H NMR (400 MHz, Acetone-d6): δ ppm 8.65 (br. s., 1H), 8.57 (d, 1H), 7.63 (t, 1H), 7.46-7.53 (m, 1H), 7.41-7.46 (m, 1H), 7.35-7.41 (m, 2H), 6.99 (d, 1H), 4.69 (d, 2H). LCMS m/z 405.9 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[F:10][C:11]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:12]=1[C:13](Cl)=[O:14]>>[OH:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[NH:1][C:13](=[O:14])[C:12]1[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:11]=1[F:10]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1F
Reactant: Nc1cc(F)ccc1O
Product: O=C(Nc1cc(F)ccc1O)c1cc([N+](=O)[O-])ccc1F

Procedure:
Prepared by the method of Example 15a), from 2-amino-4-fluorophenol (292 mg, 2.3 mmol) and 2-fluoro-5-nitrobenzoyl chloride (468 mg, 2.3 mmol) the subtitle compound was obtained. The product was used directly in the next step without purification.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH:15]2[CH2:17][CH2:16]2)[N:3]=1.C(N(C(C)C)C(C)C)C.[C:27]1([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCOCC1>[CH:15]1([NH:14][C:4]2[N:5]=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[C:7]([C:8]#[N:9])=[C:2]([N:36]3[CH2:37][CH2:38][N:33]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:34][CH2:35]3)[N:3]=2)[CH2:17][CH2:16]1
Reactant: N#Cc1c(Cl)nc(NC2CC2)nc1NCCO
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(NCCO)nc(NC2CC2)nc1N1CCN(c2ccccc2)CC1
Temperature: 100 °C
Yield: 59.3 %

Procedure:
A mixture of 70 mg (0.27 mmol) of 4-chloro-2-cyclopropylamino-6-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile and 0.047 ml (0.27 mmol) of N-ethyl-diisopropylamine in 5 ml of dioxane was treated with 49 mg (0.3 mg) of 1-phenyl-piperazine. The solution was heated to 100° C. during 18 hours, thereafter, for the working-up, evaporated under reduced pressure. For purification, the residue obtained was chromatographed by preparative HPLC on RP18-silica gel using a gradient of a mixture of acetonitrile and water (plus 0.1% of formic acid) as the eluent to give 60 mg (0.16 mmol, 58% of theory) of the 2-cyclopropylamino-4-(2-hydroxy-ethylamino)-6-(4-phenyl-piperazin-1-yl)-pyrimidine-5-carbonitrile as a white powder after lyophilization; MS: [M+H]+=380.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2].[CH3:26][NH:27][CH3:28]>>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:27]([CH3:28])[CH3:26])[N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]
Reactant: CNC
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ccnc(Cl)n3)cc(C)c21
Product: CCOC(=O)CC1OB(O)c2cc(Oc3ccnc(N(C)C)n3)cc(C)c21
Yield: 21.8 %

Procedure:
A solution of [6-(2-chloro-pyrimidin-4-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (impure, 0.42 g, 1.16 mmol) in dimethylamine (2M solution in THF, 5 mL, 10 mmol) was stirred in a sealed tube at room temperature for 3 hours. The mixture was concentrated in vacuo and the residue purified by silica gel flash column chromatography using EtOAc and hexane (1:1) as eluant, followed by MeOH and CH2Cl2 (2:98 gradient) and preparative HPLC (CH3CN/0.1% AcOH in water). The required fraction was lyophilized to give [6-(2-dimethylamino-pyrimidin-4-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester as a light yellow solid (0.094 g, 22%). 1H NMR (400 MHz, CD3OD) δ8.12 (d, J=5.85 Hz, 1H), 7.19 (s, 1H), 7.05 (s, 1H), 6.07 (d, J=5.85 Hz, 1H), 5.68-5.60 (m, 1H), 4.15-4.03 (m, 2H), 3.17 (dd, J=14.38, 2.34 Hz, 1H), 3.00 (s, 6H), 2.47 (dd, J=14.83, 8.20 Hz, 1H), 2.36 (s, 3H), 1.20 (t, J=7.03 Hz, 3H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][C:9]([N:11]1[CH2:16][CH2:15][S:14][CH2:13][CH2:12]1)=[O:10].[OH:17][C:18]1[CH:27]=[CH:26][C:25]2[N:24]=[C:23](N)[C:22]3[N:29]=[C:30]([CH2:35][O:36][CH3:37])[N:31]([CH2:32][CH2:33][CH3:34])[C:21]=3[C:20]=2[CH:19]=1.C[N:39](C=O)C>>[CH3:37][O:36][CH2:35][C:30]1([NH2:39])[NH:29][C:22]2[CH:23]=[N:24][C:25]3[CH:26]=[CH:27][C:18]([O:17][CH2:8][C:9](=[O:10])[N:11]4[CH2:16][CH2:15][S:14][CH2:13][CH2:12]4)=[CH:19][C:20]=3[C:21]=2[N:31]1[CH2:32][CH2:33][CH3:34]
Reactant: O=C(CBr)N1CCSCC1
Reactant: CN(C)C=O
Reactant: CCCn1c(COC)nc2c(N)nc3ccc(O)cc3c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCCN1c2c(cnc3ccc(OCC(=O)N4CCSCC4)cc23)NC1(N)COC
Temperature: 70 °C

Procedure:
Cesium carbonate (1.7 g, 5.22 mmol, 3 eq) was added to a mixture of 4-(bromoacetyl)thiomorpholine (468 mg, 2.09 mmol, 1.2 eq, prepared according to the method described in Part C of Example 30) and 8-hydroxy-2-methoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine (500 mg, 1.74 mmol, 1.0 eq) in 20 mL of DMF. The reaction mixture was heated to 70° C. and maintained for 14 hours. The reaction mixture was then cooled to ambient temperature, filtered, diluted with 50 mL of dichloromethane, concentrated under reduced pressure, and filtered to afford crude material. The crude material was purified by chromatography on a HORIZON HPFC system (eluting with a gradient of methanol/dichloromethane (20:80) in dichloromethane from 0:100 to 40:60), concentrated under reduced pressure, and crystallized from acetonitrile to afford 231 mg of 2-(methoxymethyl)-8-(2-oxo-2-thiomorpholin-4-ylethoxy)-1-propyl-1H-imidazo[4,5-c]quinolin-amine as an off white solid, mp 214-216° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11](Cl)=[O:12])=[C:4]2[N:3]=1.CCN(C(C)C)C(C)C.Cl.[Cl:24][CH2:25][CH2:26][NH2:27]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([NH:27][CH2:26][CH2:25][Cl:24])=[O:12])=[C:4]2[N:3]=1
Reactant: O=C(Cl)c1cnn2ccc(Cl)nc12
Reactant: NCCCl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCCCl)c1cnn2ccc(Cl)nc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To a suspension of 5-chloropyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (284 mg, 1.31 mmol) in DCM (10 mL) was added DIEA (1.14 mL, 6.57 mmol). The solution was cooled to 0° C., then treated with 2-chloroethylamine hydrochloride (183 mg, 1.58 mmol) and stirred for 1 hour. The mixture was partitioned between water (30 mL) and DCM (30 mL) and the layers were separated. The aqueous layer was extracted with DCM (2×20 mL) and the combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to afford 5-chloro-N-(2-chloroethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (290 mg, 85% yield) as a beige solid. MS (apci) m/z=258.9 (M+H).
Reaction SMILES: [C:1]([NH:9][C:10]1C=C(C=[C:52](C)[CH:53]=1)C(N[C@@H](CC1C=C(F)C=C(F)C=1)[C@@H]([C@H]1C[C@@H](OCCC)CN1C(OC(C)(C)C)=O)O[Si](C(C)(C)C)(C)C)=O)(=O)[C:2]1C=CC=C[CH:3]=1.C(OC([N:62]1[CH2:66][C@H:65]([O:67][CH2:68][CH2:69][CH3:70])[CH2:64][C@@H:63]1[C@@H:71]([O:95][Si](C(C)(C)C)(C)C)[C@@H:72]([NH:82][C:83]([C:85]1[CH:86]=[C:87]([CH:91]=[C:92]([CH3:94])[CH:93]=1)[C:88]([OH:90])=O)=[O:84])[CH2:73][C:74]1[CH:79]=[C:78]([F:80])[CH:77]=[C:76]([F:81])[CH:75]=1)=O)(C)(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NCCC)CC>ClCCl>[F:81][C:76]1[CH:75]=[C:74]([CH2:73][C@H:72]([NH:82][C:83](=[O:84])[C:85]2[CH:93]=[C:92]([CH3:94])[CH:91]=[C:87]([C:88]([N:9]([CH2:10][CH2:53][CH3:52])[CH2:1][CH2:2][CH3:3])=[O:90])[CH:86]=2)[C@H:71]([OH:95])[C@H:63]2[CH2:64][C@@H:65]([O:67][CH2:68][CH2:69][CH3:70])[CH2:66][NH:62]2)[CH:79]=[C:78]([F:80])[CH:77]=1
Reactant: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C)cc(C(=O)O)c2)N(C(=O)OC(C)(C)C)C1
Reactant: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C)cc(NC(=O)c3ccccc3)c2)N(C(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCCNCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCO[C@H]1CN[C@@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C)cc(C(=O)N(CCC)CCC)c2)C1
Reaction time: 0.33 h
Yield: 90 %

Procedure:
Step 10 (A): Preparation of (2R,4R)-tert-butyl 2-((1S,2S)-2-(3-(benzamido)-5-methylbenzamido)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propyl)-4-propoxypyrrolidine-1-carboxylate. To a solution of 3-(((1S,2S)-1-((2R,4R)-1-(tert-butoxycarbonyl)-4-propoxypyrrolidin-2-yl)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propan-2-yl)carbamoyl)-5-methylbenzoic acid (Preparation G, 26 mg, 0.037 mmol) in dichloromethane (1 mL) was added Hunig's base (15 mg, 0.114 mmol) to make a clear solution and HATU (18 mg, 0.05 mmol) was then added. After stirring for 20 min, the reaction mixture was added dipropylamine (6 mg, 0.057 mmol) and the reaction mixture was stirred at rt for 6 h. The crude mixture was purified by silica gel Flash Chromatography (0% to 10% to 30% EtOAc/Hexane step gradient) to give 27 mg of the title compound (90% yield): 1H NMR (CDCl3, 500 MHz) δ ppm 0.02 (3H, s), 0.06 (3H, s), 0.71 (3H, m), 0.85 (9H, s), 0.88 (3H, m), 0.96 (3H, m), 1.48-1.54 (12H, m), 1.67 (2H, m), 1.74 (2H, m), 2.03-2.09 (1H, m), 2.19 (1H, m), 2.38 (3H, s), 2.62 (1H, m), 2.94 (1H, m), 3.13 (2H, brd s), 3.26-3.36 (3H, m), 3.43 (2H, brd s), 3.76 (1H, m), 3.97 (1H, m), 4.04-4.07 (1H, m), 4.10-4.12 (1H, m), 4.58 (1H, m), 6.59 (1H, m), 6.76 (2H, d, J=5 Hz), 7.25 (1H, s), 7.60 (1H, s), 7.70 (1H, s), 7.98 (1H, brd s). MS (ESI) (M+H)+ 774.63.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:9]=[C:10]([CH2:15][N:16]=[N+:17]=[N-:18])[CH:11]=[CH:12][C:13]=1[Cl:14].[C:19]([O:25][CH3:26])(=[O:24])[CH2:20][C:21]([CH3:23])=O.O>CS(C)=O>[Cl:7][C:8]1[CH:9]=[C:10]([CH2:15][N:16]2[C:21]([CH3:23])=[C:20]([C:19]([O:25][CH3:26])=[O:24])[N:18]=[N:17]2)[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: [N-]=[N+]=NCc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1nnn(Cc2ccc(Cl)c(Cl)c2)c1C
Temperature: 40 °C
Reaction time: 48 h

Procedure:
To a suspension of milled potassium carbonate (38.7 g, 0.28 mol) in DMSO (100 mL) was added (3,4-dichlorophenyl)methyl azide (Intermediate 3) (14 g, 0.07 mol) and methyl acetoacetate (12.1 g, 0.1 mol). The mixture was stirred at 40° C. for 48 hours. The mixture was poured into a mixture of ice and water (100 mL). The water was extracted with ethyl acetate (100 mL×2). The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by distillation to give the title compound as white solid crystals (14 g, 67%). LC/MS: m/z 301 (M+H)+, Rt: 1.97 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:39][CH2:40][CH2:41][N:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:39][CH2:40][CH2:41][N:42]4[CH2:46][CH2:45][CH2:44][CH2:43]4)=[CH:27][CH:28]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Reactant: BrCCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCN3CCCC3)cc2)c2ccccc21
Temperature: 80 °C
Yield: 8 %

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (0.1 g, 0.23 mmol) was dissolved in DMF (5 mL) at room temperature. K2CO3 (0.317 g, 2.3 mmol) was added. 1-(3-Bromo-propyl)-pyrrolidine (0.177 g, 0.92 mmol) was added and the reaction was allowed to heat to 80° C. overnight. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO4, filtered and concentrated down. The crude residue was purified by silica gel chromatography (10% methanol/90% dichloromethane) to afford the product (0.01 g, 8%).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C@H:7]2[CH2:13][C@H:12]3[N:14]([CH2:15][CH2:16][C@H:17]([NH:24][C:25]([CH:27]4[CH2:32][CH2:31][C:30]([F:34])([F:33])[CH2:29][CH2:28]4)=[O:26])[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C@H:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]([CH:35]([CH3:37])[CH3:36])=[N:4][N:3]=1.P([O-])([O-])([O-])=O.N.C1CCCCC1>O>[CH:35]([C:5]1[N:6]([CH:7]2[CH2:13][CH:12]3[N:14]([CH2:15][CH2:16][C@H:17]([NH:24][C:25]([CH:27]4[CH2:28][CH2:29][C:30]([F:34])([F:33])[CH2:31][CH2:32]4)=[O:26])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:2]([CH3:1])=[N:3][N:4]=1)([CH3:36])[CH3:37]
Reactant: Cc1nnc(C(C)C)n1[C@@H]1C[C@H]2CC[C@@H](C1)N2CC[C@H](NC(=O)C1CCC(F)(F)CC1)c1ccccc1
Agent: N
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1CCCCC1
Product: Cc1nnc(C(C)C)n1C1CC2CCC(C1)N2CC[C@H](NC(=O)C1CCC(F)(F)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 1113.8 %

Procedure:
Crystalline form 1 of maraviroc phosphate (5 gm) was dissolved in water (40 ml) and pH of the reaction mass was adjusted to 8.0 to 8.5 with ammonia solution (4 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layer was dried with sodium sulfate and treated with carbon. The ethyl acetate was distilled off under vacuum at below 45° C. to obtain residual mass. To the residual mass was added cyclohexane (400 ml) and stirred for 15 minutes at room temperature, filtered. The solid obtained was dried under vacuum at 85° C. for 12 hours to obtain 47 gm of maraviroc amorphous form.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][C:4]=1[NH2:12])#[CH:2].S(=O)(=O)(O)[OH:14].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[K+].[K+]>O>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][C:4]=1[N:12]=[O:14])#[CH:2]
Reactant: O=S(=O)(O)O
Reactant: C#Cc1ccc(C(N)=O)cc1N
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: C#Cc1ccc(C(N)=O)cc1N=O
Reaction time: 0.05 h
Yield: 12 %

Procedure:
0.46 g (2.87 mmol) 4-ethynyl-3-aminobenzamide (Compound XI-1), 10 ml water, were added into a 50 ml single-neck flask, then 1.2 g 58% sulfuric acid was added, and then 0.92 g 18.5% potassium dichromate solution. The mixture was stirred for 3 minutes until completing the reaction, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain 0.06 g 4-ethynyl-3-nitrosobenzamide (Compound I-28, yellow-green solid), yield 12%, stored at −20° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][O:21]C(=O)C)=[CH:16][C:9]=3[CH2:8][CH2:7][C:6]=2[CH:25]=1.[F:26][C:27]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:28]=1[NH2:29].P>C1(C)C=CC=CC=1.C(O)(C)(C)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:26][C:27]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:28]=1[NH:29][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][OH:21])=[CH:16][C:9]=3[CH2:8][CH2:7][C:6]=2[CH:25]=1
Reactant: Nc1ccc(F)cc1F
Reactant: CC(=O)OCCCOc1ccc2c(c1)CCc1cc(Cl)ccc1C2=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: P
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: O=C1c2ccc(Nc3ccc(F)cc3F)cc2CCc2cc(OCCCO)ccc21
Yield: 42 %

Procedure:
In accordance with general method O, 0.65 g (1.8 mmol) of acetic acid 3-(8-chloro-5-oxo-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-2-yloxy)-propyl ester, 0.25 g (1.9 mmol) of 2,4-difluoroaniline, 0.04 g of Pd(OAc)2, 0.17 g of phosphine ligand and 0.74 g (7.7 mmol) of Na—O-tert-butylate are reacted in 10 ml of toluene and 2 ml of tert-BuOH. Yield: 42%; m.p.: 154° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH:11]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[C:9]#[N:10].[C:24]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)#[N:25].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O>[C:9]([CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:30]1[CH:29]=[CH:28][CH:27]=[C:26]([C:24]#[N:25])[CH:31]=1)[CH:11]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)#[N:10]
Reactant: N#CC(c1ccccc1Br)C(c1cccnc1)c1cccnc1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cccc(-c2ccccc2C(C#N)C(c2cccnc2)c2cccnc2)c1
Temperature: 160 °C

Procedure:
A mixture of 2-(2-bromophenyl)-3,3-dipyridin-3-ylpropanenitrile (0.050 g, 0.137 mmol), 3-cyanophenylboronic acid (0.030 g, 0.206 mmol), cesium carbonate (0.045 g, 0.137 mmol) and Pd(dppf)2 (0.100 g, 0.137 mmol) in THF (0.75 mL) and water (0.75 mL) at −78° C. was heated to 160° C. in microwave for 15 min. The reaction was diluted with water and extracted with CH2Cl2. The combined organic layer was dried, filtered, and concentrated. The residue was purified by silica gel chromatography (0-5% MeOH in CH2Cl2) to give (±)-2′-(1-cyano-2,2-dipyridin-3-ylethyl)-1,1′-biphenyl-3-carbonitrile. 1H-NMR (500 MHz, CDCl3) δ 8.57 (d, 1H, J=3.9), 8.45 (d, 1H, J=4.2), 8.42 (s, 1H), 7.88 (s, 1H), 7.71 (m, 1H), 7.66-7.56 (m, 3H), 7.51 (td, 1H, J=7.5, 1.2), 7.41 (td, 1H, J=7.6, 1.3), 7.34-7.32 (m, 2H), 7.18-7.07 (m, 3H), 7.00 (d, 1H, J=7.8), 4.57 (d, 1H, J=10.0), 4.33 (d, 1H, J=9.8). LRMS m/z (M+H) Calcd: 387.1604, found: 387.1592.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:5]=[C:6]([O:12][CH3:13])[C:7]([NH2:11])=[N:8][C:9]=1[CH3:10].[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[S:22](Cl)(=[O:24])=[O:23].ClCCl.C(O)(=O)C>CN1CCCC1=O>[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[S:22]([NH:11][C:7]1[C:6]([O:12][CH3:13])=[N:5][C:4]([Br:3])=[C:9]([CH3:10])[N:8]=1)(=[O:24])=[O:23]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: COc1nc(Br)c(C)nc1N
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: COc1nc(Br)c(C)nc1NS(=O)(=O)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.3 %

Procedure:
Sodium hydride (0.5 g of a 60% dispersion in oil) was added to a solution of 5-bromo-3-methoxy-6-methyl-2-pyrazinamine (Example 118c) (0.55 g) in N-methylpyrrolidinone (25 mL). The resultant dark solution was stirred at room temperature for 0.5 h before a solution of 2,3-dichlorobenzenesulphonyl chloride (0.67 g) in N-methylpyrrolidinone (5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 3 h, then quenched with aqueous ammonium chloride and partitioned between ethyl acetate and aqueous ammonium chloride (×5). the organic phase was dried (MgSO4), filtered and evaporated to give the crude product. Chromatography on silica gel eluting with dichloromethane/acetic acid (200:1) gave the title compound as a pale yellow solid (0.38 g).
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[S:11][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:9][C:8]=1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=O)[CH:2]=[CH2:3].P(Cl)(Cl)(Cl)(Cl)Cl.Cl.O1CCOCC1.CO[CH:41](OC)[CH2:42][NH2:43]>C(Cl)Cl>[CH2:1]([N:4]1[CH:41]=[CH:42][N:43]=[C:5]1[C:7]1[S:11][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:9][C:8]=1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[CH:2]=[CH2:3]
Reactant: C=CCNC(=O)c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Reactant: COC(CN)OC
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C=CCn1ccnc1-c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
To a solution of N-allyl-4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole-5-carboxamide (150 mg, 0.406 mmol) in DCM (2.64 mL) was added phosphorus pentachloride (101 mg, 0.485 mmol) and 4 M hydrochloric acid in 1,4-dioxane (0.0154 mL, 0.0614 mmol) and the mixture was heated to 60° C. for 1.5 h. The reaction was cooled to room temperature and aminoacetaldehyde dimethyl acetal (0.486 mL, 4.46 mmol) was added. The resulting mixture was heated at 60° C. for 2 h. The mixture was cooled to room temperature, diluted with DCM (10 mL), washed with water (2×2 mL) and brine (2 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was taken up in DCM (3.0 mL) and 4 M hydrochloric acid in 1,4-dioxane (0.608 mL, 2.43 mmol) was added and the mixture was stirred at 60° C. overnight. The reaction was cooled and concentrated in vacuo. The residue was taken up in ethyl acetate (20 mL) and saturated sodium bicarbonate (5 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (5 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (methanol/DCM=0/100→5/95) to give 99 mg of the title compound (62% yield). LC/MS (FA) ES+ 393. 1H NMR (300 MHz, CDCl3) δ: 8.72-8.70 (m, 2H), 7.80-7.72 (m, 2H), 7.26 (m, 1H), 7.22-7.14 (m, 4H), 7.06 (m, 1H), 5.84-5.71 (m, 1H), 5.23-5.19 (m, 1H), 5.01-4.96 (m, 1H), 4.38-4.34 (m, 2H), 4.20 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1([C:5]([OH:7])=O)[CH2:4][CH2:3]1.[F:8][C:9]([F:22])([F:21])[C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][C:16]=1[O:17][CH:18]([F:20])[F:19])[NH2:13].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[F:8][C:9]([F:21])([F:22])[C:10]1[CH:11]=[C:12]([NH:13][C:5]([C:2]2([CH3:1])[CH2:4][CH2:3]2)=[O:7])[CH:14]=[CH:15][C:16]=1[O:17][CH:18]([F:19])[F:20]
Reactant: Nc1ccc(OC(F)F)c(C(F)(F)F)c1
Reactant: CC1(C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC1(C(=O)Nc2ccc(OC(F)F)c(C(F)(F)F)c2)CC1
Yield: 81.6 %

Procedure:
To a solution of 1-methylcyclopropanecarboxylic acid (1.0 g) in tetrahydrofuran (50 ml), 3-trifluoromethyl-4-difluoromethoxyaniline (2.25 g) was added, and a solution of N,N'-dicyclohexylcarbodiimide (DCC) (2.2 g) in tetrahydrofuran was dropwise added while stirring. After several minutes, the by-produced N,N'-dicyclohexylurea (DCU) was eliminated by filtration. To the filtrate, acetic acid (2 ml) was added to decompose excessive DCC, followed by elimination of DCU. The resultant filtrate was extracted with ether, and the extract was washed with 1 N hydrochloric acid, sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The crude crystals (2.85 g) were recrystallized from ethanol to give N-(3-trifluoromethyl-4-difluoromethoxyphenyl)-1-methylcyclopropanecarboxamide (2.5 g). M.P., 39°-40° C.