Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[F:22][C:23]1[C:24]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)=[N:25][CH:26]=[CH:27][C:28]=1B1OC(C)(C)C(C)(C)O1>>[Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:28]3[CH:27]=[CH:26][N:25]=[C:24]([N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)[C:23]=3[F:22])=[CH:14][C:6]1=2
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(I)cc32)c1Cl
Reactant: CC1(C)OB(c2ccnc(N3CCOCC3)c2F)OC1(C)C
Product: Fc1ccc(F)c(CN2CCNc3ncc(-c4ccnc(N5CCOCC5)c4F)cc32)c1Cl
Yield: 35 %

Procedure:
1-(2-Chloro-3,6-difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (100 mg) was reacted with 4-[3-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]morpholine as in General Procedure 4A to give the title compound as a tan foam (35% yield). M.p. (foam), LCMS: m/z=476.02 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.28 (t, J=4.8 Hz, 2H), 3.48 (t, J=4.8 Hz, 4H), 3.52-3.65 (m, 2H), 3.87 (t, J=4.6 Hz, 4H), 4.50 (s, 2H), 5.38 (bs, 1H), 6.82-6.86 (m, 1H), 6.97-7.04 (m, 1H), 7.08 (s, 1H), 7.04-7.15 (m, 1H), 7.70 (s, 1H), 8.00 (d, J=5.0 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1ccc2[nH]ccc2c1
Product: c1ccc(-c2ccc3[nH]ccc3c2)cc1
Yield: 87 %

Procedure:
The title compound was prepared from 5-bromoindole and benzeneboronic acid by the method of Suzuki (N. Miyaura, T Yanagi, A Suzuki, Synth. Commun, 1981, 513) in 87% yield.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH2:10][CH2:9][CH:8]([NH:16][C:17]([CH:19]3[CH2:21][CH2:20]3)=[O:18])[CH2:7][C:6]2=1)#[N:2].Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[N:25]=1>>[C:1]([C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[N:25]=1)[C:11]1[CH2:10][CH2:9][CH:8]([NH:16][C:17]([CH:19]3[CH2:21][CH2:20]3)=[O:18])[CH2:7][C:6]2=1)#[N:2]
Reactant: Fc1cccc(CBr)n1
Reactant: N#Cc1ccc2[nH]c3c(c2c1)CC(NC(=O)C1CC1)CC3
Product: N#Cc1ccc2c(c1)c1c(n2Cc2cccc(F)n2)CCC(NC(=O)C2CC2)C1

Procedure:
Prepare the title compound from cyclopropanecarboxylic acid(6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)amide (Preparation 69) (10.0 g, 35.8 mmol) and 2-bromomethyl-6-fluoro-pyridine (Preparation 44) (7.49 g, 39.4 mmol) by essentially following procedures as described in Preparation 45 to obtain 4.30 g (31%) of a salmon colored solid. Resolve the enantiomers using chiral chromatography essentially as described for Example 194, but using 0.2% DMEA/EtOH eluent. (R)-Isomer is first to elute. Slurry the solid in EtOAc and filter to give the title compound. m.p.=243-245° C.; MS (ES): m/z 389 (M+1).
Reaction SMILES: C=O.[CH3:3][C:4]1[CH:5]=[C:6]([NH:16][C:17]2[N:22]=[C:21]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH2:31][C:32]([NH2:34])=[O:33])[C:20]([C:35]([F:38])([F:37])[F:36])=[CH:19][N:18]=2)[CH:7]=[CH:8][C:9]=1[CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[C:39](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:3][C:4]1[CH:5]=[C:6]([NH:16][C:17]2[N:22]=[C:21]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH2:31][C:32]([NH2:34])=[O:33])[C:20]([C:35]([F:38])([F:36])[F:37])=[CH:19][N:18]=2)[CH:7]=[CH:8][C:9]=1[CH:10]1[CH2:15][CH2:14][N:13]([CH3:39])[CH2:12][CH2:11]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1cc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3CC(N)=O)n2)ccc1C1CCNCC1
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: Cc1cc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3CC(N)=O)n2)ccc1C1CCN(C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.4 %

Procedure:
Formaldehyde (37 wt. % in H2O; 0.040 mL, 0.50 mmol) was added to a suspension of 2-(2-(2-(2-((3-methyl-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (11) (0.035 g, 0.070 mmol) in MeOH (5 mL) under an atmosphere of nitrogen. Sodium triacetoxyborohydride (0.19 g, 0.10 mmol) was added in one portion and the resulting mixture stirred at room temperature for 3 hours. The volatiles were removed in vacuo and the residue was partitioned between EtOAc (10 mL) and saturated aqueous NaHCO3 (10 mL). Solid NaHCO3 was added until the formation of gas ceased then the layers were separated and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were washed with water (10 mL), brine (10 mL) and dried over Na2SO4. The volatiles were removed under reduced pressure to yield the title compound 12 as a white solid (0.032 g, 89%); 1H NMR (400 MHz, d4-MeOH) δ 8.52 (s, 1H), 7.53 (dd, J=8.4, 2.3 Hz, 1H), 7.44 (d J=2.2 Hz, 1H), 7.28-7.22 (m, 1H), 7.24-7.15 (m, 4H), 3.67 (s, 2H), 3.20-3.11 (m, 2H), 3.11-2.95 (m, 4H), 2.81-2.70 (m, 1H), 2.35 (s, 3H), 2.34 (s, 3H), 2.28-2.13 (m, 2H), 1.87-1.70 (m, 4H). LCMS-A: rt 4.908 min; m/z 512.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[CH:31][C:32]([F:41])=[C:33]([NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])[CH:34]=2)[CH2:25][CH2:24]1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][CH:26]([C:29]3[CH:30]=[CH:31][C:32]([F:41])=[C:33]([NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])[CH:34]=3)[CH2:27][CH2:28]2)=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CCCC(=O)Nc1cc(C2CCN(CCCN)CC2)ccc1F
Product: CCCC(=O)Nc1cc(C2CCN(CCCNC(=O)C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)CC2)ccc1F

Procedure:
Example 108 was prepared from bis(4-chlorophenyl)acetic acid and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}butanamide according to the procedures described in Scheme 10: ESMS m/e: 584.2 (M+H)+.
Reaction SMILES: Cl.[OH:2]/[N:3]=[C:4](/[C:10]1[N:11]=[C:12]([NH:15][C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:13][CH:14]=1)\[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:35]1([CH2:38]Br)[CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH:35]1([CH2:38][O:2]/[N:3]=[C:4](/[C:10]2[N:11]=[C:12]([NH:15][C:16]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:13][CH:14]=2)\[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:37][CH2:36]1
Reactant: BrCC1CC1
Reactant: CCOC(=O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)/C(=N\OCC1CC1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 67.3 %

Procedure:
Ethyl (Z)-2-hydroxyimino-2-(2-tritylaminothiazol-4-yl)acetate, hydrochloride salt (30 g) was stirred with cyclopropylmethyl bromide (13.5 g) in dimethylsulphoxide (150 ml) containing potassium carbonate (30 g) under nitrogen at 21° for 7 hours. The mixture was partitioned between methylene chloride and water. The aqueous layer was extracted with more methylene chloride and the combined organic solutions were washed with water. After drying with magnesium sulphate, the solution was concentrated and loaded onto a column of Sorbsil U30 silica gel (200 g). The column was eluted with ethyl acetate (10 to 30%) in petroleum ether (b.p. 40°-60°). Evaporation of appropriate fractions gave the title compound (20.9 g); λmax (ethanol) 234.5 nm (E1 cm1% 403); λinf. 254.5 nm (E1 cm1% 302), 259.5 nm (E1 cm1% 267), 265 nm (E1 cm1% 229), 271.5 nm (E1 cm1% 190) and 294 nm (E1 cm1% 111); νmax (CHBr3) 3398 (NH), 1730 (ester), and 1593 and 1491 cm-1 (aromatic double bond).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Br:26])[CH2:5][N:6]1[N:15]=[C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:28].C(OCC)(=O)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Br:26])[CH2:5][N:6]1[N:15]=[C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[S:28]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCOC(=O)Cc1nn(Cc2ccc(Br)c(Cl)c2)c(=O)c2ccccc12
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1nn(Cc2ccc(Br)c(Cl)c2)c(=S)c2ccccc12
Temperature: 25 °C
Yield: 58.9 %

Procedure:
A mixture of ethyl 2-(3-chloro-4-bromobenzyl)-1,2-dihydro-1-oxophthalazin-4-ylacetate (1.8 g.) and phosphorus pentasulphide (2.5 g.) in xylene (100 ml.) was stirred and heated under reflux for 1 hour. The reaction solution was then cooled to room temperature, ethyl acetate (25 ml.) was added and the mixture was filtered through chromatographic silica (20 g.), the subsequent filtrate was evaporated and the residual solid obtained was recrystallised from ethanol to give ethyl 2-(3-chloro-4-bromobenzyl)-1,2-dihydro-1-thioxophthalazin-4-ylacetate (1.1 g.), m.p. 124°-126° C.
Reaction SMILES: Cl.[F:2][CH2:3][CH2:4][CH2:5][NH2:6].C(N(C(C)C)CC)(C)C.[F:16][CH:17]([F:47])[C:18]([N:20]1[C@H:24]([CH2:25][F:26])[C@@H:23]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:34]=[CH:35][C:36]([CH2:39]OS(C)(=O)=O)=[N:37][CH:38]=3)=[CH:29][CH:28]=2)[O:22][C:21]1([CH3:46])[CH3:45])=[O:19]>C(#N)C>[F:47][CH:17]([F:16])[C:18]([N:20]1[C@H:24]([CH2:25][F:26])[C@@H:23]([C:27]2[CH:28]=[CH:29][C:30]([C:33]3[CH:38]=[N:37][C:36]([CH2:39][NH:6][CH2:5][CH2:4][CH2:3][F:2])=[CH:35][CH:34]=3)=[CH:31][CH:32]=2)[O:22][C:21]1([CH3:45])[CH3:46])=[O:19]
Reactant: CC1(C)O[C@H](c2ccc(-c3ccc(COS(C)(=O)=O)nc3)cc2)[C@@H](CF)N1C(=O)C(F)F
Reactant: NCCCF
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC1(C)O[C@H](c2ccc(-c3ccc(CNCCCF)nc3)cc2)[C@@H](CF)N1C(=O)C(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
To a solution of 3-Fluoro-propylamine hydrochloride (0.072 g, 0.636 mmol) in acetonitrile (5 mL) is added diisopropylethylamine (0.082 mL, 0.636 mmol) at room temperature. After stirring for 30 minutes methane sulfonic acid 5-{4-[(4S,5R)-3-(2,2-difluoro-acetyl)-4-fluoromethyl-2,2-dimethyl-oxazolidin-5-yl]-phenyl}-pyridin-2-ylmethyl ester (0.1 g, 0.211 mmol) is added then the resulting mixture is stirred at room temperature for overnight. Solvent is evaporated under reduced pressure and the crude material is purified by combi-flash chromatography using 12% methanol in CH2Cl2 as an eluent to afford the title compound (0.093 g). 1H-NMR (400 MHz, DMSO-d6) δ: 1.52 (s, 3H), 1.60 (S, 3H), 2.06-2.14 (m, 2H), 3.57-3.60 (m, 2H), 4.35 (s, 2H), 4.49-4.51 (m, 1H), 4.52-4.56 (m, 0.5H), 4.57-4.63 (m, 1H), 4.64-4.70 (m, 1H), 4.83-4.86 (m, 0.5H), 4.93-4.97 (m, 1H), 5.28 (d, J=3.48 Hz, 1H), 6.66 (t, J=52.3 Hz, 1H), 7.61-7.65 (m, 3H), 7.84 (d, J=8.2 Hz, 2H), 8.21-8.23 (dd, J1=3.04 Hz, J2=8.16 Hz, 1H), 8.97 (d, J=1.96 Hz, 1H). LC-MS (m/z): [M+H]=454.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]1.[CH3:20][CH2:21]N=C=NCCCN(C)C.C(Cl)Cl>CN(C1C=CN=CC=1)C.C(O)C>[CH2:20]([O:14][C:13]([C:12]1[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:9]=[C:10]([C:16]([F:19])([F:17])[F:18])[CH:11]=1)=[O:15])[CH3:21]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cc(C(F)(F)F)nn1-c1ccccc1Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1cc(C(F)(F)F)nn1-c1ccccc1Cl
Temperature: 25 °C

Procedure:
Into a 500 mL flask was weighed 11.5 g (39.6 mmol) of 2-(2-chlorophenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid, 8.95 g (46.7 mmol) of EDCI, 530 mg (4.34 mmol) of DMAP, and 200 mL of CH2Cl2. Ethanol (8.6 mL) was then added to the stirred solution which was maintained at room temperature for 3 h. The reaction was then concentrated in vacuo to remove CH2Cl2. The residue was washed into a separatory funnel with ethyl acetate and 1.0 M sodium carbonate. The ethyl acetate was separated, washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel flash chromatography (Jones Flashmaster, 2×70 g Silica gel, gradient elution from 100% hexanes to 40% ethyl acetate over 30 minutes). Appropriate fractions were combined and concentrated in vacuo affording 2-(2-chlorophenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid ethyl ester as a viscous yellow oil, yield: 10.0 g (79.3%); 1H NMR (400 MHz, CDCl3): δ 7.32-7.46 (m, 4H), 7.19 (d, J=6 Hz, 1H), 4.16 (q, J=7 Hz, 2H), 1.13 (t, J=7 Hz, 3H); MS (ES): 319 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[C:10]([CH2:12][C:13](OCC)=[O:14])#[N:11]>CCCCCC.C(OCC)(=O)C>[C:10]([CH2:12][C:13]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][C:4]=1[CH3:9])=[O:14])#[N:11]
Reactant: Cc1cc(F)ccc1N
Reactant: CCOC(=O)CC#N
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc(F)ccc1NC(=O)CC#N
Temperature: 150 °C
Reaction time: 4 h
Yield: 67.1 %

Procedure:
4-Fluoro-2-methylaniline (3.9 g, 31 mmol) was added to ethyl cyanoacetate (5.3 g, 46 mmol) and the mixture was stirred at 150° C. for 4 hr. After cooling to room temperature, hexane-ethyl acetate was added to the reaction mixture, and the precipitate was collected by filtration to give the title compound (4.0 g, 67%) as a pale-yellow solid.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH2:13][NH:14][C:15](=[O:31])[C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:23]=[CH:24][C:25](OC)=[N:26][CH:27]=4)=[CH:18][C:17]=3[CH3:30])[CH:10]=2)[NH:5][CH:4]=1)#[N:2].Cl.[NH+]1C=CC=CC=1.[OH2:39]>>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH2:13][NH:14][C:15](=[O:31])[C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:27](=[O:39])[NH:26][CH:25]=[CH:24][CH:23]=4)=[CH:18][C:17]=3[CH3:30])[CH:10]=2)[NH:5][CH:4]=1)#[N:2]
Reactant: COc1ccc(-c2ccc(C(=O)NCCc3ccc4[nH]cc(C#N)c4c3)c(C)c2)cn1
Reactant: O
Agent: Cl
Agent: c1cc[nH+]cc1
Product: Cc1cc(-c2ccc[nH]c2=O)ccc1C(=O)NCCc1ccc2[nH]cc(C#N)c2c1
Temperature: 160 °C
Reaction time: 0.05 h

Procedure:
A mixture of N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-(2-methoxy-pyridin-5-yl)-2-methyl-benzamide (146 mg, 0.35 mmol) (reference example 1n) and pyridinium hydrochloride (3 g) is heated to 160° C. and stirred at this temperature for 3 minutes. The liquid is then cooled and mixed with water. The resulting precipitated solid is filtered, washed with water (3×) then dried under vacuum to give 133 mg of th title compound as a solid. This material is used without further purification. MS (ion spray) m/z 397 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[S:9]1[C:13]([Sn](C)(C)C)=[CH:12][N:11]=[CH:10]1>C1C=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>[CH3:8][C:4]1[CH:3]=[C:2]([C:13]2[S:9][CH:10]=[N:11][CH:12]=2)[CH:7]=[CH:6][N:5]=1
Reactant: C[Sn](C)(C)c1cncs1
Reactant: Cc1cc(Br)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: Cc1cc(-c2cncs2)ccn1
Temperature: 25 °C

Procedure:
At room temperature, tetrakis(triphenylphosphine)palladium (470 mg) was added to a solution of 4-bromo-2-methylpyridine (1.65 g) and (5-thiazolyl)trimethyltin (1.56 g) in benzene (80 ml), followed by heating under reflux for 14 hours. After allowed to cool down to room temperature, the reaction mixture was washed with a saturated aqueous solution (100 ml) of sodium bicarbonate. The water layer was extracted with ethyl acetate (50 ml). The organic layers were combined, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (methylene chloride:ethyl acetate=4:1→1:1), whereby 2-methyl-4-(5-thiazolyl)pyridine was obtained as a colorless solid. The resulting solid was dissolved in diethyl ether (30 ml) and tetrahydrofuran (30 ml), followed by the dropwise addition of n-butyl lithium (a 1.52N hexane solution, 4.35 ml) at −78° C. After stirring for 30 minutes, a carbon dioxide gas was blown into the reaction mixture. Thirty minutes later, the reaction mixture was heated gradually to room temperature. The reaction mixture was concentrated, whereby the residue of lithium 5-(2-methylpyridin-4-yl)thiazole-2-carboxylate was obtained as a colorless solid. To a solution of the resulting residue in N,N-dimethylformamide (40 ml) were added 1-(tert-butoxycarbonyl)piperazine (1.30 g), 1-hydroxybenzotriazole monohydrate (945 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.34 g) at room temperature. After stirring for 3 days, ethyl acetate (200 ml) and water (800 ml) were added to the reaction mixture to separate it into layers. The water layer was extracted with ethyl acetate (2×100 ml). The organic layers were combined, washed with water (800 ml) and a saturated aqueous solution (200 ml) of sodium bicarbonate, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (methylene chloride:acetone=6:1), whereby the title compound (810 mg) was obtained as a colorless transparent viscous substance.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([N:15]([CH3:17])[CH3:16])=[N:11][N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.[H-].[Na+].[CH:20](OC(=O)C)=[O:21]>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH:20]=[O:21])[C:10]([N:15]([CH3:17])[CH3:16])=[N:11][N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1
Reactant: CN(C)C(=N[N+](=O)[O-])NCc1ccc(Cl)nc1
Reactant: CC(=O)OC=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C(=N[N+](=O)[O-])N(C=O)Cc1ccc(Cl)nc1
Reaction time: 0.5 h
Yield: 34.7 %

Procedure:
To a mixture of 0.26g of 1-(6-chloro-3-pyridylmethyl)-3,3-dimethyl-2-nitroguanidine (Compound No. 6) and 3ml of dry THF was added 0.08g of 60% sodium hydride (in mineral oil) in a water bath of 20° C., followed by stirring for 30 minutes. A solution of 0.26g of acetic formic anhydride in 0.5ml of THF was added to the reaction mixture in one minute, and then stirred for 12 hours after the bath was removed. After adding 0.5ml of acetic: acid, the reaction mixture was concentrated. The residue was purified by a column chromatography [developing solvent: dichloromethanemethanol (30:1)] to obtain 0.10g of 1-(6-chloro-3-pyridylmethyl)-1-formyl-3, 3-dimethyl-2-nitroguanidine (Compound No. 22) as a syrup.
Reaction SMILES: [Br:1][C:2]1[C:7](/[CH:8]=[CH:9]/N2CCCC2)=[C:6]([N+:15]([O-])=O)[C:5]([O:18][CH3:19])=[CH:4][CH:3]=1.NN>C1COCC1.CO.[Ni]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]2[C:7]=1[CH:8]=[CH:9][NH:15]2
Reactant: COc1ccc(Br)c(/C=C/N2CCCC2)c1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Br)c2cc[nH]c12
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-[(E)-2-(6-bromo-3-methoxy-2-nitrophenyl)vinyl]pyrrolidine (1.3 g, 3.97 mmol) in THF (6 mL) and methanol (6 mL) was added Raney Ni (≈500 mg) followed by hydrazine (0.19 mL). (CAUTION: Exothermic reaction with vigorous gas evolution). Hydrazine (0.19 mL) was added again, two times, after 30 min and 1 h. The reaction was stirred at 45° C. for 2 h, filtered through a pad of celite. The filtrate was concentrated in vacuo and the residue purified by chromatography over silica gel eluting with EtOAc/hexane to afford pure 4-bromo-7-methoxy-1H-indole. 1H NMR (400 MHz, CDCl3) δ=3.94 (s, 3H), 6.52 (d, J=8.08 Hz, 1H), 6.56 (dd, J=3.16, 2.40 Hz, 1H), 7.17 (d, J=8.08 Hz, 1H), 7.22 (t, J=2.78 Hz, 1H) and 8.47 (br. s., 1H); MS (ES+): m/z 226.12 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]3[CH:18]=2)=[CH:5][CH:4]=1.C1(C)C=CC=CC=1.[C:26]([O:30][CH2:31][CH3:32])(=[O:29])[CH:27]=[O:28].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:31]([O:30][C:26](=[O:29])[CH:27]([OH:28])[C:18]1[N:12]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]2=[N:10][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[CH3:32]
Reactant: COc1ccc(-c2cn3cc(C)ccc3n2)cc1
Reactant: CCOC(=O)C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(O)c1c(-c2ccc(OC)cc2)nc2ccc(C)cn12
Temperature: 25 °C
Yield: 19.8 %

Procedure:
To a magnetically stirred solution of 2-(4-methoxy-phenyl)-6-methyl-imidazo[1,2-a]pyridine 13a (2.55 g, 10.71 mmol) and ethyl glyoxylate toluene solution (11.79 mL, 54.62 mmol) in toluene (130 mL) under Ar atmosphere was added p-toluenesulfonic acid monohydrate (60.9 mg, 0.32 mmol). The reaction mixture was equipped with a dean-stark trap and refluxed for 4 h. The mixture was cooled to room temperature and concentrated in vacuo. The crude product was purified by column chromatography over silica gel (40:60 EtOAc/hexane, then 100% EtOAc as eluent), which gave the title compound (0.72 g, 20%) as an off white solid. 1H NMR (400 MHz, CDCl3) 1.15 (t, J=7.0 Hz, 3H), 2.31 (s, 3H), 3.83 (s, 3H), 4.13 (m, 1H), 4.24 (m, 1H), 5.75 (s, 1H), 6.91 (d, J=8.8 Hz, 2H), 7.04 (dd, J=1.4, 9.1 Hz, 1H), 7.47 (d, J=9.1 Hz, 1H), 7.60 (d, J=8.8 Hz, 2H), 7.99 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][N:8]=[CH:7][C:6]=2[CH:12]=1.[N:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[N:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:3]=[CH:4][C:5]3[NH:11][CH2:10][CH2:9][N:8]=[CH:7][C:6]=3[CH:12]=2)=[CH:15][CH:14]=1
Reactant: Brc1ccc2c(c1)C=NCCN2
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C1=NCCNc2ccc(-c3ccncc3)cc21
Temperature: 160 °C

Procedure:
A 20 mL microwave tube was charged 7-bromo-2,3-dihydro-1H-1,4-benzodiazepine (115 mg), 4-pyridylboronic acid (2 equiv), potassium carbonate (2 equiv), dichlorobis(triphenyl-phosphine)palladium(II) (10 mol %), DMF (3.5 mL) and water (0.7 mL) then heated to 160° C. for 360 s using microwave irradiation. The reaction was concentrated to dryness and the residue was taken up in water then extracted with ethyl acetate/tetrahydrofuran (3:1). The organic extracts were combined and dried over sodium sulfate. The drying salts were removed by filtration and the filtrate was concentrated. The residue was triturated with diethyl ether and the resulting solids were collected on filter. Recrystallization from hot tetrahydrofuran provided 7-(4-pyridinyl)-2,3-dihydro-1H-1,4-benzodiazepine as a tan powder (9 mg). H1 NMR (d6-dmso): 8.49 (d, 2H), 8.23 (s, 1H), 7.85 (d, 1H), 7.62 (m, 3H), 7.29 (br t, 1H), 6.80 (d, 1H), 3.85 (m, 2H), 3.25 (m, 2H). Mass (ES+)=224.2 (100%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[C:26]1(=[O:39])[N:30]([CH2:31][CH2:32]Br)[C:29](=[O:34])[C:28]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:27]12>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:32][CH2:31][N:30]2[C:26](=[O:39])[C:27]3=[CH:38][CH:37]=[CH:36][CH:35]=[C:28]3[C:29]2=[O:34])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(SCCN2C(=O)c3ccccc3C2=O)nc2c1nc(O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.5 %

Procedure:
6-Amino-9-benzyl-8-hydroxy-2-mercaptopurine (120 mg, 0.44 mmol) was suspended in dimethylformamide (10 ml). To the suspension were added potassium carbonate (60 mg, 0.43 mmol) and 2-phthalimidoethyl bromide (112 mg, 0.44 mmol) in order. The mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo and to the residue was added saturated brine. The mixture was extracted with ethyl acetate, the organic layer was dried on magnesium sulfate, and the solvent was removed in vacuo. Methanol was added to the residue, and the resulting crystals were taken by filtration to give the subject compound (107 mg, yield 54%).