Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:29])=[C:4]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[C:5]([I:23])=[C:6]([C:21]=1[I:22])[C:7]([NH:9][CH2:10][CH:11]([O:17][C:18](=[O:20])[CH3:19])[CH2:12][O:13][C:14](=[O:16])[CH3:15])=[O:8].[C:30]([O:33][CH:34]([CH:38]([O:44][C:45](=[O:47])[CH3:46])[CH2:39][O:40][C:41](=[O:43])[CH3:42])[C:35](Br)=[O:36])(=[O:32])[CH3:31].C([O-])(O)=O.[Na+]>CN(C)C(=O)C>[C:30]([O:33][CH:34]([CH:38]([O:44][C:45](=[O:47])[CH3:46])[CH2:39][O:40][C:41](=[O:43])[CH3:42])[C:35]([NH:1][C:2]1[C:3]([I:29])=[C:4]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[C:5]([I:23])=[C:6]([C:21]=1[I:22])[C:7]([NH:9][CH2:10][CH:11]([O:17][C:18](=[O:20])[CH3:19])[CH2:12][O:13][C:14](=[O:16])[CH3:15])=[O:8])=[O:36])(=[O:32])[CH3:31]
Reactant: CC(=O)OCC(OC(C)=O)C(OC(C)=O)C(=O)Br
Reactant: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(=O)OCc1c(I)c(NC(=O)C(OC(C)=O)C(COC(C)=O)OC(C)=O)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I
Temperature: 25 °C
Reaction time: 5 h
Yield: 34.7 %

Procedure:
5-Amino-3-acetoxymethyl-N-(2,3-diacetoxypropyl)-2,4,6-triiodobenzamide (30.0 g, 40.3 mmol) was dissolved in dry N,N-dimethylacetamide (50 ml) and added dropwise to 2,3,4-triacetoxybutanoyl bromide (26.0 g, 0.93 mol) at 0° C. The mixture was stirred at ambient temperature for 5 h, and then added slowly to an aqueous solution of NaHCO3 (5%, 500 ml). A semi-crystalline precipitate was formed, filtered off and dissolved in ethyl acetate (200 ml). The organic phase was washed three times with diluted HCl (5%, 80 ml) and then twice with water (80 ml). After drying (Na2SO4) the solvent was evaporated to a semisolid residue. The residue was purified on a column of silica using methylene chloride/acetonitrile (4:1-3:2) as the eluent. The solvent was evaporated and the residue was further purified by preparative HPLC to give 13.8 g (35%) of the product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[C:5]#[N:6].[F:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1>>[F:10][C:9]1[C:2]([C:13]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=2[F:11])=[CH:3][C:4]([C:5]#[N:6])=[CH:7][CH:8]=1
Reactant: N#Cc1ccc(F)c(Br)c1
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Product: N#Cc1ccc(F)c(-c2cc([N+](=O)[O-])ccc2F)c1
Yield: 99.9 %

Procedure:
3-Bromo-4-fluorobenzonitrile (2.00 g, 10 mmol) was coupled to 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (4.01 g, 15 mmol) following the procedure described in Example 14 part a), affording 6,2′-difluoro-5′-nitrobiphenyl-3-carbonitrile as a brown solid (2.60 g, 100%). δH (360 MHz, CDCl3) 7.38 (2H, q, J 8.8), 7.77-7.82 (2H, m), 8.33-8.38 (2H, m).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([N+:29]([O-])=O)[C:12]([CH2:26][CH2:27][Cl:28])=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[C:14]2[C:22]([O:24][CH3:25])=[O:23])C1C=CC=CC=1.CCN=C=NCCCN(C)C.[CH3:43][O:44][C:45]1[CH:46]=[C:47]2[C:51](=[C:52]([O:56][CH3:57])[C:53]=1[O:54][CH3:55])[NH:50][C:49]([C:58]([OH:60])=O)=[CH:48]2>[Pd].C1COCC1>[Cl:28][CH2:27][CH2:26][C:12]1[C:11]([NH:29][C:58]([C:49]2[NH:50][C:51]3[C:47]([CH:48]=2)=[CH:46][C:45]([O:44][CH3:43])=[C:53]([O:54][CH3:55])[C:52]=3[O:56][CH3:57])=[O:60])=[CH:10][C:9]([OH:8])=[C:17]2[C:13]=1[C:14]([C:22]([O:24][CH3:25])=[O:23])=[C:15]([C:18]([F:21])([F:19])[F:20])[NH:16]2
Reactant: COc1cc2cc(C(=O)O)[nH]c2c(OC)c1OC
Reactant: COC(=O)c1c(C(F)(F)F)[nH]c2c(OCc3ccccc3)cc([N+](=O)[O-])c(CCCl)c12
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Solvent: C1CCOC1
Product: COC(=O)c1c(C(F)(F)F)[nH]c2c(O)cc(NC(=O)c3cc4cc(OC)c(OC)c(OC)c4[nH]3)c(CCCl)c12
Temperature: 25 °C

Procedure:
10% Pd/C (0.023 g) was added to methyl 7-benzyloxy-4-(2-cloroethyl)-5-nitro-2-trifluoromethylindole-3-carboxylate (0.0468 g, 0.102 mmol) and chilled THF (7 mL) was added quickly to the flask. The mixture was placed under reduced pressure and purged three times with H2. The reaction was stirred under H2 at room temperature and atmospheric pressure until completed by TLC. The solution was filtered through Celite pad in a sinter funnel and washed with THF. The amine was then concentrated under reduced pressure and co-evaporated twice with dry CH2Cl2 (2 mL). To the amine were added EDCI (0.040 g, 0.208 mmol) and 5,6,7-trimethoxyindole-2-carboxylic acid (0.026 g, 0.104 mmol). The flask was covered and flushed with N2. The amine was dissolved in dry DMF (10 mL) and stirred for four days under N2. The yellow solution was then diluted with ethyl acetate (100 mL), washed with water three times (100 mL) and 5% NaHCO3 (75 mL). The organic layer was collected, dried with sodium sulfate, gravity filtered and concentrated under reduced pressure. The residue was then purified on a preparative TLC in 2.5% methanol chloroform to yield the crude product. The product was further purified on a preparative TLC in methylene chloride to yield methyl 4-(2-chloroethyl)-7-hydroxy-2-trifluoromethyl-5-(5,6,7-trimethoxyindole-2-carboxamido)indole-3-carboxylate as a yellow solid. Total yield: 0.001 g (0.002 mmol, 2%). TLC (methylene chloride) Rf320.56.500 MHz 1H-NMR (CDCl3): 9.53 (s, 1H), 9.37 (s, 1H), 9.07 (s, 2H), 7.89 (s, 1H), 7.42 (s, 1H), 6.85 (s, 1H), 4.12 (s, 3H), 4.00 (s, 3H), 3.96 (s, 3H), 3.93 (s, 3H), 3.87 (t, 8.0, 2H), 3.72 (t, 8.0, 2H). IR (Neat) 3018, 2965, 2922, 2847, 1729, 1531, 1472, 1344, 1253, 1227, 1178, 1109, 1002, 799.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][C:22]([NH2:26])=[CH:23][C:24]=3[CH2:25][C@H:14]12)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>ClCCl>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][C:22]([NH:26][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:23][C:24]=3[CH2:25][C@H:14]12)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]2c3ccc(N)cc3C[C@@H]21
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H]2c3ccc(NS(C)(=O)=O)cc3C[C@@H]21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methylsulfonyl chloride (42 μL) is added to a solution of cis-7-amino-2,3,4,4a,9,9a-hexahydro-indeno[2,1-b]pyridine-1-carboxylic acid tert-butyl ester (160 mg) and triethylamine (76 μL) in dichloromethane (3 mL) at room temperature. The solution is stirred for 1 h at room temperature and then aqueous NaHCO3 solution is added. The mixture is stirred vigorously for 20 min and then extracted with dichloromethane. The combined extract is concentrated and the residue is chromatographed (cyclohexane/ethyl acetate 7:3→1:9) to give the title compound. Yield: 120 mg (59% of theory); LC (method 1): tR=3.80 min; Mass spectrum (ESI+): m/z=365 [M−H]+.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][CH:16]=3)[NH:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:22]I.O>CN(C=O)C>[CH3:22][N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH:13]=2)[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:10]1
Reactant: CI
Reactant: COC(=O)c1ccc2c(-c3ccccc3)c[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(-c3ccccc3)cn(C)c2c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
NaH (60% dispersion in mineral oil, 4.52 mmol, 186 mg) was added portion-wise to a solution of methyl 3-phenyl-1H-indole-6-carboxylate (2.07 mmol, 757 mg) in DMF at 0° C. and the mixture was stirred for 20 min. Methyl iodide (2.28 mmol, 0.14 mL) was added and the reaction mixture was maintained at 0° C. for 1 h. Water was then added and the reaction was extracted with EtOAc. The organics were concentrated and purified by flash column chromatography (silica gel, 15% EtOAc/hexanes) to give 16c.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:10]([CH3:14])([CH3:13])[CH2:11][OH:12])=[CH:8][CH:9]=1)=[O:4].[CH3:15][C:16]1[CH:21]=[C:20](O)[CH:19]=[C:18]([CH3:23])[C:17]=1[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CO>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:10]([CH3:14])([CH3:13])[CH2:11][O:12][C:20]2[CH:21]=[C:16]([CH3:15])[C:17]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:33])[F:32])=[CH:26][CH:25]=3)=[C:18]([CH3:23])[CH:19]=2)=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(C(C)(C)CO)s1
Reactant: Cc1cc(O)cc(C)c1-c1ccc(C(F)(F)F)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1ccc(C(C)(C)COc2cc(C)c(-c3ccc(C(F)(F)F)cc3)c(C)c2)s1
Temperature: 80 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
A mixture of 5-(2-hydroxy-1,1-dimethyl-ethyl)-thiophene-2-carboxylic acid methyl ester (0.436 g, 2.04 mmol), 2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-ol (0.596 g, 2.24 mmol), and PPh3 (0.793 g, 3.02 mmol) is dissolved in toluene (20 mL), treated with 1,1′-(azodicarbonyl)dipiperidine (ADDP, 0.763 g, 3.02 mmol), and stirred overnight at 80° C. The mixture is then cooled to rt, diluted with MeOH until homogeneous, and concentrated. The residue is loaded onto silica gel and eluted using hexanes with an ethyl acetate gradient from 0% to 40% to afford 5-[2-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-yloxy)-1,1-dimethyl-ethyl]-thiophene-2-carboxylic acid methyl ester (0.394 g, 42%). MS (ES): 463.3 [M+H]+.
Reaction SMILES: CC[O-].[Na+].[C:5]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:6][C:7]([O-])=[O:8].[C:14]1([C:20]2[N:21]=[CH:22][C:23]3[C:28](=O)[O:27]C(=O)[N:25]([CH2:31][CH2:32][CH3:33])[C:24]=3[N:34]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>>[CH2:12]([O:11][C:5]([C:6]1[C:7](=[O:8])[N:25]([CH2:31][CH2:32][CH3:33])[C:24]2[N:34]=[C:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:21]=[CH:22][C:23]=2[C:28]=1[OH:27])=[O:10])[CH3:13]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: CCCn1c(=O)oc(=O)c2cnc(-c3ccccc3)nc21
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Product: CCCn1c(=O)c(C(=O)OCC)c(O)c2cnc(-c3ccccc3)nc21

Procedure:
50 ml. of NaOEt (0.24 g.-0.011 mole) was added to 1.7 g. (0.011 mole) of ethyl malonate and stirred 10 minutes, then evaporated to dryness. DMF was added until a solution formed and 1.5 g. (0.005 mole) of 7-phenyl-1-propyl-2H-pyrimido[4,5-d][1,3]oxazine-2,4(1H)-dione was added and the mixture refluxed 2 hours. The chilled reaction was poured into dilute HCl and the resulting precipitate filtered off and rinsed with water. Recrystallization from ethyl acetate gave 1.5 g. of the title compound--m.p. 164°-167° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccc(Br)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCCc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
To a solution of 3-(4-bromo-phenyl)-propionic acid (4.0 g, 18 mmol) in THF (30 mL) at 0° C. under the argon atmosphere was added LiAlH4 (1.0 M in THF; 14 mL, 14 mmol). After the addition, the ice-bath was removed and the mixture refluxed for 18 h. After cooling to room temperature, the reaction was quenched with 1 M HCl and the mixture extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated and the crude product used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.Br[CH2:11][C:12]([C:14]1[O:15][C:16]([Br:19])=[CH:17][CH:18]=1)=O>>[Br:19][C:16]1[O:15][C:14]([C:12]2[N:1]=[C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]3[CH:11]=2)=[CH:18][CH:17]=1
Reactant: N#Cc1ccc(N)nc1
Reactant: O=C(CBr)c1ccc(Br)o1
Product: N#Cc1ccc2nc(-c3ccc(Br)o3)cn2c1

Procedure:
Referring now to Scheme 2, the acetate salt of 2-[5-(4-Amidinophenyl)-furan-2-yl]-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine-6-carboxamidine (7) was synthesized from 2-[5-(4-Cyanophenyl)-furan-2-yl]-imidazo[1,2-a]pyridine-6-carbonitrile (4a), through the bis-O-acetoxyamidoxime followed by hydrogenation in glacial acetic acid. Compound 4a was obtained in four steps starting with two successive brominations of 2-acetylfuran first with N-bromosuccinimide, and second with bromine to form 2-Bromo-1-(5-bromofuran-2-yl)-ethanone (2) in a moderate yield. A condensation reaction between 6-Amino-nicotinonitrile and compound 2 gave 2-(5-Bromofuran-2-yl)-imidazo[1,2-a]pyridine-6-carbonitrile (3a). A subsequent Suzuki coupling of 3a with 4-Cyanophenyl boronic acid furnished 4a in good yield. Interestingly, 2-[5-(4-Amidinophenyl)-furan-2-y]-imidazo[1,2-a]pyridine-6-carbox-amidine acetate salt (8a) was obtained from 4a, through the bis-O-acetoxyamidoxime followed by hydrogenation in a mixture of ethanol/ethylacetate. Thus, by choice of hydrogenation solvent the saturated or unsaturated imidazo[1,2-a]pyridine can be obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:24]1[CH:28]=[C:27](B(O)O)[CH:26]=[N:25]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:27]2[CH:28]=[N:24][NH:25][CH:26]=2)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cn[nH]c1
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C1CN(c2ccc(-c3cn[nH]c3)cc2OCc2ccccc2)S(=O)(=O)N1
Temperature: 110 °C

Procedure:
A mixture of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (100 mg, 0.225 mmol), 4-pyrazoleboronic acid (87 mg, 0.45 mmol), resin-bound PPh3Pd (346 mg, loading 0.13 mmol/g) and aqueous Na2CO3 (0.45 mL of a 2M solution) in DME (3 mL) is heated in a microwave apparatus at 110° C. for 30 min. The mixture is filtered and the solvent removed under reduced pressure. The residue is purified by reverse phase MPLC to give the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][CH:11]([O:17][CH:18]([CH3:20])[CH3:19])[C:12]([O:14]CC)=[O:13])[CH:7]=[CH:8][CH:9]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>>[CH:18]([O:17][CH:11]([CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][CH2:2][O:1][C:30]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)=[O:31])[CH:5]=1)[C:12]([OH:14])=[O:13])([CH3:19])[CH3:20]
Reactant: CCOC(=O)C(Cc1cccc(CCO)c1)OC(C)C
Reactant: COc1ccc(N=C=O)cc1
Product: COc1ccc(NC(=O)OCCc2cccc(CC(OC(C)C)C(=O)O)c2)cc1

Procedure:
Using ethyl 3-[3-(2-hydroxyethyl)phenyl]-2-isopropoxypropanoate and 4-methoxyphenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][CH:28]=[N:27]2)=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[C:30]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([C:11]5[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=5)=[CH:9][N:10]=4)[CH:7]=3)=[CH:29][CH:28]=[N:27]2)=[CH:24][CH:25]=1
Reactant: CC1(C)OB(c2ccnn2-c2ccc(F)cc2)OC1(C)C
Reactant: N#Cc1ccc(-c2cnc3ccc(Br)cn23)cc1
Product: N#Cc1ccc(-c2cnc3ccc(-c4ccnn4-c4ccc(F)cc4)cn23)cc1

Procedure:
The title compound, white solid (88 mg, 69%), MS (ISP) m/z=380.5 [(M+H)+], mp 215° C., was prepared in accordance with the general method of example 1 from 4-(6-bromo-imidazo[1,2-a]pyridin-3-yl)-benzonitrile (intermediate N) (0.1 g, 0.335 mmol) and 1-(4-fluoro-phenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate A) (0.13 mg, 0.44 mmol).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)[CH3:4].S(=O)(=O)(O)O.[CH3:19]O>>[NH2:2][C@@H:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][CH3:19])=[O:10])=[CH:7][CH:6]=1)[CH3:4]
Reactant: C[C@@H](N)c1ccc(C(=O)O)cc1
Reactant: CO
Agent: Cl
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc([C@@H](C)N)cc1
Yield: 70 %

Procedure:
To a solution of (R)-4-(1-amino-ethyl)-benzoic acid hydrochloride (0.20 g, 0.99 mmol) in methanol (3.2 mL) was added sulfuric acid (5.29 μL, 0.0992 mmol). The resulting solution was heated at reflux overnight. The methanol was removed under reduced pressure leaving a light brown oil which was partitioned between half-saturated sodium bicarbonate solution (50 mL) and ethyl acetate (75 mL). The aqueous phase was extracted with additional ethyl acetate (50 mL). The extracts were combined, washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification via silica chromatography (0-50% EtOAc/hexane) afforded product as a white solid (0.124 g, 70%). LC-MS: (FA) ES+ 180.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.C([Li])CCC.[C:22]1([C:28]2[C:41]3[C:32](=[C:33]4[C:38](=[CH:39][CH:40]=3)[C:37]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:36][CH:35]=[N:34]4)[N:31]=[CH:30][CH:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>C1COCC1>[S:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([C:35]2[CH:36]=[C:37]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:38]3[C:33](=[C:32]4[C:41](=[CH:40][CH:39]=3)[C:28]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:29][CH:30]=[N:31]4)[N:34]=2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(-c2nc3ccccc3s2)cc1
Reactant: c1ccc(-c2ccnc3c2ccc2c(-c4ccccc4)ccnc23)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(-c2ccnc3c2ccc2c(-c4ccccc4)cc(-c4ccc(-c5nc6ccccc6s5)cc4)nc23)cc1
Temperature: -78 °C
Yield: 41.9 %

Procedure:
To a three-necked flask of 250 ml, 1.63 g (5.6 mmol) of 2-(4-bromophenyl)benzo[d]thiazole and 70 ml of THF were charged, then 3.5 ml (5.6 mmol) n-butyllithium (1.6M in Hexane solution) was dropped under stirring at −78° C. in a nitrogen atmosphere. The mixture was stirred for one hour at −78° C., and a solution of 1.86 g (5.6 mmol) 4,7-diphenyl-1,10-phenanthroline in 30 ml THF was dropped. Then the mixture was stirred at room temperature for overnight and was added with water. The organic layer was extracted with Dichloromethane and dried with anhydrous magnesium sulfate, the solvent was removed by rotary evaporation. The product was purified by column chromatography on alumina using Dichloromethane/Hexane as eluent and dried in vacuo, obtaining white powder compound 1.27 g (yield of 41.91%), MS (m/z, FAB+) 541.6.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:18])[CH:11]=[C:12](C(O)=O)O[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:21]=[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:23]=[CH:24][CH:25]=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:10](=[O:18])[CH:11]=[CH:12][N:19]([C:20]2[CH:21]=[C:22]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:23]=[CH:24][CH:25]=2)[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(=O)c(OCc2ccccc2)co1
Reactant: Nc1cccc(-c2ccccc2)c1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=c1ccn(-c2cccc(-c3ccccc3)c2)cc1OCc1ccccc1
Temperature: 250 °C
Reaction time: 0.17 h

Procedure:
5-(Benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid (36.9 g, 150 mmol) and 3-aminobiphenyl (25.35 g, 150 mmol) were combined in diphenyl ether (110 ml). The mixture was heated to 250° C. (pre-heated block) in an open flask. After 10 min, the mixture was cooled to room temperature. The residue was purified by silica gel chromatography to provide 3-(benzyloxy)-1-(biphenyl-3-yl)pyridin-4(1H)-one. 1H NMR δ (400 MHz, d6-DMSO): 7.55 (d, J=7.6 Hz, 1H), 7.46 (m, 4H), 7.44-7.31 (m, 5H), 7.29-7.11 (m, 4H), 6.51 (d, J=7.2 Hz, 1H), 5.17 (s, 2H).MS (M+H)+ 354.
Reaction SMILES: [CH2:1]([OH:6])[C:2]#[C:3][CH2:4][OH:5].[H-].[Na+].[CH:9]([C:12]1[CH:13]=[CH:14][C:15]([S:18]([NH:21][C:22]2[C:27]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])=[C:26](Cl)[N:25]=[CH:24][N:23]=2)(=[O:20])=[O:19])=[N:16][CH:17]=1)([CH3:11])[CH3:10]>CN(C=O)C.CN1C(=O)N(C)CCC1>[CH:9]([C:12]1[CH:13]=[CH:14][C:15]([S:18]([NH:21][C:22]2[C:27]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])=[C:26]([O:5][CH2:4][C:3]#[C:2][CH2:1][OH:6])[N:25]=[CH:24][N:23]=2)(=[O:20])=[O:19])=[N:16][CH:17]=1)([CH3:11])[CH3:10]
Reactant: COc1ccccc1Oc1c(Cl)ncnc1NS(=O)(=O)c1ccc(C(C)C)cn1
Reactant: OCC#CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: CN(C)C=O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)C)cn2)ncnc1OCC#CCO
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 41 %

Procedure:
To a solution of 11.02 g of 2-butyne-1,4-diol in 100 ml of DMF and 30 ml of DMPU was added 2.8 g sodium hydride in portions. After completion of the addition stirring was continued for 1.5 h followed by the addition of 2.78 g of 5-isopropyl-N-[6-chloro-5-(o-methoxyphenoxy)-4-pyrimidinyl]-2-pyridine sulfonamide. The mixture was heated to 90° C. and stirred for 65 h. The solvent was removed in vacuo, the residue was taken up in 250 ml of 10% aqueous citric acid and extracted twice with 250 ml of ethyl acetate. The organic phase was washed with water and brine, dried over MgSO4 and evaporated. Column chromatography of the crude product on silica gel eluting with hexane:ethyl acetate 1:1 to 1:4 furnished 1.27 g of 5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)4-pyrimidinyl]-2-pyridine sulfonamide as a brown solid. Beige crystals were obtained for analytical purposes after crystallisation of a part of the isolated product from 2-propanol. LC-MS: tR=4.50 min, [M+1]+=485.27, [M−1]−=483.41.
Reaction SMILES: [Br:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4](I)[C:3]=1[F:11].[C:12]([Si:14]([CH3:17])([CH3:16])[CH3:15])#[CH:13].CN(C=O)C>C(N(CC)CC)C.[Cu](I)I.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>[Br:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([C:13]#[C:12][Si:14]([CH3:17])([CH3:16])[CH3:15])[C:3]=1[F:11]
Reactant: Nc1cc(F)c(Br)c(F)c1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1c(N)cc(F)c(Br)c1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63.9 %

Procedure:
A solution of 4-bromo-3,5-difluoro-2-iodoaniline (3.0 g, 9.0 mmol) in triethylamine (50 mL) was degassed with nitrogen for 10 minutes, then treated with copper iodide (209 mg, 1.10 mmol), Dichlorobis(triphenylphosphine)palladium(II), (769 mg 1.10 mmol), and ethynyl(trimethyl)silane (1.42 mL, 10.1 mmol). The reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture turned dark and formed a precipitate. After two hours, the reaction mixture was treated with DMF (8 mL) and stirred for an additional 72 hours at room temperature. The reaction mixture was heated to 50° C. for 16 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo, azeotroping with heptanes (3×100 mL). The black oil was partitioned between diethyl ether (300 mL) and water (300 mL), and the organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give a dark solid. The crude product was purified by flash chromatography to give the title compound (1.75 g). MS (ES+) 306.0 ((M+2)+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]=[C:12]([NH:14][NH2:15])[CH2:11][N:10]=[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:8]=2[CH:22]=1)([O-:3])=[O:2].[Cl:23][CH2:24][C:25](=O)[CH2:26][OH:27]>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]=[C:12]([NH:14][N:15]=[C:25]([CH2:26][OH:27])[CH2:24][Cl:23])[CH2:11][N:10]=[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:8]=2[CH:22]=1)([O-:3])=[O:2]
Reactant: NNC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2)=NC1
Reactant: O=C(CO)CCl
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1)=NCC(NN=C(CO)CCl)=N2

Procedure:
In the manner given in Example 1, 7-nitro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in tetrahydrofuran can be treated with 1-chloro-3-hydroxypropanone under nitrogen to give 7-nitro-2[[2-chloro-1-(hydroxymethyl)ethylidene]hydrazino]-5-phenyl-3H-1,4-benzodiazepine.