Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[N:17][C:16]1=[NH2+:23].[OH-].[Na+].CO[C:28](=O)[CH2:29][Cl:30]>CCO>[Cl:30][CH2:29][C:28]1[N:23]=[C:16]2[N:17]=[C:18]([CH3:22])[CH:19]=[C:20]([CH3:21])[N:15]2[N:14]=1
Reactant: Cc1cc(C)n(N)c(=[NH2+])n1
Reactant: COC(=O)CCl
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C)n2nc(CCl)nc2n1
Temperature: 55 °C
Reaction time: 1 h
Yield: 10.2 %

Procedure:
A mixture of 1-Amino-4,6-dimethyl-1H-pyrimidin-2-ylidene-ammonium 2,4,6-Trimethyl-benzenesulfonate (40 g, 0.1 mol) and NaOH (10 g, 0.2 mol) in 500 mL of EtOH was stirred at 50-60° C. for 1 hour. After chloroacetic acid methyl ester (16.6 g, 0.15 mol) was added, the resultant mixture was stirred at reflux for 4 hours. After being concentrated under reduce pressure, the residue was diluted with water (1000 mL) and extracted with CH2Cl2 (300 mL×3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography on silica gel (petroleum ether/EtOAc=2/1) to give 2 g of 2-Chloromethyl-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine in 9% yield. 1H NMR (300 MHz, DMSO-d6): δ 8.55 (s, 1H), 6.25 (s, 2H), 4.05 (s, 3H), 3.95 (s, 3H); LC-MS (MH+): m/z=196.9, tR (minutes, method A)=0.52
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][C@H:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:23](=[O:25])[NH:24][C:10]([C:11]=34)=[C:9]([CH:26]=O)[CH:8]=2)=[C:5]([CH3:28])[O:4][N:3]=1.[CH3:29][CH:30]([NH2:32])[CH3:31].C([BH3-])#N.[Na+]>CO>[CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][CH:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:23](=[O:25])[NH:24][C:10]([C:11]=34)=[C:9]([CH2:26][NH:32][CH:30]([CH3:31])[CH3:29])[CH:8]=2)=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: CC(C)N
Reactant: Cc1noc(C)c1-c1cc(C=O)c2[nH]c(=O)n3c2c1OC[C@@H]3c1ccccn1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1noc(C)c1-c1cc(CNC(C)C)c2[nH]c(=O)n3c2c1OCC3c1ccccn1
Temperature: 60 °C

Procedure:
7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-9-carbaldehyde (15 mg, 0.04 mmol) from Example 137, Step 3 was stirred in methanol (1.0 mL) with 2-propanamine (10 μL, 0.12 mmol), followed by addition of sodium cyanoborohydride (7.5 mg, 0.12 mmol). The mixture was heated at 60° C. overnight, then diluted with methanol. Purification by preparative LCMS (pH 10) afforded the title compound. LCMS calc. for C23H26N5O3 (M+H)+: m/z=420.2. found: 420.1.
Reaction SMILES: [C:1](=O)([O-])[O-].CI.[CH2:7]([N:14]1[C:26]2[C:25]([OH:27])=[C:24]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:23]=[C:22]([CH3:33])[C:21]=2[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:7]([N:14]1[C:26]2[C:25]([O:27][CH3:1])=[C:24]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:23]=[C:22]([CH3:33])[C:21]=2[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)Cc1cc(C)c2c3ccccc3n(Cc3ccccc3)c2c1O
Reactant: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)Cc1cc(C)c2c3ccccc3n(Cc3ccccc3)c2c1OC
Reaction time: 1 h
Yield: 101.1 %

Procedure:
120 mg of anhydrous pottasium carbonate and 0.14 ml of methyl iodide were added to 4 ml of a solution of 80 mg of methyl (9-benzyl-1-hydroxy-4-methylcarbazol-2-yl)acetate, as obtained in Example 219, in dimethyl formamide, at room temperature, and the reaction mixture was stirred for 1 hour. After this time, the reaction mixture was diluted with an excess of ethyl acetate, and then washed with a saturated aqueous solution of sodium chloride. The resulting organic layer was dried over anhydrous sodium sulfate and then the solvent was removed by evaporation under reduced pressure. The residue was subjected to column chromatography (eluent: a 15-20% v/v solution of ethyl acetate in hexane) to yield 84 mg of the title compound as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH2:18][CH2:19][OH:20])(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:30][O:31][CH2:32]Cl>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH2:18][CH2:19][O:20][CH2:30][O:31][CH3:32])(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCl
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)CCCO)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOCCCS(=O)(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In dichloromethane (60 ml), 4-tert-butoxycarbonyl-1-[(3-hydroxy-1-propyl)sulfonyl]piperazine (3.00 g) was dissolved. To the resulting solution, diisopropylethylamine (2.72 ml) was added, followed by the addition of methoxymethyl chloride (1.11 ml) under ice cooling. After stirring at room temperature for 15 hours, the reaction mixture was diluted with dichloromethane, washed with water, 5% aqueous citric acid solution and saturated aqueous NaCl solution and then dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (hexane:ethyl acetate=2:1), whereby the title compound (3.32 g, 97%) was obtained.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH:18][CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=3)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: OCc1ccc2ccccc2c1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Product: N=C(OCc1ccc2ccccc2c1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and 2-hydroxymethylnaphthalene, there is obtained 2-naphthylmethyl 5,7-dihydro-6H-dibenz[c,e]-azepine-6-carboximidate as a resin, mass spectrum m/e: M+ 378 (19), 237 (15), 194 (90), 141 (100), 115 (53);
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[C:24]([NH2:26])=[O:25]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]3[C:24]([NH2:26])=[O:25])=[O:17])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[CH2:2][CH2:3]1
Reactant: NC(=O)C1CCCCN1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Product: NC(=O)C1CCCCN1C(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 47 b, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3 c, 100 mg, 429 μmol) and 2-piperidinecarboxamide (CAN 19889-77-1, 60.4 mg, 472 μmol) as starting materials and isolated (135 mg, 92%) as white solid; LC-MS (UV peak area, ESI) 100%, 344.1972 [MH+].
Reaction SMILES: [CH2:1]([SH:4])[CH:2]=[CH2:3].[OH-].[Na+].C(O[CH:11]1[NH:14][C:13](=[O:15])[C@H:12]1[C@H:16]([O:18][Si:19]([CH3:25])([CH3:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH3:17])(=O)C>O.CO>[CH2:1]([S:4][C@H:11]1[NH:14][C:13](=[O:15])[C@@H:12]1[C@H:16]([O:18][Si:19]([CH3:24])([CH3:25])[C:20]([CH3:22])([CH3:21])[CH3:23])[CH3:17])[CH:2]=[CH2:3]
Reactant: CC(=O)OC1NC(=O)[C@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: C=CCS
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CCS[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1.14 ml of allyl mercaptan (70%) and 0.4 g of sodium hydroxide in 25 ml of water under an argon atmosphere was added a solution of 2.87 g of 4-acetoxy-3(S)-[1(R)-{dimethyl-(2-methylprop-2-yl)silyloxy}ethyl]-azetidin-2-one in 10 ml of methanol. After 30 minutes, the mixture was partitioned between dichloromethane and water. The separated organic layer was washed with water, dried over MgSO4, evaporated to dryness, and then chromatographed on silica gel. Elution with ethyl acetate-hexane mixtures afforded 1.8 g of the title compound as white crystals.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(O)C.[O-]CC.[Na+].Br[CH2:20]/[CH:21]=[CH:22]/[CH2:23]Br.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:10]([O:9][C:1]([C:2]1([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:23][CH:22]1[CH:21]=[CH2:20])=[O:8])[CH3:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: BrC/C=C/CBr
Agent: CC[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: C=CC1CC1(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 105.3 %

Procedure:
80.2 g (501 mmol) of diethyl malonate and 850 mL of toluene were added into a four-necked flask (2 L), and thereafter, 191.7 mL (489 mmol) of a 20% sodium ethoxide ethanol solution was added thereto as a base. The obtained mixture was stirred at room temperature for 1.5 hours, and 51.0 g of trans-1,4-dibromo-2-butene (238 mmol; a reagent manufactured by Aldrich) was then added to the reaction solution. The obtained mixture was stirred at room temperature for 3 hours, and 537 mL of a 1 M sodium hydroxide aqueous solution was then added to the reaction solution. The mixture was stirred for 1 hour, and an organic layer was then separated. A water layer was re-extracted with 173 mL of toluene, and organic layers were then gathered. The gathered organic layer was washed with 86 mL of water twice, and it was then dried over anhydrous sodium sulfate, followed by filtration. The obtained filtrate was concentrated at 45° C. under reduced pressure, so as to obtain 53.3 g of 1,1-di-ethoxycarbonyl-2-vinylcyclopropane in the form of a crude product of a light yellow oily substance. This crude product contained 49.7 g of 1,1-di-ethoxycarbonyl-2-vinylcyclopropane (yield: 98.5%). In addition, it contained no diethyl malonates.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:8][C:7]([CH2:9][N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[N:12]=[C:11]2[NH:19][CH:20]2[CH2:26][CH2:25][CH2:24][N:23]([CH2:27][CH2:28][OH:29])[CH2:22][CH2:21]2)=[CH:6][CH:5]=1.Cl[C:31]1[N:36]=[CH:35][CH:34]=[CH:33][N:32]=1.O>CN(C)C=O>[N:32]1[CH:33]=[CH:34][CH:35]=[N:36][C:31]=1[O:29][CH2:28][CH2:27][N:23]1[CH2:24][CH2:25][CH2:26][CH:20]([NH:19][C:11]2[N:10]([CH2:9][C:7]3[O:8][C:4]([CH3:3])=[CH:5][CH:6]=3)[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[N:12]=2)[CH2:21][CH2:22]1
Reactant: Cc1ccc(Cn2c(NC3CCCN(CCO)CC3)nc3cccnc32)o1
Reactant: Clc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Cn2c(NC3CCCN(CCOc4ncccn4)CC3)nc3cccnc32)o1
Reaction time: 0.25 h
Yield: 34.8 %

Procedure:
To a stirred mixture of 1 part of a sodium hydride dispersion 50% and 94 parts of N,N-dimethylformamide is added dropwise a solution of 5.5 parts of hexahydro-4-[[3-[(5-methyl-2-furanyl)methyl]-3H-imidazo[4,5-b]-pyridin-2-yl]amino]-1H-azepine-1-ethanol in N,N-dimethylformamide. Upon complete addition, stirring is continued for 15 minutes at room temperature. 1.9 Parts of 2-chloropyrimidine are added portionwise and upon completion, stirring is continued for 2 hours at room temperature. The reaction mixture is decomposed with water and the product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent was evaporated. The residue is converted into the ethanedioate salt in ethanol. The salt is filtered off and dried, yielding 3.4 parts (34.8%) of N-[hexahydro-1-[2-(2-pyrimidinyloxy)ethyl]-1H-azepin-4-yl]-3-[(5-methyl-2-furanyl)methyl]-3H-imidazo[4,5-b]pyridin-2-amine (compound 169).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][C:12]2[NH:16][N:15]=[N:14][N:13]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:24][CH3:25]>C(#N)C>[CH2:24]([N:13]1[C:12]([CH2:11][S:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[N:16][N:15]=[N:14]1)[CH3:25].[CH2:24]([N:14]1[N:15]=[N:16][C:12]([CH2:11][S:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[N:13]1)[CH3:25]
Reactant: O=[N+]([O-])c1ccc(SCc2nnn[nH]2)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCn1nnc(CSc2ccc([N+](=O)[O-])cc2)n1
Product: CCn1nnnc1CSc1ccc([N+](=O)[O-])cc1
Temperature: 50 °C
Reaction time: 140 h

Procedure:
To 5-[[(4-nitrophenyl)sulfanyl]methyl]-1,2,3,4-tetrazole (4.1 g) was added acetonitrile (203 ml), potassium carbonate (7.1 g) and iodoethane (3.3 ml) were added to the mixture, and the mixture was stirred for 140 hours at 50° C. The solvent was removed under reduced pressure, and to the obtained residue was added ethyl acetate, and the mixture was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the obtained residue was washed with hexane/ethyl acetate, to give 1-ethyl-5-[[(4-nitrophenyl)sulfanyl]methyl]-1,2,3,4-tetrazole and 2-ethyl-5-[[(4-nitrophenyl)sulfanyl]methyl]-1,2,3,4-tetrazole as mixture (4.2 g).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[CH3:10][C:11]1[CH:12]=[C:13]([C:17]2([C:21]([Cl:23])=[O:22])[CH2:20][CH2:19][CH2:18]2)[CH:14]=[CH:15][CH:16]=1>>[ClH:23].[CH3:10][C:11]1[CH:12]=[C:13]([C:17]2([C:21]([O:9][CH:3]3[CH:4]4[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]4)[CH2:2]3)=[O:22])[CH2:20][CH2:19][CH2:18]2)[CH:14]=[CH:15][CH:16]=1
Reactant: OC1CN2CCC1CC2
Reactant: Cc1cccc(C2(C(=O)Cl)CCC2)c1
Product: Cc1cccc(C2(C(=O)OC3CN4CCC3CC4)CCC2)c1
Product: Cl

Procedure:
The title compound was prepared in an analogous manner to that in Example 36 from the compound prepared in Example 16 and 3-quinuclidinol. 1-(3-Methylphenyl)cyclobutanecarbonyl chloride was reacted with 3-quinuclidinol at room temperature for 15 min. The eluent was evaporated and the residue was partitioned beween Et2O and NaOH. The organic layer was extracted with 3 M HCl that was basidified and extracted with Et2O. HCl (g)/Et2O was then added whereby the product crystallized to yield 0.25 g (53%); mp 196.5-198° C.; 1H NMR (CDCl3) δ 1.51 (m, 2H), 1.76-2.20 (m, 5H), 2.32 (s, 3H), 2.51 (m, 2H), 2.70-2.80 (m, 3H), 3.03 (d, 1H), 3.24 (m, 3H), 3.52 (m, 1H), 5.00 (m, 1H), 7.05-7.30 (m, 4H)1 12.31 (bs, 1H). Anal. (C19H25NO2.HCl) C, H, N, Cl.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[C:10]([OH:16])(=[O:15])[CH2:11]C(O)=O.C([O-])(=O)C.[NH4+:21]>COCCO>[NH2:21][CH:5]([C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([CH3:1])[CH:3]=1)[CH2:11][C:10]([OH:16])=[O:15]
Reactant: [NH4+]
Reactant: Cc1cccc(C=O)c1
Reactant: O=C(O)CC(=O)O
Agent: CC(=O)[O-]
Solvent: COCCO
Product: Cc1cccc(C(N)CC(=O)O)c1
Temperature: 80 °C

Procedure:
11.8 ml of 3-methylbenzaldehyde are added to a mixture of 10.4 g of malonic acid and 15.4 g of ammonium acetate in 150 ml of 2-methoxyethanol, and the mixture is heated overnight at 80° C. After cooling to RT, the precipitate formed is filtered off under suction, washed with ether and dried. 6.8 g of the expected product are obtained.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][S:19]([N:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH:16]=2)[NH:11][CH:10]=1)(=O)=O.[I-].[Na+].C(N(CC)C(C)C)(C)C.[CH3:36][O:37][C:38]1[C:39]([N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)=[N:40][CH:41]=[N:42][CH:43]=1>C(#N)C>[CH3:23][N:22]([CH3:24])[S:19]([CH2:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:8][CH2:7][CH2:6][N:47]1[CH2:48][CH2:49][N:44]([C:39]2[C:38]([O:37][CH3:36])=[CH:43][N:42]=[CH:41][N:40]=2)[CH2:45][CH2:46]1)(=[O:21])=[O:20]
Reactant: CN(C)S(=O)(=O)Cc1ccc2[nH]cc(CCCOS(C)(=O)=O)c2c1
Reactant: COc1cncnc1N1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cncnc1N1CCN(CCCc2c[nH]c3ccc(CS(=O)(=O)N(C)C)cc23)CC1
Yield: 60.9 %

Procedure:
To a solution of crude 3-[5-[[(dimethylamino)sulfonyl]methyl]-1H-indol-3-yl]propyl methanesulfonate (1.4 mmol, 1.0 equiv.) in 10 mL of anhydrous acetonitrile was added 0.225 g (1.50 mmol, 1.1 equiv.) of sodium iodide, 0.26 mL (1.50 mmol, 1.1 equiv.) of N,N-diisopropylethylamine and 0.291 g (1.50 mmol, 1.1 equiv.) of 1-(5-methoxy-4-pyrimidinyl)piperazine. The mixture was heated to reflux for sixteen hours. The reaction mixture was concentrated in vacuo and the residue was taken up in 50 mL of ethyl acetate. The organic layer was washed with a 10 mL portion of 10% potassium carbonate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield an oil. The oil was purified by chromatography on silica gel using 5% methanol in methylene chloride containing 0.5% concentrated aqueous ammonium hydroxide to obtain 0.403 g (62%) of 1-[3-[5-[ [(dimethylamino)sulfonyl]-methyl]-1H-indol-3-yl]propyl]-4-(5-methoxy-4-pyrimidinyl)piperazine. The hydrochloride salt was prepared by addition of 3N ethanolic HCl. Two recrystallizations from methanol gave 0.323 g (64%) of 1-[3-[5-[[(dimethyl-amino)sulfonyl]methyl]-1H-indol-3-yl]propyl]-4-(5-methoxy-4-pyrimidinyl)piperazine hydrochloride hydrate, m.p. 210° C. (d). Elemental analysis calculated for C23H32N6O3S/3 HCl/0.5 H20 : C, 46.74; H, 6.14; N, 14.22; found: C, 46.82; H, 6.42; N, 14.09.
Reaction SMILES: O[C@@H:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.C1(P([N:30]=[N+:31]=[N-:32])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1.CCOC(C)=O>[N:30]([C@H:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc2c(c1)OCC[C@@H]2O
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(c1)OCC[C@H]2N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a 3 L three-neck round-bottomed flask equipped with argon inlet/outlet, thermometer, and magnetic stirring was added (S)-methyl 4-hydroxychroman-7-carboxylate (71 g, 340 mmol) in 800 mL of toluene. The reaction vessel was cooled with a ice/salt bath, and treated with a solution of diphenylphosphoryl azide (88 mL, 407 mmol, Aldrich) in 200 mL toluene (internal temp.=−4° C.). After 10 min, a solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (61 mL, 407 mmol, Aldrich) in toluene (350 mL) was added over 30 min (the internal temperature did not exceed 1 ° C.). The reaction mixture was warmed to room temp and stirred for 40 h. The reaction mixture was diluted with 800 mL EtOAc and washed with 1M H3PO4, water, 5% NaHCO3, and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (10:1 hexane-EtOAc) to provide the title compound. MS (+ion ESI) m/z=234 (MH+).
Reaction SMILES: B.C1COCC1.[Br:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:18][CH2:17][C@H:16]([NH:19][C:20](=O)[CH:21]([F:23])[F:22])[CH2:15]2)=[N:12][CH:13]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].FC(F)(F)C(O)=O>O1CCCC1.ClCCl>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:18][CH2:17][C@H:16]([NH:19][CH2:20][CH:21]([F:23])[F:22])[CH2:15]2)=[N:12][CH:13]=1
Reactant: O=C(N[C@H]1CCN(c2ccc(Br)cn2)C1)C(F)F
Agent: B
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)CN[C@H]1CCN(c2ccc(Br)cn2)C1
Reaction time: 8 h
Yield: 83.4 %

Procedure:
Add via syringe 1M BH3-THF (78 mL, 78 mmol) to a solution of N—[(S)-1-(5-bromo-pyridin-2-yl)-pyrrolidin-3-yl]-2,2-difluoro-acetamide (8.3 g, 25 mmol) in tetrahydrofuran (65 mL) and heat the mixture at reflux overnight. Cool the reaction to 0° C. and slowly quench with 5N NaOH until no gas evolution is observed. Concentrate the material in vacuo to remove THF. Dilute the residue with water (150 mL) and extract with CH2Cl2 (3×150 mL). Dry the combined organics over Na2SO4, filter, and concentrate to dryness. Add sodium triacetoxyborohydride (35.4 g, 167 mmol) to the residue in dichloromethane (75 mL). Add dropwise trifluoroacetic acid (150 mL) with vigorous stirring. After 10 min concentrate the mixture in vacuo and dilute with CH2Cl2 (150 mL). Cool the mixture in an ice bath and slowly basify to pH 9 with 5N NaOH. Stir the basic mixture overnight. Dilute the mixture with water (200 mL) and extract with CH2Cl2 (3×150 mL). Dry the combined organics over Na2SO4, filter, and concentrate to dryness. Purify by chromatography to afford 6.38 g (85%) of the title compound. MS/ES m/z (79Br) 306.0 [M+H]+.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([O:7][C:8]1[CH:13]=[CH:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:10](=[O:21])[C:9]=1[C:22](Cl)=[O:23])[CH3:6].[NH2:25][C:26]1[C:59]([F:60])=[CH:58][C:29]([O:30][C:31]2[CH:36]=[CH:35][N:34]=[C:33]([N:37]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:32]=2[C:52]2[CH:53]=[N:54][N:55]([CH3:57])[CH:56]=2)=[C:28]([F:61])[CH:27]=1.CCN(CC)CC>C1COCC1>[CH3:50][C:48]([CH3:51])([O:47][C:45]([N:37]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:33]1[C:32]([C:52]2[CH:53]=[N:54][N:55]([CH3:57])[CH:56]=2)=[C:31]([O:30][C:29]2[C:28]([F:61])=[CH:27][C:26]([NH:25][C:22]([C:9]3[C:10](=[O:21])[N:11]([C:14]4[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=4)[CH:12]=[CH:13][C:8]=3[O:7][CH2:5][CH3:6])=[O:23])=[C:59]([F:60])[CH:58]=2)[CH:36]=[CH:35][N:34]=1)=[O:46])[CH3:49]
Reactant: Cn1cc(-c2c(Oc3cc(F)c(N)cc3F)ccnc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cn1
Reactant: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2-c2cnn(C)c2)cc1F
Yield: 65 %

Procedure:
Using the method of Example 4, thionyl chloride (5 mL) and Example B2 (0.19 g, 0.7 mmol) were combined to prepare 4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonyl chloride as a solid. This solid was dissolved in THF (3 mL) and added to a solution of Example A6 (0.18 g, 0.35 mmol) and Et3N (0.2 ml, 1.4 mmol) in THF (3 mL). The resultant mixture was stirred at RT for 2 h. The mixture was partitioned between EtOAc (20 mL) and sat aq NaHCO3 (30 mL). The aqueous layer was further extracted with EtOAc (15 ml) and the combined organics were washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc-hexanes) to afford N-(4-(2-[bis[(1,1-dimethylethoxy)carbonyl]amino]-3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide as colorless foam (175 mg, 65% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.22 (s, 1H), 8.33 (dd, J=12.7 Hz, 7.2 Hz, 1H), 8.20 (d, J=5.7 Hz, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.87 (s, 1H), 7.48 (m, 4H), 7.36 (t, J=8.8 Hz, 2H), 6.83 (d, J=5.6 Hz, 1H), 6.55 (d, J=7.9 Hz, 1H), 4.28 (q, J=7.0 Hz, 2H), 3.86 (s, 3H), 1.33 (t, J=7.1 Hz, 3H), 1.26 (s, 18H); MS (ESI) m/z: 777.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH3:20][N:21]([CH3:32])[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]1>C(O)(C)C>[ClH:1].[CH3:32][N:21]([CH3:20])[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)=[O:3])[CH2:27]1
Reactant: CN(C)CCCCC1CCCNC1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Solvent: CC(C)O
Product: CN(C)CCCCC1CCCN(C(=O)N2c3ccccc3C(=O)Nc3cccnc32)C1
Product: Cl
Yield: 69 %

Procedure:
Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 3-[4-(dimethylamino)butyl]piperidine in a yield of 69% of theory. Colourless crystals, m.p. 234°-235° C. (isopropanol).