Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[CH:26]=[CH:25][C:3]=1[O:4][CH:5]([CH3:24])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([O:22][CH3:23])[CH2:16][C:17]([O:19]CC)=[O:18])=[CH:11][CH:10]=1)=[O:7].O.Cl>C(#N)C.[OH-].[Na+]>[Br:1][C:2]1[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[CH:26]=[CH:25][C:3]=1[O:4][CH:5]([CH3:24])[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]([O:22][CH3:23])[CH2:16][C:17]([OH:19])=[O:18])=[CH:13][CH:14]=1)=[O:7]
Reactant: CCOC(=O)CC(OC)c1ccc(NC(=O)C(C)Oc2ccc(C(C)C)cc2Br)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: COC(CC(=O)O)c1ccc(NC(=O)C(C)Oc2ccc(C(C)C)cc2Br)cc1
Reaction time: 0.17 h
Yield: 49 %

Procedure:
A solution of 331 mg of ethyl 3-{4-[2-(2-bromo-4-isopropylphenoxy)propionylamino]-phenyl}-3-methoxypropionate in 7 ml of acetonitrile and 7 ml of 1 N NaOH (aq) was stirred at room temperature for 20 h. The reaction mixture was admixed with water and adjusted to pH=1 with 1 N HCl (aq) and then extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated under high vacuum. The crude mixture was purified by means of preparative HPLC (Merck Hibar Purospher Star RP-18e 10 μm 25×250 mm; A: H2O+0.05% TFA; B: ACN+0.05% TFA; flow rate: 50 ml/min; in 10 minutes 10% B→80% B; in 5 minutes 80% B→90% B). This gave 152 mg of 3-{4-[2-(2-bromo-4-isopropylphenoxy)propionylamino]phenyl}-3-methoxypropionic acid in 49% yield over the two stages.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[C:14]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)(=[O:16])[CH3:15].C([O-])([O-])=O.[K+].[K+]>C1(C)C=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>[N+:11]([C:3]1[CH:4]=[C:5]([C:8](=[O:10])[CH3:9])[CH:6]=[CH:7][C:2]=1[C:20]1[CH:21]=[CH:22][C:17]([C:14](=[O:16])[CH3:15])=[CH:18][CH:19]=1)([O-:13])=[O:12]
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: CC(=O)c1ccc(Br)c([N+](=O)[O-])c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(-c2ccc(C(C)=O)cc2[N+](=O)[O-])cc1
Temperature: 110 °C

Procedure:
1-(4-bromo-3-nitrophenyl)ethanone (2 g, 8.20 mmol) and (4-acetylphenyl)boronic acid (2.016 g, 12.29 mmol), aq.K2CO3 (2M, 12.08 mL, 24.17 mmol) and Pd(PPh3)4 (0.33 g, 0.286 mmol) were dissolved in toluene (40 mL) and heated at 110° C. for 2 days. The crude product was extracted with DCM and purified on silica gel (0-100% EtOAc/Hexane). Fractions were concentrated to give the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][CH:10]2[CH2:12][CH2:11]2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:13][S:14][C:15]1[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=1.Cl.O>C(#N)C.O1CCOCC1>[Br:1][C:2]1[C:3]([NH:9][CH:10]2[CH2:12][CH2:11]2)=[N:4][C:5]([NH:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([S:14][CH3:13])[CH:16]=2)=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(NC2CC2)n1
Reactant: CSc1cccc(N)c1
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: C1COCCO1
Product: CSc1cccc(Nc2ncc(Br)c(NC3CC3)n2)c1

Procedure:
In analogy to compound 2.1, 0.58 g (2.33 mmol) of (5-bromo-2-chloropyrimidin-4-yl)-cyclopropylamine is reacted with 0.296 g (2.12 mmol) of 3-methylsulphanyl-phenylamine in 7.0 ml of acetonitrile in the presence of 0.53 mol of a 4 molar solution of hydrogen chloride in dioxane, and 0.67 ml of water. 0.6 g (73% of theory) of the product is obtained.
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]([C:20]#[N:21])=[C:7]([N:9]2[CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[CH2:11][CH2:10]2)[N:8]=1.[NH2:22][CH2:23][CH:24]1[CH2:26][CH2:25]1>O1CCOCC1>[CH:24]1([CH2:23][NH:22][C:3]2[N:4]=[N:5][C:6]([C:20]#[N:21])=[C:7]([N:9]3[CH2:15][CH2:14][C:13]4[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=4[CH2:11][CH2:10]3)[N:8]=2)[CH2:26][CH2:25]1
Reactant: NCC1CC1
Reactant: CSc1nnc(C#N)c(N2CCc3ccccc3CC2)n1
Solvent: C1COCCO1
Product: N#Cc1nnc(NCC2CC2)nc1N1CCc2ccccc2CC1
Temperature: 120 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
A mixture of 150 mg (0.50 mmol) of 3-methylsulfanyl-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile as prepared in example 1b and 74 mg (1.0 mmol) of aminomethyl-cyclopropane in 5 ml of dioxane was stirred at 120° C. overnight. The solution was evaporated under reduced pressure and the residue was chromatographed on silica gel with a 98:2 v/v mixture of dichloromethane and methanol as the eluent. There were obtained 57 mg (35% of theory) of 3-(cyclopropylmethyl-amino)-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile as a white solid; MS: 321 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.Cl[CH2:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:19][CH2:18]1)=[O:16]>C(OCC)C>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([O:23][CH:20]2[CH2:19][CH2:18][N:17]([C:15](=[O:16])[CH2:14][NH:1][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]4)[CH2:22][CH2:21]2)=[CH:29][CH:28]=1
Reactant: O=C(CCl)N1CCC(Oc2ccc(Cl)cc2)CC1
Reactant: Nc1ccc2c(c1)CCC(=O)N2
Solvent: CCOCC
Product: O=C1CCc2cc(NCC(=O)N3CCC(Oc4ccc(Cl)cc4)CC3)ccc2N1

Procedure:
The title compound is prepared from 6-amino-3,4-dihydro-quinolin-2-one and 2-chloro-1-[4-(4-chloro-phenoxy)-piperidin-1-yl]-ethanone (Example 233a) according to the method described in Example 206. Melting Point: 248-251° C. (diethylether)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH2:11]C)=[O:9])=[CH:4][CH:3]=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>N1C=CC=CC=1>[CH3:13][S:14]([NH:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1)(=[O:16])=[O:15]
Reactant: CCOC(=O)c1ccc(N)nc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NS(C)(=O)=O)nc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 131.1 %

Procedure:
Ethyl 6-aminopyridine-3-carboxylate (738 mg, 4.44 mmol) was dissolved in pyridine (20 mL), cooled to 0° C. and methanesulfonyl chloride (1.72 mL, 22.2 mmol) was added. The reaction mixture was stirred at room temperature for 16 h, concentrated in vacuo and partitioned between DCM (50 mL) and 1M aq citric acid (50 mL). The organic fraction was dried (MgSO4) and concentrated in vacuo to give the crude title compound (1.34 g) as a brown solid. LCMS (ES+): 245.1 [MH]+.
Reaction SMILES: CO[C:3]1[CH:8]=C[C:6]([C:9]2[C@@H:13]3[CH2:14][N:15]([C:17]4[C:26]([O:27][CH3:28])=[C:25]5[C:20]([C:21](=[O:35])[C:22]([C:32]([OH:34])=[O:33])=[CH:23][N:24]5[CH:29]5[CH2:31][CH2:30]5)=[CH:19][C:18]=4F)[CH2:16][C@@H:12]3[O:11][N:10]=2)=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O.FC(F)(F)C(O)=O.[N:51]1C=CC=CC=1C1[C@@H]2CNC[C@@H]2ON=1>>[N:51]1[CH:8]=[CH:3][CH:4]=[CH:5][C:6]=1[C:9]1[C@@H:13]2[CH2:14][N:15]([C:17]3[C:26]([O:27][CH3:28])=[C:25]4[C:20]([C:21](=[O:35])[C:22]([C:32]([OH:34])=[O:33])=[CH:23][N:24]4[CH:29]4[CH2:31][CH2:30]4)=[CH:19][CH:18]=3)[CH2:16][C@@H:12]2[O:11][N:10]=1
Reactant: c1ccc(C2=NO[C@H]3CNC[C@@H]23)nc1
Reactant: COc1ccc(C2=NO[C@H]3CN(c4c(F)cc5c(=O)c(C(=O)O)cn(C6CC6)c5c4OC)C[C@@H]23)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1c(N2C[C@@H]3ON=C(c4ccccn4)[C@@H]3C2)ccc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
The title compound was prepared according to the procedure for the synthesis of 120, but using activated core 71 and TFA salt 4e. Acid 150 was isolated in 23% yield.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].N12CCCN=C1CCCCC2.[NH2:17][C:18]1[N:39]=[C:38](Cl)[CH:37]=[CH:36][C:19]=1[C:20]([NH:22][CH2:23][C:24]1[S:25][C:26]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:27][CH:28]=1)=[O:21].C1C=CC(CC(NCN[C@H](C(O)=O)CC2C=CC([N+]([O-])=O)=CC=2)=O)=CC=1>CS(C)=O>[NH2:17][C:18]1[N:39]=[C:38]([NH:1][CH2:2][C:3]([OH:5])=[O:4])[CH:37]=[CH:36][C:19]=1[C:20](=[O:21])[NH:22][CH2:23][C:24]1[S:25][C:26]([O:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:27][CH:28]=1
Reactant: NCC(=O)O
Reactant: Nc1nc(Cl)ccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Agent: O=C(Cc1ccccc1)NCN[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CS(C)=O
Product: Nc1nc(NCC(=O)O)ccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Temperature: 190 °C
Reaction time: 4 h
Yield: 20 %

Procedure:
Glycine (610 mg, 8.13 mmol) and 1,8-diazabicyclo[5,4,0]undec-7-ene (405 μl, 2.71 mmol) were added to 2-amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide described in Example A-101 (195 mg, 0.542 mmol) under nitrogen atmosphere, and the solution was stirred at 190° C. for 4 hours. Dimethylsulfoxide (5 mL) was added to the reaction mixture, which was then filtered with a polytetrafluoroethylene membrane filter (Whatman Inc), the filtrate was purified by reverse phase high performance liquid chromatography (acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid) was used), title compound (55.36 mg, 0.108 mmol, 20%) was obtained.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][CH:6]=1)=[O:4].C([O-])=[O:14].[Na+]>CO>[OH:14][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C[O-]
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc(C(=O)CO)cc1
Yield: 50 %

Procedure:
To a solution of 2-Bromo-1-(4-cyanophenyl)ethanone (15 g, 0.067 mol) in methanol (200 ml) was added sodium formate (13.6 g, 0.201 mol) at RT. The reaction mixture was refluxed for 15 h and filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved with ethyl acetate, washed with water and brine solution, dried over Na2SO4 and evaporated. The crude material was purified by column chromatography using petroleum ether and ethyl acetate (60:40) as an eluent to afford (5.4 g, 50%) of title compound as an off white solid. 1H NMR: (DMSO-d6, 400 MHz) δ 8.06-8.04 (dd, J=1.9, 6.7 Hz, 2H), 8.00-7.98 (dd, J=1.9, 6.7 Hz, 2H), 5.27-5.24 (t, J=5.9 Hz, 1H), 4.82-4.80 (d, J=5.9 Hz, 2H).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22]C)[CH:18]=3)[N:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C(O)(=O)C.Br>CCCCCC>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([OH:22])[CH:18]=3)[N:13]=2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(-c2ccc3cc(OC)ccc3n2)cc1
Agent: Br
Solvent: CCCCCC
Solvent: CC(=O)O
Product: CCCCCc1ccc(-c2ccc3cc(O)ccc3n2)cc1
Temperature: 0 °C
Yield: 86.8 %

Procedure:
0.70 g (2.29 mM) of 2-(4-pentylphenyl)-6-methoxyquinoline, 4.6 ml of acetic acid and 4.3 ml of 47%-hydrobromic acid were placed in a 30 ml-round bottomed flask, followed by refluxing for 33 hours under stirring. After the reaction, the reaction mixture was poured into ice water to precipitate a crystal. The crystal was recovered by filtration and dispersed in water. To the mixture, an appropriate amount of ethyl acetate was added, followed by stirring at room temperature. Under stirring, 1.5 g of sodium hydrogencarbonate was gradually added to the resultant mixture. The organic (ethyl acetate) layer was washed with water and dried with anhydrous sodium sulfate, followed by evaporation under reduced pressure to obtain a residue. To the residue, an appropriate amount of hexane was added, followed by filtration to obtain 0.58 g of 2-(4-pentylphenyl)-6-hydroxyquinoline (as a precipitated crystal) (Yield: 86.8%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:18])[CH3:17])=[C:11]2[C:6]=1[C:7](=[O:20])[CH:8]=[CH:9][C:10]2=[O:19])(=[O:3])[CH3:2].[CH:21]([N:23]1[CH:32](C(O)=O)[CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24]1)=O>C(OC(=O)C)(=O)C>[C:16]([O:15][C:12]1[C:11]2[C:10](=[O:19])[C:9]3[C:8]([C:7](=[O:20])[C:6]=2[C:5]([O:4][C:1](=[O:3])[CH3:2])=[CH:14][CH:13]=1)=[C:32]1[N:23]([CH2:24][C:25]2[C:30]([CH2:31]1)=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]=3)(=[O:18])[CH3:17]
Reactant: O=CN1Cc2ccccc2CC1C(=O)O
Reactant: CC(=O)Oc1ccc(OC(C)=O)c2c1C(=O)C=CC2=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc(OC(C)=O)c2c1C(=O)c1cn3c(c1C2=O)Cc1ccccc1C3
Temperature: 20 °C
Yield: 41.4 %

Procedure:
5,8-bis(acetyloxy)-1,4-napthalenedione (4.28 g) and 2-formyl-1,2,3,4-tetrahydro-3-isoquinoline carboxylic acid (1.60 g) in acetic anhydride (65 ml) were heated at 100° C. (20 minutes). The reaction mixture was cooled at about 20° C. (1 h), and the solid was collected by filtration, washed with ether (3×30 ml) and dried in vacuo. The crude product was dissolved in dichloromethane and the solution was loaded onto a column of silica gel (175 g) packed in dichloromethane. The column was eluted with 5% (v/v) ethyl acetate in dichloromethane and fractions containing the major component were evaporated to dryness, and further dried in vacuo at 55° C. to give the title compound as a yellow-green solid (1.34 g), m.p. 228°-232° C. (dec), λmax (in CH2Cl2) 242 nm (ε40,700), 377 nm (ε6,400).
Reaction SMILES: [CH:1]1([C:4]2[NH:12][C:11]3[C:10](=S)[NH:9][C:8](=[S:14])[N:7]([CH2:15][CH2:16][CH3:17])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[CH:18]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19]1.C(=O)(O)[O-]>CO>[CH:18]1([NH:23][C:10]2[C:11]3[NH:12][C:4]([CH:1]4[CH2:3][CH2:2]4)=[N:5][C:6]=3[N:7]([CH2:15][CH2:16][CH3:17])[C:8](=[S:14])[N:9]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CCCn1c(=S)[nH]c(=S)c2[nH]c(C3CC3)nc21
Reactant: NC1CCCC1
Agent: O=C([O-])O
Solvent: CO
Product: CCCn1c(=S)nc(NC2CCCC2)c2[nH]c(C3CC3)nc21

Procedure:
5.33 g (20 mmoles) of 8-cyclopropyl-3-n-propyl-2,6-dithioxantine and 42 ml of cyclopentylamine were heated in a 450 ml pressure reactor to 150° C. (50 psi) with the exclusion of air. After 20 hours the solution was transferred with methanol to a round bottom flask and evaporated in vacuo to dryness. The residue is treated with 60 ml of water and 5N HCl to obtain a pH of 2. The suspension is neutralized with bicarbonate to pH 7, the solid collected, washed, dried, suspended in refluxing acetone and collected again: 5.98 g of thioisoguanine with mp 274-6° C. (decomp).
Reaction SMILES: O1CCCC1.[F:6][C:7]([F:17])=[C:8]([CH3:16])[CH2:9][CH2:10][CH2:11][C:12](OC)=[O:13].[BH4-].[Na+].CO>O>[F:6][C:7]([F:17])=[C:8]([CH3:16])[CH2:9][CH2:10][CH2:11][CH2:12][OH:13]
Reactant: COC(=O)CCCC(C)=C(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(CCCCO)=C(F)F
Temperature: 25 °C
Yield: 81 %

Procedure:
To 110 ml of tetrahydrofuran, 53 g (0.30 mol) of methyl 6,6-difluoro-5-methyl-5-hexenoate was dissolved, followed by adding 23 g (0.61 mmol) of sodium borohydride, heating the mixture under refluxing and slowly drop-wisely adding 50 ml of methanol. After the end of the drop-wise addition, the reaction liquid was stirred under refluxing for 1 hour, followed by cooling to room temperature, adding water and extracting with diethyl ether. The organic layer was washed with water, dilute hydrochloric acid and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate, and concentrating under reduced pressure to obtain 36.5 g (yield: 82%) of 6,6-difluoro-5-methyl-5-hexenol.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4].[NH2:23][C:24]1[CH:29]=[N:28][CH:27]=[CH:26][N:25]=1>C1(C)C(C)=CC=CC=1>[OH:11][C:10]1[C:9]2[CH:12]=[CH:13][C:14]3[C:19]([C:8]=2[S:7](=[O:20])(=[O:21])[N:6]([CH3:22])[C:5]=1[C:3]([NH:23][C:24]1[CH:29]=[N:28][CH:27]=[CH:26][N:25]=1)=[O:4])=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: Nc1cnccn1
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2cnccn2)=C(O)c2ccc3ccccc3c2S1(=O)=O
Reaction time: 8 h
Yield: 52.3 %

Procedure:
A mixture consisting of 4.8 gm (0.015 mol) of 4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methylester-1,1-dioxide, 2.1 gm (0.022 mol) of aminopyrazine and 200 ml of dry xylene was refluxed for 8 hours in a Soxhlet apparatus equipped with 4-A-molecular sieve. Then, another 0.5 gm of aminopyrazine was added, the mixture was refluxed for 8 hours more, and then allowed to cool and stand overnight. The precipitate formed thereby was suctionfiltered off, and thefiltrate was evaporated in vacuo. The combined precipitate and evaporation residue was recyrstallized from ethyl acetate, yielding 3.0 gm (52% of theory) of 4-hydroxy-2-methyl-N-pyrazinyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1dioxide, m.p. 245° C (decomp.).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:21]=[O:22])[C:15]=2[CH:14]=[CH:13]1>>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:12]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([CH:21]=[O:22])[C:15]=3[CH:14]=[CH:13]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: O=Cc1cccc2[nH]ccc12
Product: O=Cc1cccc2c1ccn2Cc1ccc([N+](=O)[O-])cc1
Yield: 55.4 %

Procedure:
The same procedures used in Example 7 were repeated except for using 4.46 g of 4-nitrobenzyl bromide and 2.00 g of indole-4-carbaldehyde as a starting material to give 2.14 g of 1-(4-nitrobenzyl) indole-4-carbaldehyde as an orange-colored oily substance. The yield thereof was found to be 59%.
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH2:24][CH2:25][NH:26][CH2:27][CH3:28])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:29])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.[O:31]1[CH2:34][C:33](=O)[CH2:32]1>>[O:30]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH2:24][CH2:25][N:26]([CH2:27][CH3:28])[CH:33]3[CH2:34][O:31][CH2:32]3)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:29])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: CCNCCNc1cc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccc(C)cc12
Reactant: O=C1COC1
Product: CCN(CCNc1cc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccc(C)cc12)C1COC1

Procedure:
The title compound was prepared in analogy to Example 44-1 in Scheme 20 by using N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N′-ethylethane-1,2-diamine (prepared in analogy to Example 3-37) and oxetan-3-one. MS obsd. (ESI+) [(M+H)+] 481, 1H NMR (400 MHz, CD3OD) δ ppm 8.02 (d, J=7.6 Hz, 1 H), 7.87 (d, J=7.2 Hz, 1 H), 7.66 (t, 2 H), 7.50 (t, 2 H), 7.36 (d, J=7.6 Hz, 1 H), 6.04 (s, 1 H), 5.20 (s, 2 H), 4.68-4.50 (m, 6 H), 4.07-4.00 (m, 1 H), 3.65 (s, 2 H), 3.45 (t, J=12.4 Hz, 2 H), 2.84 (t, J=12.8 Hz, 2 H), 2.73-2.67 (m, 2 H), 2.45 (s, 3 H), 1.07 (t, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH:35]([F:37])[F:36])=[C:6]([C:8]2[N:12](COCC[Si](C)(C)C)[N:11]=[CH:10][C:9]=2[NH:21][C:22]([C:24]2[CH:25]=[N:26][N:27]3[CH:32]=[CH:31][C:30]([NH2:33])=[N:29][C:28]=23)=[O:23])[CH:7]=1.Cl>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH:35]([F:37])[F:36])=[C:6]([C:8]2[C:9]([NH:21][C:22]([C:24]3[CH:25]=[N:26][N:27]4[CH:32]=[CH:31][C:30]([NH2:33])=[N:29][C:28]=34)=[O:23])=[CH:10][NH:11][N:12]=2)[CH:7]=1
Reactant: C[Si](C)(C)CCOCn1ncc(NC(=O)c2cnn3ccc(N)nc23)c1-c1cc(Cl)ccc1OC(F)F
Agent: Cl
Solvent: CO
Product: Nc1ccn2ncc(C(=O)Nc3c[nH]nc3-c3cc(Cl)ccc3OC(F)F)c2n1
Temperature: 80 °C
Yield: 68.7 %

Procedure:
A suspension of 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [5-(5-chloro-2-difluoromethoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-4-yl]-amide (720 mg, 1.31 mmol) in methanol (20 mL) was treated with concentrated aqueous HCl (3 mL) and the mixture heated at 80° C. for 1 hour. The solvent was evaporated and the residue azeotroped with methanol (×3). The resultant solid was triturated with ethyl acetate, collected by filtration, washed with ethyl acetate and diethyl ether and left to air dry. The residual solid was purified by flash chromatography on silica eluting with 0-12% 2M NH3/MeOH in DCM. Collecting appropriate fractions, followed by evaporation gave 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [3-(5-chloro-2-difluoromethoxy-phenyl)-1H-pyrazol-4-yl]-amide as a brown solid (378 mg, 69%). LCMS (Method 4) [M+H]+=419.9, RT=2.93
Reaction SMILES: [F:1][C:2]([F:14])([F:13])I1C2C=CC=CC=2C(=O)O1.[CH3:15][O:16][C:17](=[O:24])[C@:18]([CH2:22][OH:23])([CH3:21])[CH:19]=[CH2:20]>[2H]C(Cl)(Cl)Cl.ClCCl.[N-](S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.[Zn+2].[N-](S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O>[CH3:15][O:16][C:17](=[O:24])[C@@:18]([CH3:21])([CH2:22][O:23][C:2]([F:14])([F:13])[F:1])[CH:19]=[CH2:20]
Reactant: O=C1OI(C(F)(F)F)c2ccccc21
Reactant: C=C[C@](C)(CO)C(=O)OC
Agent: O=S(=O)([N-]S(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [2H]C(Cl)(Cl)Cl
Agent: [Zn+2]
Solvent: ClCCl
Product: C=C[C@](C)(COC(F)(F)F)C(=O)OC
Temperature: 25 °C
Reaction time: 120 h
Yield: 23.1 %

Procedure:
Zinc bis(trifluoromethylsulfonyl)imide (750 mg, 1.2 mmol) and (1-(trifluoromethyl)-1,2-benziodoxol-3(1H)-one (758 mg, 2.4 mmol) were added to a stirred solution of (R)-2-hydroxymethyl-2-methyl-but-3-enoic acid methyl ester (288 mg, 2.0 mmol) in dry deuterochloroform (4 mL) under nitrogen. The reaction mixture was stirred at room temperature under nitrogen in a sealed flask for 5 days. The resulting suspension was diluted with dichloromethane and the supernatant was separated and evaporated. Dichloromethane (5 mL) was added to the residue and the supernatant solution was purified by silica gel chromatography using a gradient of pentane/diethyl ether 10:1 to 5:1 to afford crude (R)-2-methyl-2-trifluoromethoxymethyl-but-3-enoic acid methyl ester (98 mg) as a clear oil which was used in the next step.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.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>[C:14]1([C:2]2[C:11]([CH:12]=[O:13])=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1ccccc1
Reactant: O=Cc1cc2ccccc2nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=Cc1cc2ccccc2nc1-c1ccccc1
Yield: 90 %

Procedure:
A solution of 960 mg (5 mmol) of 2-chloroquinolin-3-carbaldehyde, 570 mg (0.5 mmol) of Pd(PPh3)4, and 1.2 g of benzeneboronic acid in a mixture of 7.5 ml of 2M aqueous sodium carbonate solution and 20 ml of dioxane was heated for 40 h to 95° C. It was extracted with ethyl acetate, and the organic layer was dried and evaporated. The residue was chromatographed on silica gel with a hexane/ethyl acetate gradient 98:2 to 90:10 to give 1.05 g (90%) of the title aldehyde.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([Cl:16])[N:3]=1.[CH2:17]([O:19][CH2:20][CH2:21][O:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[CH3:18].C(N(CC)CC)C.Cl>C(O)CCC.C(O)C>[ClH:16].[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:26]2[CH2:27][CH2:28][CH:23]([O:22][CH2:21][CH2:20][O:19][CH2:17][CH3:18])[CH2:24][CH2:25]2)[N:3]=1
Reactant: CCOCCOC1CCNCC1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CCCCO
Product: CCOCCOC1CCN(c2nc(N)c3cc(OC)c(OC)cc3n2)CC1
Yield: 45.9 %

Procedure:
4-Amino-2-chloro-6,7-dimethoxyquinazoline (4.3 g.), 4-(2-ethoxyethoxy)piperidine (3.2 g.) and triethylamine (10 ml.) in n-butanol (400 ml.) were heated at reflux overnight under an atmosphere of nitrogen. The mixture was then cooled, evaporated in vacuo, and the residue basified (aqueous Na2CO3) and extracted 3 times with chloroform. The combined chloroform extracts were evaporated and the residue chromatographed on neutral alumina (150 g., Grade I, deactivated with 5 ml water). Elution with chloroform gave the crude product (3.6 g.) which was converted to the hydrochloride salt by treatment with hydrogen chloride in ethanol. The hydrochloride was then recrystallized from ethanol/isopropanol to give 4-amino-6,7-dimethoxy-2-[4-(2-ethoxyethoxy)piperidino]quinazoline hydrochloride (3.4 g.), m.p. 219°-220° C.