Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].CO.[C:15]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)(=[O:17])[CH3:16].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>COC(C)(C)C>[F:9][C:2]([F:1])([F:8])[C:3](=[O:5])[CH2:16][C:15]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)=[O:17]
Reactant: CC(=O)c1ccncc1
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: COC(C)(C)C
Product: O=C(CC(=O)C(F)(F)F)c1ccncc1
Reaction time: 22 h
Yield: 62.2 %

Procedure:
Ethyl trifluoroacetate (6.32 g) was dissolved in tert-butyl methyl ether (10 mL) and a 28% sodium methoxide-methanol solution (9.40 g) and a solution of 4-acetylpyridine (4.90 g) in tert-butyl methyl ether (20 mL) were added successively at room temperature. The mixture was stirred for 22 hr. A 10% a aqueous citric acid solution was added until the reaction solution became about pH 4, and the precipitate was collected by filtration, washed with water and dried to give 4-trifluoroacetoacetylpyridine (5.46 g) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[CH:8]1([C:11]2[N:16]=[C:15]([C:17]([NH:19][C:20]3[CH:28]=[N:27][CH:26]=[CH:25][C:21]=3[C:22](O)=[O:23])=[O:18])[C:14]([NH:29][C:30]3[CH:31]=[N:32][CH:33]=[N:34][CH:35]=3)=[CH:13][CH:12]=2)[CH2:10][CH2:9]1>>[CH3:1][O:2][CH:3]1[CH2:7][CH2:6][N:5]([C:22]([C:21]2[CH:25]=[CH:26][N:27]=[CH:28][C:20]=2[NH:19][C:17]([C:15]2[C:14]([NH:29][C:30]3[CH:31]=[N:32][CH:33]=[N:34][CH:35]=3)=[CH:13][CH:12]=[C:11]([CH:8]3[CH2:10][CH2:9]3)[N:16]=2)=[O:18])=[O:23])[CH2:4]1
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Reactant: COC1CCNC1
Product: COC1CCN(C(=O)c2ccncc2NC(=O)c2nc(C3CC3)ccc2Nc2cncnc2)C1
Yield: 18 %

Procedure:
According to the general method described in step 3 of example 53, reaction of 3-methoxy-pyrrolidine with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound (18%) as off-white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.F[C:10](F)(F)C(O)=O>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]=[CH2:10])=[N:3][CH:4]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Nc1ccc(Br)cn1
Solvent: Cc1ccccc1
Product: C=Nc1ccc(Br)cn1
Temperature: 25 °C
Yield: 34 %

Procedure:
To a suspension of 2-amino-5-bromopyridine (2.34 g, 13.5 mmol) and p-formaldehyde (3.0 g) in toluene (50 mL) was added trifluoroacetic acid (0.1 mL) and the reaction mixture was heated at reflux for 16 h, allowed to cool to ambient temperature, filtered through a pad of diatomaceous earth and concentrated in vacuo. The residue was triturated in methanol to afford 5-bromo-N-methylenepyridin-2-amine as a colorless solid in 34% yield (0.849 g): 1H NMR (300 MHz, CDCl3) δ8.13 (s, 1H), 7.48 (dd, J=8.9, 2.4 Hz, 1H), 6.86 (d, J=8.9 Hz, 1H), 5.51 (s, 2H); MS (ES+) m/z 184.9 (M+1), 186.9 (M+1).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.Cl[C:16]1[N:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C>CS(C)=O>[C:22]([C:19]1[CH:18]=[CH:17][C:16]([NH:1][CH:2]2[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]2)=[N:21][CH:20]=1)#[N:23]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(Nc2ccc(C#N)cn2)C1
Temperature: 140 °C

Procedure:
1.0 g (4.99 mmol) of tert-butyl 3-aminopiperidine-1-carboxylate and 1.383 g (9.99 mmol) of 6-chloropyridine-3-carbonitrile and 1.29 g (9.99 mmol) of diisopropylethylamine were suspended in 40 ml of DMSO and heated in a microwave reactor at 140° C. for 45 min. Most of the DMSO was removed from the mixture by kugelrohr distillation, water was added and the resulting precipitate was filtered off. Drying under high vacuum gave 2.24 g (46% of theory) of the product.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]2[CH2:24][C:25]([O:27]C)=[O:26])(=[O:13])=[O:12])=[CH:7][CH:6]=1>C1COCC1.O>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]2[CH2:24][C:25]([OH:27])=[O:26])(=[O:13])=[O:12])=[CH:9][CH:10]=1
Reactant: COC(=O)CC1c2ccccc2CCN1S(=O)(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(S(=O)(=O)N2CCc3ccccc3C2CC(=O)O)cc1
Reaction time: 8 h

Procedure:
A 6 M aqueous NaOH solution was added to a mixture of methyl 2-(2-(4-methoxyphenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate (15.22 g, 40.54 mmol) in THF (200 ml) and water (120 ml), and stirring was carried out overnight at room temperature. The solvent was then removed under reduced pressure, and a 6 M aqueous HCl solution (125 ml) and DCM (400 ml) were added. The phases were separated and then the organic phase was washed with concentrated NaCl solution, dried over sodium sulfate and concentrated. Yield: 14.65 g (100%)
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[CH3:15][O:16][CH:17]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[C:18]([N:20]([CH3:22])[CH3:21])=O.N1C=CC=CC=1.[OH-].[Na+]>O>[CH3:15][O:16][CH:17]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[C:18]([N:20]([CH3:22])[CH3:21])=[S:2]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COC(C(=O)N(C)C)c1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: COC(C(=S)N(C)C)c1ccccn1

Procedure:
Phosphorus pentasulfide (4 g.) is added to 9.7 g. of 2-methoxy-N,N-dimethyl-2-(2-pyridyl)acetamide in 25 ml. of pyridine. The mixture is heated on a steam bath for 2 hours, then 250 ml. of water and 10 ml. of 5% aqueous sodium hydroxide solution are added. The mixture is extracted with chloroform and the extracts are dried and concentrated and the residue is recrystallized to give 2-methoxy-N,N-dimethyl-2-(2-pyridyl)thioacetamide.
Reaction SMILES: [OH:1][C:2]1C=C2C(C=CN2)=[CH:4][CH:3]=1.C(O[C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([C:24]([NH2:26])=[O:25])[CH:19]=[C:18]2[N:27]=[C:28]=[O:29])C=C>>[CH2:2]([O:1][C:23]1[CH:22]=[C:21]2[C:17]([C:18]([N:27]=[C:28]=[O:29])=[CH:19][N:20]2[C:24]([NH2:26])=[O:25])=[CH:16][CH:15]=1)[CH:3]=[CH2:4]
Reactant: Oc1ccc2cc[nH]c2c1
Reactant: C=CCOc1ccc2c(c1)c(N=C=O)cn2C(N)=O
Product: C=CCOc1ccc2c(N=C=O)cn(C(N)=O)c2c1

Procedure:
was prepared from 6-hydroxy-indole using the protocol described for the preparation of 5-allyloxy-3-isocyanato-indole-1-carboxylic acid amide in Scheme A4.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:33][NH:34][CH2:35][CH2:36][C:37]1([OH:51])[CH2:42][CH:41]2[CH2:43][CH2:44][CH:38]1[CH:39]=[C:40]2[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[C:4]([O:3][C:1](=[O:2])[NH:8][CH2:9][CH2:10][C:11](=[O:13])[N:34]([CH2:35][CH2:36][C@:37]1([OH:51])[CH2:42][C@H:41]2[CH2:43][CH2:44][C@@H:38]1[CH:39]=[C:40]2[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[CH3:33])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: CNCCC1(O)CC2CCC1C=C2c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(CC[C@]1(O)C[C@H]2CC[C@@H]1C=C2c1ccccc1)C(=O)CCNC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 46.6 %

Procedure:
To a solution of 159 mg of BOC-beta-alanine in 4 mL DCM were added 0.36 mL DIPEA and 113 mg of HOBt. After stirring for 15 min, 300 mg of rac-(1R*,2R*,4R*)-2-(2-methylamino-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-ol in 4 mL DCM were added followed by 161 mg of EDCI. The resulting suspension was stirred for 2 h at rt, then quenched with water. The water phase was reextracted with DCM, the combined organic phases were washed with sat. aq. NaHCO3, dried and concentrated in vacuo. The residue was purified by preparative TLC with EtOAc to give 168 mg of rac-(2-{[2-((1R*,2R*,4R*)-2-hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl)-ethyl]-methyl-carbamoyl}-ethyl)-carbamic acid tert.-butyl ester as white foam.
Reaction SMILES: [SH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][SH:7].[OH-].[Na+].Cl[CH2:11][CH2:12][OH:13]>C(O)C>[SH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][S:7][CH2:11][CH2:12][OH:13]
Reactant: OCCCl
Reactant: SCCOCCS
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OCCSCCOCCS
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
2-Mercaptoethyl ether (53.8 ml; 0.434 mol) was added to a solution of sodium hydroxide (17.36 g; 0.434 mol) in ethanol (300 ml) at ambient temperature and stirred for 15 min. 2-Chloroethanol (29.1 ml; 0.434 mol) was added to the solution at ambient temperature and after addition was complete the stirred solution was heated to 80° C. for 1 hr. The reaction mixture was then cooled to ambient temperature and the solid sodium chloride separated by filtration. The filtrate was transferred to a distillation apparatus and ethanol and unreacted 2-mercaptoethyl ether removed under vacuum (the latter distilling at 62° C. and 0.4 mbar). Fractional distillation of the remaining product yielded 2-[2-(2-mercapto-ethoxy)-ethylsulfanyl]-ethanol at 128° C. and 0.3 mbar. Pure fractions were combined to afford 2-[2-(2-mercapto-ethoxy)-ethylsulfanyl]-ethanol (31 g; 0.17 mol; 39% yield) as a colourless oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][CH:9]([N:11]2[C:24]3[CH:23]=[C:22]([C:25](=[S:27])[NH2:26])[CH:21]=[CH:20][C:19]=3[S:18][C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH3:10])[CH2:3]1.[CH2:28](N)[CH2:29][CH3:30].S>C(O)C>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][CH:9]([N:11]2[C:24]3[CH:23]=[C:22]([C:25](=[S:27])[NH:26][CH2:28][CH2:29][CH3:30])[CH:21]=[CH:20][C:19]=3[S:18][C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH3:10])[CH2:3]1
Reactant: CCCN
Reactant: CC1CCCN(CC(C)N2c3ccccc3Sc3ccc(C(N)=S)cc32)C1
Agent: S
Solvent: CCO
Product: CCCNC(=S)c1ccc2c(c1)N(C(C)CN1CCCC(C)C1)c1ccccc1S2
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 10-{(2RS)-1-[(3RS)-3-methyl-1-piperidyl]-2-propyl}-2-phenothiazinecarbothioamide acid fumarate (1 g) and propylamine (2.5 cc) in absolute ethanol (20 cc) is saturated with hydrogen sulphide and heated for 16 hours to a temperature in the region of 100° C. After cooling, the mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual orange oil (1.5 g) is purified by chromatography on a column (height: 25 cm; diameter: 2 cm) of silica gel (0.04-0.063 mm) with a slight excess pressure of nitrogen (40 kPa), eluting with a mixture (80:20 by volume) (250 cc) of ethyl acetate and cyclohexane and collecting 40-cc fractions. The combined fractions 3 and 4 are concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual yellow oil (0.9 g) is dissolved in ethanol (3 cc) at 60° C., and this hot solution is poured, with stirring, into a solution of fumaric acid (0.23 g) in ethanol (3.5 cc) under reflux. After cooling, stirring is continued for 2 hours at a temperature in the region of 5° C. The solid formed is drained, washed with ethanol (2×1 cc) and dried under reduced pressure (5 mm Hg; 0.68 kPa) at 40° C. 10-{(2RS}-1-[(3RS)-3-Methyl-1-piperidyl]-2-propyl}-N-propyl-2-phenothiazinecarbothioamide neutral fumarate (0.53 g) is thereby obtained in the form of a yellow solid, m.p. 126° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Br[CH2:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].C([O-])([O-])=O.[K+].[K+]>>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)C(=O)CN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21
Yield: 58.5 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (2 g) is alkylated using 1-bromo-3,3-dimethyl-butan-2-one (2.72 g; 15.2 mmol) and K2CO3 (2.1 g; 15.2 mmol) at 40° C. for 16 h. After aqueous work-up and purification by RP chromatography the pure material (1.65 g) is de-acetylated in hydrochloric acid (6 N, 10 ml) at reflux. After aqueous work-up 5-amino-1-(3,3-dimethyl-2-oxo-butyl)-3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one (1.42 g) is obtained and used without further purification.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[CH:24]([C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)([CH2:26][CH3:27])[CH3:25]>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:8][CH2:9][C:4]([C:1]([NH:32][C:31]4[CH:33]=[CH:34][C:28]([CH:24]([CH3:25])[CH2:26][CH3:27])=[CH:29][CH:30]=4)=[O:3])([CH2:5][CH2:6]2)[CH2:11][CH2:10]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: CCC(C)c1ccc(N)cc1
Product: CCC(C)c1ccc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Yield: 18.5 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-sec-butylaniline (51.5 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-[4-(1-methylpropyl)phenyl]amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl)pyrrolidine-2-carbonitrile (13.0 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:47])/[C:32](/[C:45]#[N:46])=[CH:33]/[C:34]([NH:37]C(=O)OC(C)(C)C)([CH3:36])[CH3:35])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51]>C(Cl)Cl>[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].[NH2:37][C:34]([CH3:36])([CH3:35])[CH:33]=[C:32]([C:31]([N:27]1[CH2:28][CH2:29][CH2:30][C@@H:26]1[CH2:25][N:8]1[C:4]2=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]2[C:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][C:12]=2[F:24])=[N:9]1)=[O:47])[C:45]#[N:46]
Reactant: CC(C)(/C=C(\C#N)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(N)C=C(C#N)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (R,E)-tert-butyl (5-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-4-cyano-2-methyl-5-oxopent-3-en-2-yl)carbamate (90 mg, 0.14 mmol, 1 equiv) in 16 mL DCM was added 4 mL trifluoroacetic acid dropwise. The resulting solution was stirred for 3 h at room temperature. The solution was concentrated under reduced pressure. The residue was purified on Prep-HPLC. Conditions: (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (40% CH3CN up to 100% in 20 min); Detector, 254 nm to give the title compound as a pale light yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.Br.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([F:20])=[C:17]([OH:19])[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:20][C:16]1[CH:15]=[CH:14][C:13]([NH2:12])=[CH:18][C:17]=1[O:19][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: Nc1ccc(F)c(O)c1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(F)c(Oc2ccc([N+](=O)[O-])cn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
A mixture of 2-chloro-5-nitropyridine (3.17 g, 20 mmol), 5-amino-2-fluorophenol hydrobromide (4.16 g, 20 mmol) and potassium carbonate (5.52 g, 40 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature overnight. The reaction mixture was poured into water (200 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→50/50), and crystallized from diethyl ether to give the title compound (4.36 g, 88%) as an orange powder.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C>C(Cl)Cl>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:23][CH:24]=1)(=[O:34])=[O:33]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(NS(=O)(=O)c2ccccc2Cl)cc1)N1Cc2ccccc2Cc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 128.6 %

Procedure:
A mixture of 0.13 g of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine, 0.21 g of 2-chlorobenzenesulfonyl chloride, 0.12 g of triethylamine and 5 mg of N,N-dimethylaminopyridine in 2 ml of methylene chloride is stirred at room temperature for 18 hours. The mixture is partitioned between 1N NaOH and ethyl acetate. The organic layer is washed with 50% NH4Cl and brine, dried over Na2SO4 and evaporated to give 0.26 g of the desired product as a yellow solid. MS(CI):663(M+H; C35).
Reaction SMILES: [NH2:1][C@H:2]([C:12]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16](=[O:24])[C:15]2=[CH:25][CH:26]=[CH:27][N:14]2[N:13]=1)[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:28][C:29]1[C:34]([C:35]#[N:36])=[C:33](Cl)[N:32]=[CH:31][N:30]=1.C(N(CC)C(C)C)(C)C>>[NH2:28][C:29]1[C:34]([C:35]#[N:36])=[C:33]([NH:1][C@H:2]([C:12]2[N:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:16](=[O:24])[C:15]3=[CH:25][CH:26]=[CH:27][N:14]3[N:13]=2)[CH2:3][CH2:4][O:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:32]=[CH:31][N:30]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: N[C@@H](CCOc1ccccc1)c1nn2cccc2c(=O)n1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(N)ncnc1N[C@@H](CCOc1ccccc1)c1nn2cccc2c(=O)n1-c1ccccc1
Yield: 55 %

Procedure:
(S)-2-(1-Amino-3-phenoxypropyl)-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one was treated with 4-amino-6-chloropyrimidine-5-carbonitrile (6 mg, 0.02 mmol) and N,N-diisopropylethylamine (16 μl, 0.09 mmol) according to the method described in Example 17. The residue was purified using SP1® Purification System (0% to 50%, dichloromethane-acetonitrile) to obtain 4 mg (55% yield) of the title compound as a yellow solid. Purity 89%.
Reaction SMILES: CO.[H-].[Na+].[C:5]([N:9]=[N:10][C:11]([N:14]=[C:15]=[O:16])([CH3:13])[CH3:12])([CH3:8])([CH3:7])[CH3:6].[N-]=[C:18]=[O:19]>O>[C:5]([N:9]=[N:10][C:11]([NH:14][C:15]([O:19][CH3:18])=[O:16])([CH3:13])[CH3:12])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)N=NC(C)(C)N=C=O
Reactant: [N-]=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)NC(C)(C)N=NC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 50 ml of methanol in a 125 ml erlenmeyer flask stirred with a magnetic stirrer was slowly added 3.1 grams (0.075 moles) of 57% sodium hydride. The reaction mixture was cooled back to 25° C. and 12.7 grams (0.075 moles) of 2-t-butylazo-2-isocyanatopropane (from Example XIV) was added dropwise over 5 minutes. The reaction mixture was stirred for approximately 1 hour, poured into 200 ml water and the product extracted with pentane. The pentane extract was washed with water, 10% NaHCO3 solution, dried over anhydrous Na2SO4, filtered and the pentane evaporated under reduced pressure to leave 11.8 grams (78% crude yield) of a yellow liquid. The product contained a strong carbonyl band at approximately 1740 cm-1 and a sharp NH band at approximately 3375 cm-1 in its infrared spectrum and there was no isocyanate band at 2225 cm-1.
Reaction SMILES: [NH3:1].[CH3:2][N:3]1[C:8]([CH3:9])=[CH:7][C:6](=[O:10])[CH:5]([CH3:11])[S:4]1(=[O:13])=[O:12]>CO>[NH2:1][C:8]([CH3:9])=[CH:7][C:6](=[O:10])[CH:5]([CH3:11])[S:4]([NH:3][CH3:2])(=[O:13])=[O:12]
Reactant: CC1=CC(=O)C(C)S(=O)(=O)N1C
Reactant: N
Solvent: CO
Product: CNS(=O)(=O)C(C)C(=O)C=C(C)N
Reaction time: 8 h

Procedure:
A moderately rapid stream of dry ammonia was introduced at 20°-25° during 3 hours into a solution of 2.5 g of 2,3,6-trimethyl-2H-1,2-thiazin-5(6H)-one 1,1-dioxide in 25 ml of methanol and the mixture was thereupon left to stand overnight. The dark yellow solution obtained was concentrated to dryness under reduced pressure and the crystalline residue was recrystallized from ethanol. There were obtained 2.3 g of 4-amino-N,1-dimethyl-2-oxo-3-pentenesulfonamide in the form of colorless crystals, m.p. 140°-143°.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([CH3:23])([CH3:22])[C:19]([NH2:21])=[O:20])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[F:30][C:31]1[CH:40]=[C:39]2[C:34]([C:35](B3OC(C)(C)C(C)(C)O3)=[CH:36][N:37]=[C:38]2[NH2:41])=[CH:33][CH:32]=1>>[NH2:41][C:38]1[C:39]2[C:34](=[CH:33][CH:32]=[C:31]([F:30])[CH:40]=2)[C:35]([C:2]2[N:3]=[C:4]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([C:18]([CH3:23])([CH3:22])[C:19]([NH2:21])=[O:20])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:36][N:37]=1
Reactant: CC1(C)OB(c2cnc(N)c3cc(F)ccc23)OC1(C)C
Reactant: CC(C)(C(N)=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: CC(C)(C(N)=O)N1CCN(Cc2cc3nc(-c4cnc(N)c5cc(F)ccc45)nc(N4CCOCC4)c3s2)CC1

Procedure:
Following General Procedure A for Suzuki coupling, 2-(4-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methylpropanamide and 7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-amine were reacted to give 185. LCMS: M+H+=565.3
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:19][CH:18]=2)=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=1.C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37]>C(Cl)Cl>[C:36]([N:26]1[CH2:25][CH2:24][N:23]([C:20]2[CH:19]=[CH:18][C:17]([C:11]3[O:10][C:9]([C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])=[N:13][C:12]=3[C:14]([NH2:16])=[O:15])=[CH:22][CH:21]=2)[CH2:28][CH2:27]1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(N2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(c2ccc(-c3oc(-c4c(F)cccc4F)nc3C(N)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
To a solution of 2-(2,6-difluorophenyl)-5-(4-(piperazin-1-yl)phenyl)oxazole-4-carboxamide (0.029 g, 0.075 mmol) in DCM (3 mL) was added triethylamine (12 uL, 0.086 mmol) followed by acetyl chloride (6 uL, 0.084 mmol). The resulting solution was stirred at room temperature for 2 hours when further portion of triethylamine (12 uL, 0.086 mmol) and acetyl chloride (6 uL, 0.084 mmol) were added and the reaction stirred at room temperature for 1 hour. The solvent was then removed in vacuo. The residue was purified by preparative HPLC to afford 5-(4-(4-acetylpiperazin-1-yl)phenyl)-2-(2,6-difluorophenyl)oxazole-4-carboxamide (0.025 g, 0.059 mmol, 78%) as a white solid. 1H NMR (DMSO) 2.06 (3H, s), 3.28 (2H, m), 3.56 (2H, m, masked by water), 3.59 (4H, m), 7.08 (2H, d), 7.38 (2H, t), 7.63 (1H, br. s), 7.64 (1H, br. s), 7.72 (1H, m), 8.18 (2H, d). LCMS (2) Rt: 2.52 min; m/z (ES+) 427.