Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[N:5]([CH2:9][C:10]#[CH:11])[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[N:12]([CH:15]([CH2:18][F:19])[CH2:16][OH:17])=[N+:13]=[N-:14]>>[F:19][CH2:18][CH:15]([N:12]1[CH:11]=[C:10]([CH2:9][N:5]2[CH:6]=[CH:7][N:8]=[C:4]2[N+:1]([O-:3])=[O:2])[N:14]=[N:13]1)[CH2:16][OH:17]
Reactant: C#CCn1ccnc1[N+](=O)[O-]
Reactant: [N-]=[N+]=NC(CO)CF
Product: O=[N+]([O-])c1nccn1Cc1cn(C(CO)CF)nn1
Temperature: 60 °C

Procedure:
To a vial is added alkyne 10 (1.9 g, 12.6 mmol) and 29 (1.5 g, 12.6 mmol). The solution is heated at 60° C. overnight. The material is then purified on a silica gel column using 10% MeOH:CH2Cl2 as the eluent. The material is then further purified via recrystallization using EtOAc:Hex to afford 1 as a solid.
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[CH3:8][N:9]([CH2:23][CH2:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1)[C:10]1[N:15]=[CH:14][CH:13]=[C:12]([C:16]2[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=2)[N:11]=1.C([O-])(=O)C.[NH2+]1CCCCC1>C1(C)C=CC=CC=1>[CH3:8][N:9]([CH2:23][CH2:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([CH:30]=[C:5]2[S:1][C:2](=[O:7])[NH:3][C:4]2=[O:6])=[CH:32][CH:33]=1)[C:10]1[N:15]=[CH:14][CH:13]=[C:12]([C:16]2[CH:17]=[CH:18][C:19]([NH2:20])=[CH:21][CH:22]=2)[N:11]=1
Reactant: O=C1CSC(=O)N1
Reactant: CN(CCOc1ccc(C=O)cc1)c1nccc(-c2ccc(N)cc2)n1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CN(CCOc1ccc(C=C2SC(=O)NC2=O)cc1)c1nccc(-c2ccc(N)cc2)n1
Yield: 69.5 %

Procedure:
A solution of 2,4-thiazolidinedione (120 mg) and 4-[2-(N-methyl-N-(6-(4-anilinyl)pyrimidinyl)amino)ethoxy]benzaldehyde (280 mg) in a catalytic amount of piperidinium acetate containing toluene (60 mL), was stirred under reflux on a Dean-stark device for 4 hours. The resultant mixture was cooled and filtered. The filtered solid was dried to give the title compound (250 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[C:5]2[CH2:16][N:17]([CH:33]1[CH2:35][CH2:34]1)[C:18]([C@@H:20]1[O:25][CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]1)=[O:19].C(=O)(O)[O-].[Na+]>ClCCCl.[Br-].[Zn+2].[Br-]>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[C:5]2[CH2:16][N:17]([CH:33]1[CH2:35][CH2:34]1)[C:18]([C@@H:20]1[O:25][CH2:24][CH2:23][NH:22][CH2:21]1)=[O:19]
Reactant: COCCCn1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CCO2)C2CC2)c2cc(Br)ccc21
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCCl
Product: COCCCn1cc(CN(C(=O)[C@H]2CNCCO2)C2CC2)c2cc(Br)ccc21
Temperature: 40 °C
Reaction time: 3 h

Procedure:
Zinc bromide (209 mg) was added to a solution of tert-butyl(2R)-2-{[{[5-bromo-1-(3-methoxypropyl)indol-3-yl]methyl}(cyclopropyl)amino]carbonyl}morpholin-4-carboxylate (a compound of Reference Example 128, 200 mg) in 1,2-dichloroethane (12 ml) and the mixture was stirred at 40° C. for 3 hours. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate and extracted with chloroform. The organic layer was washed with water and saturated brine, dried over magnesium sulfate and concentrated in vacuo. The resulted residue was purified with a silica gel column chromatography (eluting solvent: chloroform/methanol=98/2 to 93/7) to give (2R)—N-{[5-bromo-1-(3-methoxypropyl)indol-3-yl]methyl}-N-cyclopropylmorpholin-2-carboxamide (117 mg) as a colorless oil.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[OH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[OH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=2)=[CH:22][CH:21]=1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Reactant: OCc1ccc(B(O)O)cc1
Product: N#Cc1cc(-c2ccc(CO)cc2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, light brown solid (18 mg, 23%), MS (ISN) m/z=318.5 [(M+H)+], mp 257.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 4-hydroxymethyl-phenylboronic acid (49.4 mg, 0.325 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][NH2:17])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH:19]1([C:22]2[C:27]([CH2:28][C:29](O)=[O:30])=[CH:26][N:25]=[C:24]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=3)[N:23]=2)[CH2:21][CH2:20]1.ClCC1C(C2CC2)=NC(C2C=CC(C(F)(F)F)=CC=2)=NC=1>>[CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][NH:17][C:29](=[O:30])[CH2:28][C:27]2[C:22]([CH:19]3[CH2:20][CH2:21]3)=[N:23][C:24]([C:32]3[CH:33]=[CH:34][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:36][CH:37]=3)=[N:25][CH:26]=2)[CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(CCN)c1
Reactant: O=C(O)Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Agent: FC(F)(F)c1ccc(-c2ncc(CCl)c(C3CC3)n2)cc1
Product: CCOC(=O)C(C)(C)Oc1cccc(CCNC(=O)Cc2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)c1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-[3-(2-amino-ethyl)-phenoxy]-2-methyl-propionic acid ethyl ester (example 55C]) was reacted with [4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-acetic acid (prepared from 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 27F]) in analogy to the sequences described in examples 26D] and 26E]) to give 2-[3-(2-{2-[4-cyclopropyl-2(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-acetylamino}-ethyl)-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[CH:18]=[N:19][CH:20]=[C:21]([C@@H:23]3[CH2:27][CH2:26][CH2:25][N:24]3C(C3C=CC(OC)=CC=3)C)[CH:22]=2)=[CH:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O>[NH:24]1[CH2:25][CH2:26][CH2:27][C@H:23]1[C:21]1[CH:22]=[C:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:8][CH:9]=2)[CH:18]=[N:19][CH:20]=1
Reactant: COc1ccc(C(C)N2CCC[C@H]2c2cncc(-c3cn(C(=O)OC(C)(C)C)c4ccccc34)c2)cc1
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2c(-c3cncc([C@@H]4CCCN4)c3)c[nH]c2c1
Yield: 47 %

Procedure:
A solution of 3-(5-{(S)-1-[1-(4-Methoxy-phenyl)-ethyl]-pyrrolidin-2-yl}-pyridin-3-yl)-indole-1-carboxylic acid tert-butyl ester 5 (300 mg, 0.63 mmole) in 4 mL of TFA was heated at 100° C. in a microwave reactor for 20 minutes. The result solution was concentrated to remove TFA as much as possible. The residue was purified by HPLC (Column: Waters Sunfire, 30×30 mm; Mobile phase: CH3CN 15% H2O 85% with 0.1% TFA to CH3CN 60% H2O 40% with 0.1% TFA by gradient in 11 minutes; Flow rate 45 mL/minute; Detector: 215 nm UV) to give 3-((S)-5-Pyrrolidin-2-yl-pyridin-3-yl)-1H-indole 6 (78 mg, yield 49%) as white solid.
Reaction SMILES: N1C2C(=CC(/C=C3/C(=O)NC4C/3=CC=CC=4)=CC=2)C=N1.[I:21][C:22]1[C:30]2[C:25](=[CH:26][C:27]([CH:31]=O)=[CH:28][CH:29]=2)[NH:24][N:23]=1.[CH3:33][N:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][C:35]1=[O:43]>>[I:21][C:22]1[C:30]2[C:25](=[CH:26][C:27](/[CH:31]=[C:36]3/[C:35](=[O:43])[N:34]([CH3:33])[C:42]4[C:37]/3=[CH:38][CH:39]=[CH:40][CH:41]=4)=[CH:28][CH:29]=2)[NH:24][N:23]=1
Reactant: CN1C(=O)Cc2ccccc21
Reactant: O=Cc1ccc2c(I)n[nH]c2c1
Agent: O=C1Nc2ccccc2/C1=C\c1ccc2[nH]ncc2c1
Product: CN1C(=O)/C(=C/c2ccc3c(I)n[nH]c3c2)c2ccccc21

Procedure:
The title compound was synthesized according to the method described for (E)-3-((1H-indazol-5-yl)methylene)indolin-2-one, except substituting 3-iodo-1H-indazole-6-carbaldehyde (462 mg, 1.70 mmol) and 1-methylindolin-2-one (250 mg, 1.70 mmol), the title compound was obtained as a yellow-orange solid (545 mg, 80%); MS ESI 402.2 [M+H]+, calcd for [C17H12IN3O+H]+ 402.01.
Reaction SMILES: O.Cl.C(=[N:16][CH:17]([CH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)[C:18]#[N:19])(C1C=CC=CC=1)C1C=CC=CC=1>C(O)C>[NH2:16][CH:17]([CH2:20][C:21]1[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=1)[C:18]#[N:19]
Reactant: N#CC(Cc1ccncc1)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: N#CC(N)Cc1ccncc1
Reaction time: 0.5 h

Procedure:
To a solution of ethanol (10 mL), water (0.09 mL, 5 mmol), hydrogen chloride (9.6 mL, 1M in diethyl ether) was added a solution of 2-(benzhydrylidene-amino)-3-pyridin-4-yl-propionitrile (1.50 g, 5 mmol) in ethanol (10 mL). The reaction was stirred for 30 minutes, then concentrated to one third volume. The crude residue was triturated with five 30 mL portions of hexane:ether (4:1 vol:vol) and seven 30 mL portions of hexane. The precipitate was dried in vacuo to give 2-amino-3-pyridin-4-yl-propionitrile as an off white powder (1.05 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]([O:12]CC)=[O:11])=[C:4]([S:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])=[CH:18][C:17]=2[Cl:27])[CH:3]=1.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]([OH:12])=[O:11])=[C:4]([S:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])=[CH:18][C:17]=2[Cl:27])[CH:3]=1
Reactant: CCOC(=O)CSc1ccc(Cl)cc1Sc1ccc(S(=O)(=O)CC)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCS(=O)(=O)c1ccc(Sc2cc(Cl)ccc2SCC(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of the product from step (iv) (0.10 g), sodium hydroxide (0.018 g) in methanol (5 ml) and water (5 ml) was stirred at RT for 1 h. The mixture was partitioned between 2M hydrochloric acid/ethyl acetate, the organics separated, dried and evaporated under reduced pressure. The residue was purified by reverse phase HPLC. Yield 0.012 g
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[F:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[CH3:27][Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1.S(=O)(=O)(O)[O-].[Na+]>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])[C@H:15]([C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[F:23])[CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: O=C(Cc1ccc(Br)cc1F)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: C[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)c1ccc(Br)cc1F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 45.5 %

Procedure:
To a solution of (S)-4-benzyl-3-(2-(4-bromo-2-fluorophenyl)acetyl)oxazolidin-2-one (3.6 g, 9.2 mmol) in THF (40 mL) was added a solution of methyl iodide (1 M solution in toluene, 9.6 mL, 9.6 mmol). The mixture was cooled to −78° C. and a solution of sodium bis(trimethylsilyl)amide (1 M in THF, 9.6 mL, 9.6 mmol) was added dropwise. The resultant dark red mixture was stirred for 15 min at ca. −78° C. and allowed to warm up to room temperature. After 3.5 h the reaction mixture was diluted with saturated aqueous sodium bisulfate (ca. 20 mL), and extracted with ethyl acetate (1×50 mL). The extract was washed with brine (2×50 mL), dried over sodium sulfate, and evaporated under vacuum. Flash chromatography of the residue afforded the desired product (1.7 g, 45%) as light yellow solid: ESI MS m/z 407 [C19H17BrFNO3+H]+
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH:11]=[C:12]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:45])[CH2:27][C:28]2[CH:44]=[CH:43][C:31]3[N:32]=[C:33]([NH:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[CH3:42])[O:34][C:30]=3[CH:29]=2)=[CH:21][CH:20]=1)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[OH:8][CH2:9][CH2:10][CH2:11][CH:12]([C:19]1[CH:20]=[CH:21][C:22]([NH:25][C:26](=[O:45])[CH2:27][C:28]2[CH:44]=[CH:43][C:31]3[N:32]=[C:33]([NH:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[CH3:42])[O:34][C:30]=3[CH:29]=2)=[CH:23][CH:24]=1)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)CC(=CCCOCc1ccccc1)c1ccc(NC(=O)Cc2ccc3nc(Nc4ccccc4C)oc3c2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(CCCO)c1ccc(NC(=O)Cc2ccc3nc(Nc4ccccc4C)oc3c2)cc1
Yield: 84.2 %

Procedure:
A mixture of ethyl 6-benzyloxy-3-{4-[2-(2-o-tolylamino-benzoxazol-6-yl)-acetylamino]-phenyl}-3-hexenoate (640 mg, Reference Example 22(a)) and 10% palladium on charcoal (250 mg) in ethanol (50 mL) was hydrogenated at room temperature and pressure. After 24 hours further catalyst (200 mg) was added and the mixture again subjected to a hydrogen atmosphere for a further 24 hours. The mixture was filtered through filter-aid and the filtrate evaporated to dryness to give the title compound (460 mg) as a colourless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1C.CC1C=C(C)C=CC=1S.BrC1C=C(C)C=CC=1I>>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=1
Reactant: Cc1ccc(Sc2ccc(C)cc2Br)c(C)c1
Agent: Cc1ccc(I)c(Br)c1
Agent: Cc1ccc(S)c(C)c1
Product: Cc1ccc(Sc2ccc(C)cc2Br)cc1

Procedure:
1-Bromo-2-(2,4-dimethyl-phenylsulfanyl)-5-methyl-benzene (intermediate for 1 g) Prepared from 2,4-dimethyl-benzenethiol and 2-bromo-1-iodo-4-methyl-benzene.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)=[C:5]([C:14](O)=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].[CH3:26][S:27]([NH2:30])(=[O:29])=[O:28].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.Cl.O>[C:1]([C:3]1[C:4]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)=[C:5]([C:14]([NH:30][S:27]([CH3:26])(=[O:29])=[O:28])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2]
Reactant: CS(N)(=O)=O
Reactant: N#Cc1c(N2CCOCC2)sc(C(=O)O)c1Cc1ccc(Cl)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1sc(N2CCOCC2)c(C#N)c1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.2 %

Procedure:
To a mixture of 4-cyano-3-(3,4-dichlorobenzyl)-5-morpholinothiophene-2-carboxylic acid (291 mg, 0.732 mmol), in DCM (5.0 mL) was added methanesulfonamide (87.1 mg, 0.916 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (176 mg, 0.916 mmol), and N,N-dimethylaminopyridine (103 mg, 0.842 mmol) and the resulting solution was stirred at room temperature overnight. The reaction was diluted with DCM (10 mL), 1N HCl (3 mL) and with water (3 mL). The organic layer was dried, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/DCM=0/100→20/80) to give 250 mg of crude product. This material was purified by preparative reverse phase chromatography to give 70 mg (20% yield) of the title compound. as a white solid. LC/MS (FA) ES+ 474, 476. 1H NMR (400 MHz, MeOH-d4) δ: 7.45 (d, 1H, J=2.0 Hz)), 7.38 (d, 1H, J=8.4 Hz), 7.25 (dd, 1H, J=8.0, 2.0 Hz), 4.38 (s, 2H), 3.82-3.80 (m, 4H), 3.57-3.55 (m, 4H), 3.18 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:15][C:16]#[N:17]>>[CH3:10][O:11][C:12]1[CH:13]=[C:14](/[C:15](=[CH:5]/[C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=2)/[C:16]#[N:17])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: O=Cc1cccc(F)c1
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(/C(C#N)=C/c2cccc(F)c2)cc1OC
Yield: 15.3 %

Procedure:
3-Fluorobenzaldehyde (2.0 g) and 3,4-dimethoxybenzyl cyanide (2.9 g) were subjected to condensation in accordance with process A of (production process 2), to thereby produce the target product (0.7 g, yield: 15%).
Reaction SMILES: [C:1]([C:4]1[CH:23]=[CH:22][C:7]2[NH:8][C:9]([C:11]3[N:16]=[CH:15][C:14]([C:17]([O:19]CC)=[O:18])=[CH:13][CH:12]=3)=[N:10][C:6]=2[CH:5]=1)(=[NH:3])[NH2:2]>Cl>[C:1]([C:4]1[CH:23]=[CH:22][C:7]2[NH:8][C:9]([C:11]3[N:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][CH:12]=3)=[N:10][C:6]=2[CH:5]=1)(=[NH:2])[NH2:3]
Reactant: CCOC(=O)c1ccc(-c2nc3cc(C(=N)N)ccc3[nH]2)nc1
Agent: Cl
Product: N=C(N)c1ccc2[nH]c(-c3ccc(C(=O)O)cn3)nc2c1
Yield: 87.7 %

Procedure:
A mixture comprising ethyl 6-(5-amidino-1H-benzimidazol-2-yl)pyridine-3-carboxylate (1.7 g, 5.7 mmol) and 3N hydrochloric acid (60 mL) was heated at reflux for 24 hours. The mixture was cooled, concentrated to one quarter volume and poured into stirring acetonitrile (200 mL) to give a precipitate. The precipitate was filtered and dried under vacuum to provide 6-(5-amidino-1H-benzimidazol-2-yl)pyridine-3-carboxylic acid (1.4 g, 5.0 mmol). 1H-NMR (300 Mhz, DMSO-d6): 7.7 (m, 2H), 8.2 (s, 1H), 8.5 (m, 2H), 9.2 (s, 1H), 9.3 (s, 2H) 9.5 (s, 2H); MS (ESI), Calculated for C14H11N5O2 : 281.3, Found (MH+): 281.9.
Reaction SMILES: [CH:1]1([CH:7]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C@@H:9]1([NH2:19])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1>>[CH:1]1([CH2:7][NH:19][C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][CH2:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=CC1CCCCC1
Product: c1ccc2c(c1)CCC[C@@H]2NCC1CCCCC1

Procedure:
Cyclohexanecarbaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH2:10])=[O:4].[C:11]([N:19]=[C:20]=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CC(C)=O>[C:12]1([C:11]([NH:19][C:20](=[S:21])[NH:10][C:9]2[CH:8]=[CH:7][S:6][C:5]=2[C:3]([O:2][CH3:1])=[O:4])=[O:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COC(=O)c1sccc1N
Solvent: CC(C)=O
Product: COC(=O)c1sccc1NC(=S)NC(=O)c1ccccc1

Procedure:
Methyl-3-amino-2-thiophene carboxylate (30 g, 1 equiv) and benzoyl isothiocyanate (46 ml, 1.8 equiv) in acetone (250 ml) were heated to 65° C. for 30 minutes. After cooling the solution was concentrated and the resulting solid filtered off and dried (40.54 g). 1H-NMR (CDCl3) δ 3.98 (3H, s), 7.54 (4H, m), 7.94 (2H, m), 8.81 (1H, d), 9.15 (1H, br s); MS (APCI+) found (M+1)=321; C14H12N2O3S2 requires 320.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:25])[CH:10]([NH:14]C(OCC1C=CC=CC=1)=O)[CH2:11][O:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[CH2:1]([NH:8][C:9](=[O:25])[CH:10]([NH2:14])[CH2:11][O:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCC(NC(=O)OCc1ccccc1)C(=O)NCc1ccccc1
Solvent: CO
Product: COCC(N)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 96 %

Procedure:
To a solution of 12 (122.8 mg, 0.36 mmol) in methanol (2.0 mL) was added 10% Pd--C (11 mg) and the mixture stirred at room temperature in the presence of H2 gas for 75 min. Celite was added to the reaction mixture and the catalyst was removed by filtration. The clear filtrate was evaporated in vacuo to give pure 13 as a clear viscous oil (72 mg, 97%): Rf 0.30 (5% MeOH/CHCl3).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:8]([CH3:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:11][Mg]Br.C(#N)C1C=CC=CC=1>O1CCCC1>[C:4]1([C:8]([OH:9])([CH3:10])[CH3:11])[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=1
Reactant: CC(=O)c1cccc(Cl)c1
Reactant: C[Mg]Br
Solvent: N#Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(O)c1ccccc1

Procedure:
When n is the bridging group --C(CH3)2 --, an appropriately substituted or unsubstituted phenyl methyl ketone, for example, methyl (3-chlorophenyl) ketone, is prepared by the reaction of methylmagnesium bromide and an appropriate benzonitrile in tetrahydrofuran. The ketone is in turn treated with methylmagnesium bromide in tetrahydrofuran, yielding the corresponding 2-phenylpropan-2-ol, which is then converted to the 2-bromo-2-phenylpropane by the treatment of the alcohol with lithium bromide and trimethylsilyl chloride in acetonitrile. The Grignard reagent of the 2-bromo-2-phenylpropane is then prepared and reacted with 1,4-cyclohexanedione mono-ethylene ketal in tetrahydrofuran, yielding the corresponding 1-(2-phenylpropan-2-yl)-1-cyclohexen-4-one. The so-prepared cyclohexenone is reduced with hydrogen gas in the presence of 10% palladium on charcoal, yielding the 4-(2-phenylpropan-2-yl)cyclohexanone, which is in turn reacted with cyanoguanidine, as previously described, yielding the targeted 2,4-diamino-6-(2-phenylpropan-2-yl)-5,6,7,8-tetrahydroquinazoline. Example 7 provides a detailed description of how this reaction is conducted.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[Cl:27][C:28]1[N:37]=[C:36](Cl)[C:35]2[C:30](=[CH:31][C:32]([O:41][CH3:42])=[C:33]([O:39][CH3:40])[CH:34]=2)[N:29]=1>CN(C=O)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:36]3[C:35]4[C:30](=[CH:31][C:32]([O:41][CH3:42])=[C:33]([O:39][CH3:40])[CH:34]=4)[N:29]=[C:28]([Cl:27])[N:37]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2nc(Cl)nc(Cl)c2cc1OC
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(O)c2)no1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2nc(Cl)nc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.7 %

Procedure:
To a stirred solution of 1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea (prepared as described in Example 1A) (80 mg, 0.291 mmol) in anhydrous degassed DMF (2 mL) at rt and under an argon atmosphere, was added potassium tert-butoxide (65 mg, 0.581 mmol). The reaction mixture was stirred at rt for a further 2 h. A solution of 2,4-dichloro-6,7-dimethoxyquinazoline (75 mg, 0.291 mmol) in anhydrous DMF (1 mL) was added and the reaction mixture was stirred at rt for a further 15 h. The reaction mixture was partitioned between a mixture of ethyl acetate (20 mL) and brine solution (20 mL), and the organic layer separated. The aqueous layer was extracted further with ethyl acetate (1×20 mL) and the combined organic layers dried over magnesium sulfate. Concentration under reduced pressure gave the crude product which was purified via silica gel flash chromatography (eluting with a gradient of 25% ethyl acetate in hexanes to 100% ethyl acetate) to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(2-chloro-6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (46 mg, 32%) as a solid. 1H NMR (300 MHz, CDCl3) δ 9.60 (brs, 1H), 9.03 (brs, 1H), 7.61 (m, 1H), 7.57 (m, 1H), 7.39-7.46 (m, 2H), 7.31 (m, 1H), 7.01 (m, 1H), 6.48 (s, 1H), 4.00 (s, 3H), 3.98 (s, 3H), 1.28 (s, 9H); LC-MS (ESI) m/z 498 (M+H)+.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[N:16]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][C:26]2=[O:31])=[CH:21][CH:20]=1)=[C:17]=[O:18].[Br-].[Li+]>C(OCC)(=O)C>[O:18]=[C:17]1[N:16]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][C:26]3=[O:31])=[CH:21][CH:20]=2)[CH2:3][C@H:2]([CH2:4][N:5]2[C:13](=[O:14])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:15])[O:1]1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CO1
Reactant: O=C=Nc1ccc(N2CCOCC2=O)cc1
Agent: [Br-]
Agent: [Li+]
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Yield: 83.86 %

Procedure:
(S)-2-(oxiran-2-ylmethyl)isoindoline-1,3-dione (3.87 g, 19.06 mmol, 1.1 eq.) and 4-(4-isocyanatophenyl)morpholin-3-one (3.77 g, 17.29 mmol) were dissolved in ethyl acetate (70 mL) respectively, lithium bromide (0.15 g, 1.74 mmol) was added at 20° C., reacted for 12 h. White solid was obtained by filtration (6.11 g, yield: 83.86%).